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  • 1.
    Abrahamsson, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo2015Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 26, s. 22959-22969Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extracellular circulating microRNAs (miRNAs) have been suggested to be biomarkers for disease monitoring but data are inconsistent, one reason being that blood miRNA is of heterogeneous origin. Here, we sampled extracellular microRNAs locally in situ using microdialysis. Three different cohorts of women were included; postmenopausal women with ongoing breast cancer investigated within the cancer and in normal adjacent breast tissue, postmenopausal women investigated in their normal healthy breast and subcutaneous fat before and after six weeks of tamoxifen therapy, premenopausal women during the menstrual cycle. Samples were initially screened using TaqMan array cards with subsequently absolute quantification. 124 miRNA were expressed in microdialysates. After absolute quantifications extracellular miRNA-21 was found to be significantly increased in breast cancer. In addition, the levels were significantly higher in pre-menopausal breast tissue compared with postmenopausal. In breast tissue of pre-menopausal women miRNA-21 exhibited a cyclic variation during the menstrual cycle and in postmenopausal women six weeks of tamoxifen treatment decreased miRNA-21 suggesting that this miRNA may be important for breast carcinogenesis. None of these changes were found in plasma or microdialysates from subcutaneous fat. Our data revealed tissue specific changes of extracellular circulating miRNAs that would be otherwise unraveled using blood samples.

  • 2.
    Abrahamsson, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Morad, Vivian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Saarinen, Niina M
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo2012Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 11, s. E2044-E2054Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

  • 3.
    Abrahamsson, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rzepecka, Anna
    Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Increased nutrient availability in dense breast tissue of postmenopausal women in vivo2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 42733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.

  • 4.
    Bendrik, Christina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo2009Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, nr 1, s. 371-378Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.

  • 5.
    Bendrik, Christina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo2009Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Matrix metalloproteinases (MMPs) are largely implicated in tumor behaviour due to their extracellular matrix (ECM) remodelling capacities. Although MMP activity generally is discussed in terms of facilitating tumor invasion, MMP inhibition in clinical trials has failed. Increasing amounts of data show that MMPs may inhibit tumor progression by generating anti-angiogenic factors such as endostatin from the tumoral stroma. We have previously shown that intratumoral gene transfer of MMP-9 induced tumor regression and reduced angiogenesis of breast cancer in vivo. Whether MMP activities induce tumor progression or regression may depend on type of MMP and the expression level in the tumor tissue. In this study we treated established breast cancers in nude mice with adenovirus vectors carrying the human genes of MMP-3 or MMP-9 in low or high dose. Microdialysis was used to sample endostatin in situ and tumor growth was monitored for 35 days. Tumors in mice treated with low-dose of either MMP-3 or MMP-9 vectors exhibited tumor stasis throughout the experiment whereas high-dose gene transfer of either MMP-3 or MMP-9 induced significant tumor regression compared to controls treated with empty vectors. The extracellular in vivo levels of endostatin were increased in tumors that received either high or low MMP-3 or MMP-9 gene transfer and these tumors exhibited decreased microvessel area compared to controls. Our results propose that increased expression of MMP-3 and MMP-9 have therapeutic effects of established breast cancer in a dose dependent manner where a slight increase of MMP expression results in tumor stasis and a high expression of either MMP-3 or MMP-9 by gene transfer results in a potent tumor regression.

  • 6.
    Bendrik, Christina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo in CANCER RESEARCH, vol 69, issue 24, pp 761S-761S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 24, s. 761S-761SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 7.
    Bendrik, Christina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Lisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer2010Inngår i: CANCER LETTERS, ISSN 0304-3835, Vol. 292, nr 1, s. 32-40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are several similarities between breast and ovarian cancer but anti-estrogen treatment is rarely used in ovarian cancer. We have previously shown that the most widely used anti-estrogen tamoxifen increased MMP-9 activity and endostatin generation in breast cancer. Here, we show that tamoxifen exposure of highly hormone responsive ovarian cancer cells decreased proliferation, and increased MMP-9 activity leading to increased levels of endostatin both in cell culture in vitro and in solid tumors of nude mice. Tamoxifen exposed tumors also exhibited significantly decreased tumor growth and vascularisation. Moreover, in ascites from ovarian cancer patients, MMP-9 was undetectable in majority of cases but a significant correlation of MMP-2 and endostatin was found. The effects on MMPs and endostatin generation are previously unknown mechanisms of estradiol and tamoxifen in ovarian cancer, which may have therapeutic implications in future anti-cancer options of hormone dependent ovarian cancer.

  • 8.
    Bendrik, Christina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Robertson, Jennifer
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo2008Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, nr 9, s. 3405-3412Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer.

  • 9.
    Bergman, Malin
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Thompson, Lilian
    Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo2007Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 3, s. 1061-1067Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, which is crucial in cancer progression. We have previously shown that estradiol (E2) increases VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.

    Experimental Design: In the present study, ovariectomized mice were treated with continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or 10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or enterolactone (15 mg/kg body weight).

    Results: We show that flaxseed, enterodiol, and enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the addition of lignans.

    Conclusions: Our results suggest that flaxseed and its lignans have potent antiestrogenic effects on estrogen receptor-positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.

  • 10.
    Block, Keith I.
    et al.
    Block Centre Integrat Cancer Treatment, IL 60077 USA.
    Gyllenhaal, Charlotte
    Block Centre Integrat Cancer Treatment, IL 60077 USA; National Cancer Centre, South Korea.
    Lowe, Leroy
    Getting Know Canc, Canada; University of Lancaster, England.
    Amedei, Amedeo
    University of Florence, Italy.
    Ruhul Amin, A. R. M.
    University of Florence, Italy.
    Amin, Amr
    University of Florence, Italy.
    Aquilano, Katia
    United Arab Emirates University, U Arab Emirates.
    Arbiser, Jack
    Atlanta Vet Adm Medical Centre, GA USA; Emory University, GA USA.
    Arreola, Alexandra
    University of Roma Tor Vergata, Italy.
    Arzumanyan, Alla
    University of N Carolina, NC 27599 USA.
    Salman Ashraf, S.
    Temple University, PA 19122 USA.
    Azmi, Asfar S.
    United Arab Emirates University, U Arab Emirates.
    Benencia, Fabian
    Wayne State University, MI USA.
    Bhakta, Dipita
    Ohio University, OH 45701 USA.
    Bilsland, Alan
    SASTRA University, India.
    Bishayeen, Anupam
    University of Glasgow, Scotland.
    Blain, Stacy W.
    Larkin Health Science Institute, FL USA.
    Block, Penny B.
    Block Centre Integrat Cancer Treatment, IL 60077 USA.
    Boosani, Chandra S.
    Suny Downstate Medical Centre, NY USA.
    Carey, Thomas E.
    Creighton University, NE 68178 USA.
    Carnero, Amancio
    University of Michigan, MI USA.
    Carotenuto, Marianeve
    CSIC, Spain; Centre Ingn Genet and Biotecnol Avanzate, Italy.
    Casey, Stephanie C.
    University of Naples Federico II, Italy.
    Chakrabarti, Mrinmay
    Stanford University, CA 94305 USA.
    Chaturvedi, Rupesh
    University of S Carolina, SC USA.
    Zhuo Chen, Georgia
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Chenx, Helen
    Jawaharlal Nehru University, India.
    Chen, Sophie
    University of British Columbia, Canada.
    Charlie Chen, Yi
    Ovarian and Prostate Cancer Research Lab, England; Alderson Broaddus University, PA USA.
    Choi, Beom K.
    National Cancer Centre, South Korea.
    Rosa Ciriolo, Maria
    United Arab Emirates University, U Arab Emirates.
    Coley, Helen M.
    University of Surrey, England.
    Collins, Andrew R.
    University of Oslo, Norway.
    Connell, Marisa
    Jawaharlal Nehru University, India.
    Crawford, Sarah
    So Connecticut State University, CT 06515 USA.
    Curran, Colleen S.
    University of Wisconsin, WI USA.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Damia, Giovanna
    Ist Ric Farmacol Mario Negri, Italy.
    Dasgupta, Santanu
    University of Texas Health Science Centre Tyler, TX USA.
    DeBerardinis, Ralph J.
    University of Texas SW Medical Centre Dallas, TX 75390 USA.
    Decker, William K.
    Baylor Coll Med, TX 77030 USA.
    Dhawan, Punita
    Vanderbilt University, TN 37212 USA.
    Diehl, Anna Mae E.
    Duke University, NC 27710 USA.
    Dong, Jin-Tang
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Ping Dou, Q.
    United Arab Emirates University, U Arab Emirates.
    Drew, Janice E.
    University of Aberdeen, Scotland.
    Elkord, Eyad
    United Arab Emirates University, U Arab Emirates.
    El-Rayes, Bassel
    Emory University, GA 30322 USA.
    Feitelson, Mark A.
    University of N Carolina, NC 27599 USA.
    Felsher, Dean W.
    University of Naples Federico II, Italy.
    Ferguson, Lynnette R.
    University of Auckland, New Zealand.
    Fimognari, Carmela
    University of Auckland, New Zealand.
    Firestone, Gary L.
    University of Bologna, Italy.
    Frezza, Christian
    University of Calif Berkeley, CA 94720 USA.
    Fujii, Hiromasa
    University of Cambridge, England.
    Fuster, Mark M.
    Nara Medical University, Japan.
    Generali, Daniele
    University of Calif San Diego, CA 92103 USA; University of Calif San Diego, CA 92103 USA.
    Georgakilas, Alexandros G.
    University of Trieste, Italy.
    Gieseler, Frank
    Azienda Osped Ist Ospitalieri Cremona, Italy.
    Gilbertson, Michael
    National Technical University of Athens, Greece.
    Green, Michelle F.
    University Hospital Schleswig Holstein, Germany.
    Grue, Brendan
    Getting Know Canc, Canada.
    Guha, Gunjan
    Ohio University, OH 45701 USA.
    Halicka, Dorota
    Duke University, NC USA.
    Helferich, William G.
    Dalhousie University, Canada.
    Heneberg, Petr
    New York Medical Coll, NY 10595 USA.
    Hentosh, Patricia
    University of Illinois, IL 61820 USA.
    Hirschey, Matthew D.
    University Hospital Schleswig Holstein, Germany.
    Hofseth, Lorne J.
    Charles University of Prague, Czech Republic.
    Holcombe, Randall F.
    Old Domin University, VA USA.
    Honoki, Kanya
    Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan.
    Hsu, Hsue-Yin
    University of S Carolina, SC 29208 USA.
    Huang, Gloria S.
    Mt Sinai School Med, NY USA.
    Jensen, Lasse D.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Jiang, Wen G.
    Cardiff University, Wales.
    Jones, Lee W.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Karpowicz, Phillip A.
    University of Windsor, Canada.
    Nicol Keith, W.
    SASTRA University, India.
    Kerkar, Sid P.
    Mayo Clin, MN USA.
    Khan, Gazala N.
    Henry Ford Hospital, MI 48202 USA.
    Khatami, Mahin
    National Institute Heatlh, MD USA.
    Ko, Young H.
    University of Maryland BioPark, MD USA.
    Kucuk, Omer
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Kulathinal, Rob J.
    University of N Carolina, NC 27599 USA.
    Kumar, Nagi B.
    University of S Florida, FL USA.
    Kwon, Byoung S.
    National Cancer Centre, South Korea; Tulane University, LA 70118 USA.
    Le, Anne
    Johns Hopkins University, MD USA.
    Lea, Michael A.
    Rutgers State University, NJ USA.
    Lee, Ho-Young
    Seoul National University, South Korea.
    Lichtor, Terry
    Rush University, IL 60612 USA.
    Lin, Liang-Tzung
    Taipei Medical University, Taiwan.
    Locasale, Jason W.
    Cornell University, NY 14853 USA.
    Lokeshwar, Bal L.
    Georgia Regents University, GA USA.
    Longo, Valter D.
    University of So Calif, CA USA.
    Lyssiotis, Costas A.
    University of Michigan, MI USA; University of Michigan, MI USA.
    MacKenzie, Karen L.
    Childrens Cancer Institute Australia, Australia.
    Malhotra, Meenakshi
    McGill University, Canada.
    Marino, Maria
    University of Rome Tre, Italy.
    Martinez-Chantar, Maria L.
    Technology Pk Bizkaia, Spain.
    Matheu, Ander
    Biodonostia Institute, Spain.
    Maxwell, Christopher
    Jawaharlal Nehru University, India.
    McDonnell, Eoin
    University Hospital Schleswig Holstein, Germany.
    Meeker, Alan K.
    Johns Hopkins University, MD 21205 USA.
    Mehrmohamadi, Mahya
    Cornell University, NY USA.
    Mehta, Kapil
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Michelotti, Gregory A.
    Duke University, NC 27710 USA.
    Mohammad, Ramzi M.
    United Arab Emirates University, U Arab Emirates.
    Mohammed, Sulma I.
    Purdue University, IN 47907 USA.
    James Morre, D.
    Mor NuCo Inc, IN USA.
    Muqbil, Irfana
    United Arab Emirates University, U Arab Emirates.
    Muralidhar, Vinayak
    Harvard University, MA USA; MIT, MA 02139 USA.
    Murphy, Michael P.
    MRC Mitochondrial Biol Unit, England.
    Purnachandra Nagaraju, Ganji
    Emory University, GA 30322 USA.
    Nahta, Rita
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Niccolai, Elena
    University of Florence, Italy.
    Nowsheen, Somaira
    Mayo Clin, MN USA.
    Panis, Carolina
    State University of West Parana, Brazil.
    Pantano, Francesco
    University of Campus Bio Med, Italy.
    Parslow, Virginia R.
    University of Auckland, New Zealand.
    Pawelec, Graham
    University of Tubingen, Germany.
    Pedersen, Peter L.
    Johns Hopkins University, MD USA.
    Poore, Brad
    Johns Hopkins University, MD USA.
    Poudyal, Deepak
    Charles University of Prague, Czech Republic.
    Prakash, Satya
    McGill University, Canada.
    Prince, Mark
    University of Michigan, MI USA.
    Raffaghello, Lizzia
    Ist Giannina Gaslini, Italy.
    Rathmell, Jeffrey C.
    University Hospital Schleswig Holstein, Germany.
    Kimryn Rathmell, W.
    University of Roma Tor Vergata, Italy.
    Ray, Swapan K.
    Stanford University, CA 94305 USA.
    Reichrath, Joerg
    Saarland University Hospital, Germany.
    Rezazadeh, Sarallah
    University of Rochester, NY 14627 USA.
    Ribatti, Domenico
    University of Bari, Italy.
    Ricciardiello, Luigi
    National Cancer Institute Giovanni Paolo II, Italy.
    Brooks Robey, R.
    University of Bologna, Italy; White River Junct Vet Affairs Medical Centre, VT USA.
    Rodier, Francis
    Geisel School Medical Dartmouth, NH USA; University of Montreal, Canada.
    Vasantha Rupasinghe, H. P.
    Institute Cancer Montreal, Canada.
    Luigi Russo, Gian
    University of Montreal, Canada.
    Ryan, Elizabeth P.
    Dalhousie University, Canada.
    Samadi, Abbas K.
    Sanus Biosciences, San Diego, CA, United States.
    Sanchez-Garcia, Isidro
    CNR, Italy.
    Sanders, Andrew J.
    Cardiff University, Wales.
    Santini, Daniele
    University of Campus Bio Med, Italy.
    Sarkar, Malancha
    Colorado State University, CO 80523 USA.
    Sasada, Tetsuro
    Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
    Saxena, Neeraj K.
    University of Salamanca, Spain.
    Shackelford, Rodney E.
    University of Miami, FL USA.
    Shantha Kumara, H. M. C.
    St Lukes Roosevelt Hospital, NY 10025 USA.
    Sharma, Dipali
    Kurume University, Japan.
    Shin, Dong M.
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Sidransky, David
    University of Maryland, MD 21201 USA.
    David Siegelin, Markus
    Louisiana State University, LA 71105 USA.
    Signori, Emanuela
    Johns Hopkins University, MD 21205 USA; Johns Hopkins University, MD USA.
    Singh, Neetu
    Johns Hopkins University, MD USA; King Georges Medical University, India.
    Sivanand, Sharanya
    Columbia University, NY USA; University of Penn, PA 19104 USA.
    Sliva, Daniel
    Institute Translat Pharmacol, Italy; Purdue Research Pk, IN USA.
    Smythe, Carl
    University of Sheffield, England.
    Spagnuolo, Carmela
    University of Montreal, Canada.
    Stafforini, Diana M.
    University of Utah, UT USA.
    Stagg, John
    University of Utah, UT USA.
    Subbarayan, Pochi R.
    University of Montreal, Canada.
    Sundin, Tabetha
    University of Miami, FL USA.
    Talib, Wamidh H.
    Sentara Healthcare, VA USA.
    Thompson, Sarah K.
    Appl Science University, Jordan.
    Tran, Phuoc T.
    Royal Adelaide Hospital, Australia.
    Ungefroren, Hendrik
    Azienda Osped Ist Ospitalieri Cremona, Italy.
    Vander Heiden, Matthew G.
    MIT, MA 02139 USA.
    Venkateswaran, Vasundara
    Johns Hopkins University, MD USA; University of Toronto, Canada.
    Vinay, Dass S.
    Tulane University, LA USA.
    Vlachostergios, Panagiotis J.
    Johns Hopkins University, MD USA; New York University, NY USA.
    Wang, Zongwei
    Johns Hopkins University, MD USA; Harvard University, MA USA.
    Wellendx, Kathryn E.
    Columbia University, NY USA; University of Penn, PA 19104 USA.
    Whelan, Richard L.
    St Lukes Roosevelt Hospital, NY 10025 USA.
    Yang, Eddy S.
    University of Alabama Birmingham, AL USA.
    Yang, Huanjie
    Harbin Institute Technology, Peoples R China.
    Yang, Xujuan
    Dalhousie University, Canada.
    Yaswen, Paul
    Lawrence Berkeley National Lab, CA USA.
    Yedjou, Clement
    Jackson State University, MS USA.
    Yin, Xin
    Nara Medical University, Japan.
    Zhu, Jiyue
    Washington State University, WA USA.
    Zollo, Massimo
    CSIC, Spain; Centre Ingn Genet and Biotecnol Avanzate, Italy.
    Designing a broad-spectrum integrative approach for cancer prevention and treatment2015Inngår i: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 35, s. S276-S304Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.

  • 11.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    An overview of pregnancy and fertility issues in breast cancer patients2015Inngår i: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 47, nr 8, s. 673-678Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Breast cancer is one of the most common malignancies of women in the reproductive years. In the Western world there is a trend towards delaying pregnancy to later in life, and in combination with an increased incidence of breast cancer an increased number of women are diagnosed with breast cancer before they have completed their reproductive plans. In addition, breast cancer during pregnancy may affect an increased number of women as the childbearing years are delayed. The survival rate after breast cancer has improved during the last decades, and many young breast cancer survivors will consider a pregnancy subsequent to the completion of adjuvant breast cancer therapy. Traditionally, many women are advised against a pregnancy due to a fear of increased risk of recurrence, especially women with estrogen receptor-positive breast cancer. Due to feasibility issues, evidence from large prospective randomized trials is missing regarding the safety of pregnancy after breast cancer. Today guidelines are based on cohort studies and population-based registry evidence with its limitations. Overall, data suggest that pregnancy after breast cancer therapy is safe, and the current evidence is summarized in this overview.

  • 12.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Effects of sex steroids on normal human breast: studies in vivo using microdialysis and in vitro in cell culture1998Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Prolonged exposure to sex steroids may constitute a risk factor for the development of breast cancer. The biological mechanisms involved in breast carcinogenesis are not well understood.

    Basic knowledge of sex steroid effects on the normal human breast is still limited, one reason being the lack of an available in vivo technique for investigations of breast tissue metabolism.

    In this study, the microdialysis technique was developed and evaluated as a method for measurements of tissue-specific concentrations of amino acids, lactate, pyruvate and glutathione in normal human breast tissue during the menstrual cycle. The technique was successfully applied to breast tissue and it was observed that the concentrations of several amino acids as well as glutathione changed during the menstrual cycle. Oxidative damage to cells is one of the mechanisms which may be involved in the development of breast cancer. Normal aerobic metabolism generates potentially dangerous oxidants which are controlled by a variety of antioxidant systems. The exact regulatory mechanisms of these systems are not yet fully understood. We studied the effects of estradiol and progesterone on antioxidative activity in normal human breast tissue, in vivo with the microdialysis technique, and in vitro using normal human breast epithelial cells in culture. The in vivo levels of the antioxidant glutathione were measured early and late in the menstrual cycle in breast tissue and subcutaneous fat. The glutathione levels were higher late in the menstrual cycle in both tissues, when the serum levels of estradiol and progesterone were high. In vitro, breast epithelium exposed to estradiol and progesterone exhibited decreased activity of the antioxidative enzymes catalase and glutathione reductase, whereas the activity of glutathione peroxidase tended to increase compared with cells grown in medium without added sex hormones. The vulnerability to oxidative stress, induced by hydrogen peroxide, increased in cells grown with estradiol and progesterone present in the media. α-Tocopherol, and α-tocopherol in combination with ascorbic acid, but not ascorbic acid alone, protected from cell death induced by hydrogen peroxide. This effect was not dependent on estradiol and progesterone exposure.

    In conclusion, the data suggest an effect of estradiol and progesterone on antioxidative activity in normal human breast tissue both in vivo and in vitro.

    Microdialysis will be a useful tool in future research of these and other aspects concerning human breast tissue.

  • 13.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle2003Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 80, nr 2, s. 193-198Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prolonged exposure to endogenous and exogenous sex steroids increases the risk of breast cancer but the mechanisms are poorly understood. Increased levels of circulating insulin-like growth factor-1 (IGF-1) and low levels of IGF binding protein are associated with increased risk of breast cancer suggesting that IGF-1 has to be in its free form to be biologically active. Little is known about sex steroid regulation of IGF-1 locally in the breast. In this study microdialysis was used to determine the local levels of free IGF-1 in normal human breast tissue in healthy female volunteers during the menstrual cycle. The results showed that the extracellular levels of free IGF-1 locally in the breast were doubled in the luteal phase, when estradiol and progesterone levels were elevated, compared with the follicular phase. In plasma, free IGF-1 levels also exhibited a cyclic variation but to a less extent. The increased local levels of the tree form of IGF-1 may promote proliferation in the breast epithelium. This could be important in sex steroid dependent breast cancer development.

  • 14.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Increased extracellular local levels of estradiol in normal breast in vivo during the luteal phase of the menstrual cycle2005Inngår i: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 187, nr 1, s. 103-108Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Estrogen exposure is a major risk factor for breast cancer. Tissue estrogen originates from the ovaries but a significant portion is also produced by enzyme activity locally in the breast itself. How these enzymes are regulated is not fully understood. The extracellular space, where the metabolic exchange and cell interactions take place, reflects the environment that surrounds the epithelium but there has been no previous study of hormone concentrations in this compartment. In the present study microdialysis was used to measure extracellular estrogen concentrations in breast tissue and abdominal subcutaneous fat in 12 healthy women in vivo. It was found that women with high plasma progesterone levels had significant increased levels of estradiol in breast tissue compared with fat tissue (breast tissue 168 ± 6 pM, subcutaneous fat, 154 ± 5 pM, P<0.05), whereas women with low plasma progesterone exhibited no difference. Moreover, there was a significant correlation between local breast tissue estradiol and plasma progesterone levels (r=0.709, P<0.01). There was no difference in estrone sulphate in breast and fat tissue regardless of progesterone levels. Estrone was not detectable. The results in this study suggest that progesterone may be one regulator in the local conversion of estrogen precursors into potent estradiol in normal breast tissue. © 2005 Society for Endocrinology.

  • 15.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Microdialysis - an in vivo technique for studies of growth factors in breast cancer.2005Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes in the microenvironment are important in the development of cancer and further tumor growth. Although landmark discoveries have been made regarding genetic alterations in cancer at a cellular level very little is known about protein regulation in the extracellular space. In the microenvironment many growth factors are activated at a post-translational level by interactions of different cell types such as epithelial cells, fibroblasts, adipose cells, and immune cells. The extracellular space is the bioactive site for the majority of growth factors and increased knowledge of protein activation in this compartment is of utmost importance for our comprehension of tumor biology. Microdialysis is a minimally invasive technique, which enables sampling of molecules in the extracellular space. It is applicable in human cancer as well as in experimental tumors. This review describes microdialysis, its application and the up to date literature of microdialysis for detection of growth factors in cancer with special emphasis on breast cancer.

  • 16.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Positive correlation between estradiol and vascular endothelial growth factor but not fibroblast growth factor-2 in normal human breast tissue in vivo2005Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 11, nr 22, s. 8036-8041Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Angiogenesis is crucial in tumor development and progression. Ovarian hormones regulate angiogenesis in the reproductive tract but very little is known about its regulation in the normal breast. Sex steroids play an important role in breast cancer development by poorly understood mechanisms. Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) are potent stimulators of angiogenesis. Both VEGF and FGF-2 function in autocrine/ paracrine pathways and there is a major contribution of bioactive proteins by a posttranslational activation of sequestered molecules in the extracellular space. A direct measurement of these molecules in the extracellular compartment is, therefore, needed. Experimental Design: In this study, microdialysis was used to measure extracellular VEGF and FGF-2 in normal human breast tissue in situ in 11 premenopausal and 5 postmenopausal women. Results: Significantly higher level of VEGF in breast tissue of premenopausal women was found. Plasma as well as local estradiol and breast tissue VEGF exhibited significant correlations, whereas progesterone had no correlation with breast VEGF. FGF-2 did not correlate with either estradiol or progesterone. Conclusion: The result suggests that estradiol is a more potent regulator of free VEGF levels than progesterone in the normal breast. The control of free FGF-2 seems to be independent of sex steroids in the breast. Estrogen induction of free extracellular VEGF may be one mechanism involved in sex steroid - dependent breast carcinogenesis. © 2005 American Association for Cancer Research.

  • 17.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Sex steroid regulation of angiogenesis in breast tissue2005Inngår i: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 8, nr 2, s. 127-136Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiogenesis is essential for normal function in the female reproductive tract and a prerequisite for growth and metastasis of solid tumors. Several factors, both inducers and inhibitors, play essential roles in the regulation of the angiogenic process. Exposure to sex steroids increases the risk of breast cancer but the mechanisms are poorly understood and the importance of angiogenesis in breast carcinogenesis is undefined. In the female reproductive tract ovarian hormones tightly regulate angiogenesis. The breast is also a target organ for sex steroids but very little is known about sex steroid effects on angiogenesis in normal breast tissue and breast cancer. In this review several regulators of angiogenesis, and their relation to sex steroids, in breast tissue are discussed. Increased knowledge in this area is of utmost importance for future therapeutic treatment options and for breast cancer prevention. © Springer 2005.

  • 18.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi.
    Technical aspects of microdialysis of human breast2001Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 61, nr 4, s. 269-272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study a technique for insertion of microdialysis catheters and the influence of the position of the catheters within normal human breast tissue were evaluated by measuring amino acids. Moreover, to assess variability over time, the levels of amino acids were measured during a period of 3 h. In nine healthy women two parallel microdialysis catheters were implanted, guided by a catheter for intravenous use, into the breast tissue. All insertions were successful and there were no complications. The levels of amino acids were equal in the two parallel catheters and varied less than 10% over a period of 3 h. Insertion of the microdialysis catheter via an intravenous catheter is suitable for the dense breast tissue. The position of the microdialysis catheter within the same breast seems to be of minor importance for measurements of amino acids. Thus, the described technique is a safe and reproducible way of investigating the human breast in vivo.

  • 19.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle2003Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, nr 6, s. 2695-2698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exposure to sex steroids increases the risk of breast cancer, but the mechanisms are poorly understood. Angiogenesis is crucial in tumor development and progression. Very little is known about the regulation of angiogenesis in the normal breast. Vascular endothelial growth factor ( VEGF) has a key stimulatory role in angiogenesis. Interferon-inducible protein 10 (IP-10) is a potent inhibitor of angiogenesis in vivo. These factors function in autocrine/paracrine pathways, therefore, direct measurements in the target tissue are needed. I measured VEGF and IP-10 in normal human breast tissue in situ in healthy women, using microdialysis, in the follicular and luteal phase of the menstrual cycle. In breast tissue, VEGF levels increased in the luteal phase, compared with the follicular phase (17.8+/-4 pg/ml to 34+/-9 pg/ml, P<0.05). Plasma VEGF did not show a cyclic variation (10.6&PLUSMN,2.8 pg/ml vs. 14.6&PLUSMN,3.5 pg/liter, P=0.3). IP-10 levels did not vary during the menstrual cycle either in breast tissue (65&PLUSMN,17 pg/ml vs. 75&PLUSMN,21 pg/ml, P=0.6) or in plasma (64&PLUSMN,7 pg/ml vs. 81&PLUSMN,10 pg/ml, P=0.06). The data suggests that, in the luteal phase, VEGF and IP-10, in the normal human breast, exhibit a proangiogenic profile. This may be one mechanism by which sex steroids contribute to breast cancer development.

  • 20.
    Dabrosin, Charlotta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Gyorffy, S
    Margetts, P
    Ross, C
    Gauldie, J
    Therapeutic effect of angiostatin gene transfer in a murine model of endometriosis.2002Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 161, s. 909-918Artikkel i tidsskrift (Fagfellevurdert)
  • 21.
    Dabrosin, Charlotta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Johansson, Ann-Charlotte
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Öllinger, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: Mediated by the mannose-6-phosphate/IGF-II receptor?2004Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 85, nr 3, s. 229-238Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lysosomal protease Catliepsin D (Cath D) is associated with increased invasiveness and metastasis in breast cancer. Both estrogen and tamoxifen have been reported to increase Cath D, which seems to contradict the efficacy of tamoxifen as an adjuvant for estrogen dependent breast cancer. Cath D is bioactive in the extracellular space but very little is known about hormonal regulation of secreted Cath D in vivo. In this study we used microdialysis to sample the extracellular fluid in estrogen receptor positive MCF-7 tumors in nude mice. We show that tamoxifen in combination with estradiol decreased secreted Cath D compared with estradiol treatment only in solid tumors in situ. Cell culture of MCF-7 cells revealed that estradiol and tamoxifen increased intracellular proteolytic activity of Cath D in a similar fashion whereas secretion of Cath D was increased by estradiol and inhibited by tamoxifen. Immunofluorescence showed that estradiol located Cath D to the cell surface, while tamoxifen accumulated Cath D to dense lysosomes in perinuclear regions. Moreover, tamoxifen increased the intracellular transporter of Cath D, the mannose 6-phosphate/IGF-II receptor (M6P/IGF2R). In contrast, estradiol decreased the levels of this receptor. Thus, secretion of Cath D is hormone dependent and may be mediated by altered expression of the M6P/IGF2R. Our results highlight the importance of measurements of proteins in all compartments where they are biological active and show that microdialysis is a viable technique for sampling of Cath D in vivo.

  • 22.
    Dabrosin, Charlotta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Margetts, Peter J
    Gauldie, Jack
    Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer2003Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 107, nr 4, s. 535-540Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiogenesis is essential for tumor growth and metastasis and an important prognostic factor in breast cancer. VEGF, a key factor for angiogenesis, has been correlated with tumor vessel density in breast cancer. Estrogen, another crucial factor in breast cancer, stimulates VEGF, and an ERE in the VEGF gene has been defined. VEGF is bioactive in the extracellular fluid, where it becomes available to endothelial cells. Whether E2 affects VEGF levels in the extracellular fluid is not known. We show, using intratumoral microdialysis in vivo, that E2 treatment increased tumor extracellular levels of VEGF in an estrogen-dependent breast cancer model. Moreover, extracellular levels of VEGF in the tumor showed a strong correlation with total tumor VEGF, contrary to plasma levels of VEGF. Ninety-three percent of measured VEGF in the extracellular fluid in the tumor was tumor-derived, while only 45% of VEGF in circularing plasma originated from the tumor. We conclude that E2 increases extracellular VEGF and that microdialysis is a sensitive method for measurement of local VEGF production in vivo. Our results have potential application to the assessment of tumor characteristics in vivo in human tumors for individualized cancer therapy.

  • 23.
    Dabrosin, Charlotta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Palmer, K
    Gauldie, J
    Oestradiol enhances tumour regression induced by B7-I/IL-2 adenoviral gene transfer in a murine model of breast cancer2003Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 89, nr 2, s. 385-390Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The majority of breast cancers are oestrogen dependent and although current treatment strategies have improved, approximately 50% of the patients will develop metastasis. New treatments that result in long-term systemic immunity are therefore being developed. We have previously shown that adenoviral gene transfer of B7-I/IL-2 to murine breast cancer induces a high rate of complete turnout regression and systemic immunity. Since oestrogens not only affect breast cancer but also have been shown to modulate immune function and secretion of immune-regulatory cytokines, we explored whether administration of oestradiol altered the immune response induced by an adenoviral vector expressing B7-I/IL-2. An oestrogen-dependent murine breast cancer tumour was used in ovariectomised mice, supplemented either oestradiol or placebo. We report the somewhat unexpected finding that intratumoral injection of adenovirus expressing B7-I/IL-2 induces complete turnout regression in 76% of oestradiol-supplemented mice, while only 18% of the tumours regressed in the oestrogen-depleted group. Cured mice in both groups exhibited a similar CTL response against the tumour antigen. However, intratumoral IFN-? levels, 2 days after B7-I/IL-2 injection, were significantly higher in mice treated with oestradiol compared to placebo. This may be one mechanism explaining the higher response rate of tumours in oestradiol-replenished mice.

  • 24.
    Dabrosin, Charlotta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Palmer, Kay
    Muller, William J
    Gauldie, Jack
    Estradiol promotes growth and angiogenesis in polyoma middle T transgenic mouse mammary tumor explants2003Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 78Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Dabrosin, Charlotta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Öllinger, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Variability of glutathione during the menstrual cycle - Due to estrogen effects on hepatocytes?2004Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 36, nr 2, s. 145-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative stress and alterations in the antioxidative defense system may be involved in carcinogenesis. We have previously shown that the levels of glutathione (GSH) in vivo in both breast tissue and subcutaneous fat were higher in the luteal phase compared with the follicular phase, suggesting an overall increase in GSH. This result was confirmed in the present study. Moreover, we exposed normal breast tissue in vivo, breast epithelial cells in vitro, and hepatocytes in culture to ovarian hormones. We found that local perfusion with estradiol, using microdialysis, in normal human breast tissue did not alter the local GSH levels in vivo. In vitro, treatment with estradiol and progesterone of normal human breast epithelial cells did not alter GSH levels. However, levels of GSH in hepatocytes were after 8 h estradiol exposure initially decreased, 76.6 ± 5% of control cells, p < .05, whereas 20 h exposure more than doubled GSH, 209 ± 26% compared with control cells, p < .01. Progesterone had no additional effect. Exposure of hepatocytes to estradiol increased the cellular content of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis. In conclusion we suggest that estradiol affects the GSH homeostasis mainly by effects on hepatocytes, whereas local production in the breast is unaffected by estradiol.

  • 26.
    Fransén, Karin
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fenech, Matthew
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Yrkes- och miljömedicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Association between ulcerative growth and hypoxia inducible factor-1α polymorphisms in colorectal cancer patients2006Inngår i: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 45, nr 11, s. 833-840Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The hypoxia inducible factor-1α (HIF-1α) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1α is hydroxylated at normoxia and rapidly degraded via the von Hippel–Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1α gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26–21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58–26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1α C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33–13.08; P = 0.004). These results suggest that the HIF-1α polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1α allele may therefore be of importance in the selection of treatment strategies of CRC.

  • 27.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients2008Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 73, nr 8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.

    Methods: Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections.

    Results: We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF.

    Conclusion: We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo.

  • 28.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo2003Inngår i: Cancer research, ISSN 0008-5472, Vol. 63, s. 8742-8748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) is considered a key mediator of tumor angiogenesis, including neovascularization in human breast cancer. High tissue VEGF levels appear to correlate with poor prognosis and decreased overall survival in node-positive and node-negative breast cancer patients. Hormonal regulation of VEGF expression has been demonstrated, and some reports indicate that tamoxifen, a partial estrogen receptor agonist, increases VEGF mRNA in breast cancer cells. These results appear to contradict the efficacy of tamoxifen as an adjuvant for estrogen-dependent breast cancer, yet clinical data show that tamoxifen prevents metastasis and increases overall survival. In this study, we confirmed previous studies showing that intracellular levels of VEGF in vitro increased in response to tamoxifen to levels similar to those observed after estrogen treatment. To further study hormonal effects on the release of VEGF, we used microdialysis to sample the extracellular space, where VEGF is biologically active, in solid tumors in situ. We show for the first time that tamoxifen decreased extracellular VEGF in vivo in solid MCF-7 tumors in nude mice. These in vivo findings were confirmed in vitro where extracellular VEGF in the cell culture medium was decreased significantly by tamoxifen treatment. Furthermore, we illustrate that microdialysis is a viable method that may be applied in human breast tissue to detect soluble VEGF in situ released by the tumor.

  • 29.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Ulrika W.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells2005Inngår i: British journal of cancer, ISSN 0007-0920, Vol. 93, nr 9, s. 1005-1010Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiogenesis is regulated by the balance between pro- and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol+tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

  • 30.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Ulrika W.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Huss, Fredrik R. M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Brännskadevård. Linköpings universitet, Hälsouniversitetet.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Estradiol increases VEGF in normal human breast studied by whole-tissue culture2006Inngår i: Cell Tissue Research, ISSN 0302-766X, Vol. 325, nr 2, s. 245-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on the normal breast, largely because of the lack of convenient models. We have developed a method of culturing normal breast tissue ex vivo. We have applied this method to investigate the effects of estradiol and progesterone on the key angiogenic mediator, vascular endothelial growth factor (VEGF), in the breast. Whole breast tissue was obtained from routine reduction mammoplasty. Tissue biopsies were cultured in vitro for 1–3 weeks, and the expression of luminal cytokeratin 18 was determined by immunohistochemistry. As an application, tissue biopsies were treated in vitro for 1 week with or without estradiol or estradiol and progesterone. Estrogen receptor, progesterone receptor, and Ki–67 were analyzed, and VEGF levels were examined by quantitative immunoassay and immunohistochemistry. Whole breast tissue was cultured ex vivo for 1 week with preserved morphology. Increased detachment of the luminal epithelium was observed after 2 weeks. Estradiol increased extracellular levels of VEGF in normal breast tissue biopsy medium. The addition of progesterone had neither stimulatory nor inhibitory effects on secreted VEGF. The method of whole breast tissue culturing thus provide a means by which to explore the biology of normal breast tissue. Our results suggest that estradiol exerts pro-angiogenic effects in normal breast by increasing levels of biologically active VEGF.

  • 31.
    Garvin, Stina
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi.
    Öllinger, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo2006Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 231, nr 1, s. 113-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resveratrol, a polyphenol found in grapes and wine, is considered a potential cancer chemopreventive agent. Resveratrol has been shown to induce transcription via both ERα and ERβ. We observed significantly lower tumor growth, decreased angiogenesis, and increased apoptotic index in ERα- ERβ+ MDA-MB-231 tumors in resveratrol-treated nude mice compared with controls. In vitro we found a significant increase in apoptosis in resveratrol-treated MDA-MB-231 cells in addition to significantly reduced extracellular levels of VEGF. This study supports the potential use of resveratrol as a chemotherapeutic agent in breast cancers. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 32.
    Hillman, Jan
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Neurokirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Neurokirurgiska kliniken US.
    Åneman, Oscar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan.
    Persson, Mikael
    Anderson, Chris
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för dermatologi och venereologi. Östergötlands Läns Landsting, Medicincentrum, Hudkliniken i Östergötland.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Mellergård, Pekka
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Neurokirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Neurokirurgiska kliniken US.
    Variations in the response of interleukins in neurosurgical intensive care patients monitored using intracerebral microdialysis2007Inngår i: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 106, nr 5, s. 820-825Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Object. The aim of this study was to make a preliminary evaluation of whether microdialysis monitoring of cytokines and other proteins in severely diseased neurosurgical patients has the potential of adding significant information to optimize care, thus broadening the understanding of the function of these molecules in brain injury. Methods. Paired intracerebral microdialysis catheters with high-cutoff membranes were inserted in 14 comatose patients who had been treated in a neurosurgical intensive care unit following subarachnoidal hemorrhage or traumatic brain injury. Samples were collected every 6 hours (for up to 7 days) and were analyzed at bedside for routine metabolites and later in the laboratory for interleukin (IL)-1 and IL-6, in two patients, vascular endothelial growth factor and cathepsin-D were also checked. Aggregated microprobe data gave rough estimations of profound focal cytokine responses related to morphological tissue injury and to anaerobic metabolism that were not evident from the concomitantly collected cerebrospinal fluid data. Data regarding tissue with no macroscopic evidence of injury demonstrated that IL release not only is elicited in severely compromised tissue but also may be a general phenomenon in brains subjected to stress. Macroscopic tissue injury was strongly linked to IL-6 but not IL-1b activation. Furthermore, IL release seems to be stimulated by local ischemia. The basal tissue concentration level of IL-1b was estimated in the range of 10 to 150 pg/ml, for IL-6, the corresponding figure was 1000 to 20,000 pg/ml. Conclusions. Data in the present study indicate that catheters with high-cutoff membranes have the potential of expanding microdialysis to the study of protein chemistry as a routine bedside method in neurointensive care.

  • 33.
    Lindahl, Gabriel
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Saarinen, Niina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell-Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer2011Inngår i: CANCER RESEARCH, ISSN 0008-5472, Vol. 71, nr 1, s. 51-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The proinflammatory cytokines IL-1 alpha and IL-1 beta promote tumor angiogenesis that might be counteracted by the IL-1 receptor antagonist (IL-1Ra), anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens, such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL), may affect breast cancer progression in a similar fashion as the antiestrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors treated with tamoxifen and fed Flax or ENL exhibited decreased in vivo release of IL-1 beta derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects. Cancer cell-released IL-1Ra were approximately 5 times higher than stroma-derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro whereas breast cancer cell proliferation was unaffected in presence of estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen-dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer.

  • 34.
    Morad, Vivian
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Estradiol Affects Extracellular Leptin: Adiponectin Ratio in Human Breast Tissue in Vivo2014Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, nr 9, s. 3460-3467Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue. Objective: To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer. Setting and Design: Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated. Results: In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P less than .05) and positively correlated with leptin (r = 0.37; P less than .05) and leptin: adiponectin ratio (r = 0.38; P less than .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P less than 0.05) and decreased leptin (P less than .01) and the leptin: adiponectin ratio (P less than .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P less than .01) and adiponectin lower (P less than .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P less than .05). Conclusions: Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention.

  • 35.
    Morad, Vivian
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Kjölhede, Preben
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Adipokines and Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo - Correlations and Attenuation by Dietary Flaxseed2016Inngår i: Journal of mammary gland biology and neoplasia, ISSN 1083-3021, E-ISSN 1573-7039, Vol. 21, nr 1-2, s. 69-76Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exposure to sex steroids increases the risk of breast cancer but the exact mechanisms are yet to be elucidated. Events in the microenvironment are important for carcinogenesis. Diet containing phytoestrogens can affect the breast microenvironment and alter the risk of breast cancer. It has previously been shown that estrogen regulates extracellular levels of leptin, adiponectin, and VEGF in normal breast tissue in vivo. Whether these proteins correlate in breast tissue in vivo or if diet addition of flaxseed, a major source of phytoestrogens in Western diets, alters adipokine levels in breast tissue are unknown. We used microdialysis to sample proteins of normal human breast tissue and abdominal subcutaneous fat in situ in 34 pre-and postmenopausal women. In vitro, co-culture of breast cancer cells and primary human adipocytes was used. In vivo, in normal breast tissue, a significant positive correlation between VEGF and leptin was detected. No correlations were found in fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. The levels of leptin decreased and adiponectin increased after a dietary addition of 25 g of flaxseed/day for one menstrual cycle. We conclude that VEGF and leptin correlate significantly in normal human breast tissue in vivo and that dietary addition of flaxseed affect adipokine levels in the breast.

  • 36.
    Morad, Vivian
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Kjölhede, Preben
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Correlation between vascular endothelial growth factor and leptin in normal human breast tissue in vivo2015Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction: Events in the microenvironment are important for carcinogenesis of the breast. Adipocytes, which produce adipokines with paracrine effects, are the most abundant cell type in breast tissue. Exposure to sex steroids affects the risk of breast cancer. It has previously been shown that estrogen regulates the extracellular levels of leptin, adiponectin, IL-1β, and VEGF in normal human breast tissue in vivo.

    Objective: We aimed to determine if there were any relationships between leptin, adiponectin, IL-1β, and/or VEGF in normal human breast tissue in vivo and to elucidate the role of adipocytes in the regulation of these factors.

    Design and methods: Microdialysis was used to sample proteins of normal human breast tissue and abdominal subcutaneous (s.c.) fat in situ in pre-and postmenopausal women. An in vitro co-culture model of breast cancer cells and primary mature human adipocytes was used.

    Results: In vivo, in normal breast tissue, significant positive correlations between VEGF and leptin, and VEGF and leptin/adiponectin ratio were detected. No correlations were found in s.c. abdominal fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. In breast tissue, significant correlations between IL-1β and leptin and VEGF were revealed.

    Conclusions: Our results suggest that VEGF regulates leptin in normal human breast tissue. Moreover, physical contact between adipocytes and breast cancer cells, induces phenotypic changes and enhances the effects of estradiol. These mechanisms may be involved in breast cancer progression.

  • 37.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo2010Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, nr 14, s. 3659-3669Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E-2) affected angiogenin in breast tissue. Experimental Design: We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used. Results: We show that extracellular angiogenin correlated significantly with E-2 in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E-2 stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor-positive breast cancer cells, E-2 increased and tamoxifen decreased angiogenin secretion. Moreover, E-2-induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth. Conclusion: Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogen-driven breast cancer progression and a molecular target for therapeutic interventions.

  • 38.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Anti-angiogenic effects of tamoxifen in breast cancer by decreased secretion and reduced nuclear accumulation of angiogenin2009Inngår i: CANCER RESEARCH ISSN 0008-5472: Volume 69 Issue 2, 2009, Vol. 69, nr 2, s. 115S-115SKonferansepaper (Fagfellevurdert)
  • 39.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jill A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Tamoxifen decreases extracellular TGF-beta 1 secreted from breast cancer cells - A post-translational regulation involving matrix metalloproteinase activity2009Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 315, nr 1, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transforming growth factor-beta 1 (TGF-beta 1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta 1 have been associated with metastatic disease and poor prognosis in breast cancer patients. We have previously reported anti-angiogenic effects of the anti-estrogen tamoxifen in breast cancer, by increased matrix metalloproteinase-9 (MMP-9) activity and generation of endostatin. Here, we show that exposure of tamoxifen to ER-positive breast cancer cells for 7 days, decreased extracellular TGF-beta 1. Intracellular TGF-beta 1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta 1. Inhibition of MMP activity restored TGF-beta 1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta 1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta 1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta 1 protein levels, tumor growth and angiogenesis. In conclusion, our findings suggest a novel mechanism of action of tamoxifen in breast cancer via sex steroid dependent modulation of the proteolytic tumor microenvironment resulting in reduced extracellular TGF-beta 1 levels.

  • 40.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Saarinen, Niina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Nurmi, Tarja
    University of Eastern Finland.
    Engblom, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tamoxifen and Flaxseed Alter Angiogenesis Regulators in Normal Human Breast Tissue In Vivo2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The incidence of breast cancer is increasing in the Western world and there is an urgent need for studies of the mechanisms of sex steroids in order to develop novel preventive strategies. Diet modifications may be among the means for breast cancer prevention. Angiogenesis, key in tumor progression, is regulated by the balance between pro-and anti-angiogenic factors, which are controlled in the extracellular space. Sampling of these molecules at their bioactive compartment is therefore needed. The aims of this study were to explore if tamoxifen, one of the most used anti-estrogen treatments for breast cancer affected some of the most important endogenous angiogenesis regulators, vascular endothelial growth factor (VEGF), angiogenin, and endostatin in normal breast tissue in vivo and if a diet supplementation with flaxseed had similar effects as tamoxifen in the breast. Microdialysis was used for in situ sampling of extracellular proteins in normal breast tissue of women before and after six weeks of tamoxifen treatment or before and after addition of 25 g/day of ground flaxseed to the diet or in control women. We show significant correlations between estradiol and levels of VEGF, angiogenin, and endostatin in vivo, which was verified in ex vivo breast tissue culture. Moreover, tamoxifen decreased the levels of VEGF and angiogenin in the breast whereas endostatin increased significantly. Flaxseed did not alter VEGF or angiogenin levels but similar to tamoxifen the levels of endostatin increased significantly. We conclude that one of the mechanisms of tamoxifen in normal breast tissue include tipping of the angiogenic balance into an anti-angiogenic state and that flaxseed has limited effects on the pro-angiogenic factors whereas the anti-angiogenic endostatin may be modified by diet. Further studies of diet modifications for breast cancer prevention are warranted.

  • 41.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo2006Inngår i: Cancer Research, ISSN 0008-5472, Vol. 66, nr 9, s. 4789-4794Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.

  • 42.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells2007Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 102, nr 3, s. 253-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

  • 43.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, J. A.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo2007Artikkel i tidsskrift (Fagfellevurdert)
  • 44.
    Saarinen, N M
    et al.
    University of Turku.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Enterolactone but not genistein decreases estradiol-induced tumor growth, angiogenesis, and secreted VEGF in vivo in human breast cancer. in CANCER RESEARCH, vol 69, issue 2, pp 325S-325S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 2, s. 325S-325SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 45.
    Saarinen, Niina M.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Estrogen-induced angiogenic factors derived from stromal and cancer cells are differently regulated by enterolactone and genistein in human breast cancer in vivo2010Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, nr 3, s. 737-745Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiogenesis is a key in cancer progression and its regulators are released both by the tumor cells and the stroma. Dietary phytoestrogens, such as the lignan enterolactone (ENL) and the isoflavone genistein (GEN), may differently affect breast cancer growth. In this study, human breast cancer cells (MCF-7) were established in mice creating a tumor with species-specific cancer and stroma cells. Ovariectomized athymic mice supplemented with estradiol (E2) were fed basal AIN-93G diet (BD) or BD supplemented with 100 mg/kg ENL, 100 mg/kg GEN or their combination (ENL+GEN). We show that ENL and ENL+GEN inhibited E2-induced cancer growth and angiogenesis, whereas GEN alone did not. Microdialysis was used to sample extracellular proteins in tumors in vivo. ENL and ENL+GEN decreased both stroma- and cancer cell-derived VEGF, whereas cancer cell-derived PlGF increased. In subcutaneous Matrigel plugs in mice, ENL and ENL+GEN decreased E2-induced endothelial cell infiltration, whereas GEN alone did not. In endothelial cells, ENL inhibited E2-induced VEGFR-2 expression, whereas GEN did not. These results suggest that ENL has potent effects on breast cancer growth, even in combination with GEN, by downregulating E2-stimulated angiogenic factors derived both from the stroma and the cancer cells, whereas dietary GEN does not possess any antiestrogenic effects.

  • 46.
    Svensson, Susanne
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Abrahamsson, Annelie
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Vazquez Rodriguez, Gabriela
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi.
    Olsson, Anna-Karin
    Uppsala University, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Stockholm, Sweden..
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Dabrosin, Charlotta
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer2015Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, nr 16, s. 3794-3805Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. (C)2015 AACR.

  • 47.
    Söderlund, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Bendrik, Christina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Robertson, Jennifer
    McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    McMaster University, Hamilton, Ontario, Canada.
    Olsson, Anna-Karin
    Uppsala University, Sweden .
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer2013Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, nr 8, s. 4420-4430Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro-and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities. The Journal of Immunology, 2013, 190: 4420-4430.

  • 48.
    Vazquez Rodriguez, Gabriela
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jensen, Lasse D
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-82018Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, s. 1-17, artikkel-id 1767Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fat is a major tissue component in human breast cancer (BC). Whether breast adipocytes (BAd) affect early stages of BC metastasis is yet unknown. BC progression is dependent on angiogenesis and inflammation, and interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are key regulators of these events. Here, we show that BAd increased the dissemination of estrogen receptor positive BC cells (BCC) in vivo in the zebrafish model of metastasis, while dissemination of the more aggressive and metastatic BCC such as estrogen receptor negative was unaffected. While anti-VEGF and anti-IL-8 exhibited equal inhibition of angiogenesis at the primary tumor site, anti-IL-8 reduced BCC dissemination whereas anti-VEGF had minor effects on this early metastatic event. Mechanistically, overexpression of cell-adhesion molecules in BCC and neutrophils via IL-8 increased the dissemination of BCC. Importantly, the extracellular in vivo levels of IL-8 were 40-fold higher than those of VEGF in human BC. Our results suggest that IL-8 is a clinical relevant and promising therapeutic target for human BC.

  • 49.
    Vazquez Rodriguez, Gabriela
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Estradiol promotes breast cancer cell migration via recruitment and activation of neutrophils2017Inngår i: Cancer Immunology research, ISSN 2326-6066, Vol. 5, nr 3, s. 234-247, artikkel-id 28159748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Estradiol (E2) plays a key role in breast cancer progression. Most breast cancer recurrences express the estrogen receptor (ER), but nearly 50% of patients are resistant to antiestrogen therapy. Novel therapeutic targets of ER-positive breast cancers are needed. Protumoral neutrophils expressing the lymphocyte function-associated antigen 1 (LFA-1) integrin may mediate cancer metastasis, and TGFβ1 is the major chemoattractant for neutrophils. The role of E2 in neutrophil–ER+ breast cancer cell interactions is unknown. We studied this in vivo using murine breast cancers in immunocompetent mice and human breast cancers in nude mice. Cell dissemination was evaluated in a zebrafish model, and microdialysis of breast cancer patients was performed. In vitro studies were done with mammosphere cultures of breast cancer cells and human neutrophils. We found that E2 increased the number of LFA-1+ neutrophils recruited to the invasive edge of mouse tumors, increased TGFβ1 secretion and promoted neutrophil infiltration in mammospheres, and induced overexpression of LFA-1 in neutrophils. In zebrafish, in the presence of E2, neutrophils increased dissemination of ER+ breast cancer cells via LFA-1 and TGFβ1, thus causing noninvasive cancer cells to be highly metastatic. Time-lapse imaging in zebrafish revealed close interactions of neutrophils with cancer cells, which drove breast cancer metastasis. We also found that extracellular TGFβ1 was overproduced in human breast cancer tissue compared with adjacent normal breast tissue. Thus, E2 can regulate immune/cancer cell interactions in tumor microenvironments. Our results indicate that extracellular TGFβ1 is a relevant target in human breast cancer.

  • 50.
    Vazquez Rodriguez, Gabriela
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Neutrophils Promote Breast Cancer Progression and Metastasis via LFA-1 Integrin2015Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Cancer is considered an inflammatory condition where immune cells play an important role in progression and metastasis. Neutrophils may be pro- or antitumorigenic, depending on their phenotype or the number of infiltrating neutrophils in the tumor microenvironment. Massive infiltration of neutrophils in cancer tissue may elicit a cytotoxic effect, leading to tumor regression, whereas a S139 low-grade neutrophil gradient is tumor progressive. Chemokines, cytokines, and growth factors present in the tumor microenvironment, as well as cell-cell interactions mediated by integrins have shown to be determinant steps for cancer cells to break through the endothelial wall and establish metastatic niches. In this work we evaluated the role of lymphocyte functionassociated antigen 1 (LFA-1) integrin in neutrophils-mediated metastasis of estrogen receptor positive breast cancer cells (MCF-7) cells in a tumor xenograft model in zebrafish and in neutrophil infiltration in MCF-7 mammospheres. The metastatic capability of MCF-7 cells was evaluated in presence or absence of human neutrophils and with/without estradiol treatment. Two days old zebrafish embryos were injected into the perivitelline space with labeled MCF-7 cells and human neutrophils, an anti-human LFA-1 antibody (CD11a) was included. We show that estradiol treatment significantly increased the infiltration of neutrophils into MCF-7 mammospheres and this infiltration was significantly reduced by the presence of an anti-human CD11a antibody. Co-injection of MCF-7 cells with neutrophils significantly increased the migration of MCF-7 cells to distant sites in zebrafish and this effect was inhibited by using an anti-human CD11a antibody. We conclude that neutrophils affect the dissemination of breast cancer cells via LFA-1 integrin. Although estradiol increased the number of infiltrating neutrophils into mammospheres exposure to estradiol seemed to have minor effects on the dissemination in the zebrafish.

12 1 - 50 of 51
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