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  • 1.
    Arjonen, Antti
    et al.
    VTT Technical Research Centre Finland, Finland University of Turku, Finland .
    Kaukonen, Riina
    VTT Technical Research Centre Finland, Finland University of Turku, Finland .
    Mattila, Elina
    VTT Technical Research Centre Finland, Finland University of Turku, Finland .
    Rouhi, Pegah
    Karolinska Institute, Sweden .
    Hognas, Gunilla
    VTT Technical Research Centre Finland, Finland University of Turku, Finland .
    Sihto, Harri
    University of Helsinki, Finland .
    Miller, Bryan W.
    University of Glasgow, Scotland .
    Morton, Jennifer P.
    University of Glasgow, Scotland .
    Bucher, Elmar
    VTT Technical Research Centre Finland, Finland .
    Taimen, Pekka
    University of Turku, Finland Turku University Hospital, Finland .
    Virtakoivu, Reetta
    VTT Technical Research Centre Finland, Finland University of Turku, Finland .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Sansom, Owen J.
    University of Glasgow, Scotland .
    Joensuu, Heikki
    University of Helsinki, Finland University of Helsinki, Finland .
    Ivaska, Johanna
    VTT Technical Research Centre Finland, Finland University of Turku, Finland University of Turku, Finland .
    Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis2014Ingår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, nr 3, s. 1069-1082Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport 131 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

  • 2.
    Bandaru, S.
    et al.
    University of Gothenburg, Sweden.
    Zhou, A-X
    University of Gothenburg, Sweden.
    Rouhi, P.
    Karolinska Institute, Sweden.
    Zhang, Y.
    Karolinska Institute, Sweden.
    Bergo, M. O.
    University of Gothenburg, Sweden.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden.
    Akyurek, L. M.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Targeting filamin B induces tumor growth and metastasis via enhanced activity of matrix metalloproteinase-9 and secretion of VEGF-A2014Ingår i: Oncogenesis, E-ISSN 2157-9024, Vol. 3, s. e119-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Filamins regulate cell locomotion and associate with diverse signaling molecules. We have recently found that targeting filamin A (FLNA) reduces RAS-induced lung adenocarcinomas. In this study, we explored the role of another major filamin isoform, filamin B (FLNB), in tumor development. In contrast to FLNA, we report that targeting FLNB enhances RAS-induced tumor growth and metastasis which is associated with higher matrix metallopeptidase-9 (MMP-9) and extracellular signal-regulated kinase (ERK) activity. Flnb deficiency in mouse embryonic fibroblasts results in increased proteolytic activity of MMP-9 and cell invasion mediated by the RAS/ERK pathway. Similarly, silencing FLNB in multiple human cancer cells increases the proteolytic activity of MMP-9 and tumor cell invasion. Furthermore, we observed that Flnb-deficient RAS-induced tumors display more capillary structures that is correlated with increased vascular endothelial growth factor-A (VEGF-A) secretion. Inhibition of ERK activation blocks phorbol myristate acetate-induced MMP-9 activity and VEGF-A secretion in vitro. In addition, silencing FLNB in human ovarian cancer cells increases secretion of VEGF-A that induces endothelial cells to form more vascular structures in vitro. We conclude that FLNB suppresses tumor growth and metastasis by regulating the activity of MMP-9 and secretion of VEGF-A which is mediated by the RAS/ERK pathway.

  • 3.
    Brautigam, Lars
    et al.
    Karolinska Institute, Sweden .
    Dahl Ejby Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Poschmann, Gereon
    University of Dusseldorf, Germany .
    Nystrom, Staffan
    Karolinska Institute, Sweden .
    Bannenberg, Sarah
    Karolinska Institute, Sweden .
    Dreij, Kristian
    Karolinska Institute, Sweden .
    Lepka, Klaudia
    University of Dusseldorf, Germany .
    Prozorovski, Timour
    University of Dusseldorf, Germany .
    Montano, Sergio J
    Karolinska Institute, Sweden .
    Aktas, Orhan
    University of Dusseldorf, Germany .
    Uhlen, Per
    Karolinska Institute, Sweden .
    Stuehler, Kai
    University of Dusseldorf, Germany .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Holmgren, Arne
    Karolinska Institute, Sweden .
    Berndt, Carsten
    Karolinska Institute, Sweden .
    Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 12013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 50, s. 20057-20062Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Embryonic development depends on complex and precisely orchestrated signaling pathways including specific reduction/oxidation cascades. Oxidoreductases of the thioredoxin family are key players conveying redox signals through reversible posttranslational modifications of protein thiols. The importance of this protein family during embryogenesis has recently been exemplified for glutaredoxin 2, a vertebrate-specific glutathione-disulfide oxidoreductase with a critical role for embryonic brain development. Here, we discovered an essential function of glutaredoxin 2 during vascular development. Confocal microscopy and time-lapse studies based on two-photon microscopy revealed that morpholino-based knockdown of glutaredoxin 2 in zebrafish, a model organism to study vertebrate embryogenesis, resulted in a delayed and disordered blood vessel network. We were able to show that formation of a functional vascular system requires glutaredoxin 2-dependent reversible S-glutathionylation of the NAD(+)-dependent protein deacetylase sirtuin 1. Using mass spectrometry, we identified a cysteine residue in the conserved catalytic region of sirtuin 1 as target for glutaredoxin 2-specific deglutathionylation. Thereby, glutaredoxin 2-mediated redox regulation controls enzymatic activity of sirtuin 1, a mechanism we found to be conserved between zebrafish and humans. These results link S-glutathionylation to vertebrate development and successful embryonic angiogenesis.

  • 4.
    Cao, Renhai
    et al.
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Ji, Hong
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Feng, Ninghan
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Andersson, Patrik
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Sun, Yuping
    Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong , People's Republic of China.
    Tritsaris, Katerina
    Department of Cellular and Molecular Medicine, Center for Healthy Aging Panum Institute, University of Copenhagen, Copenhagen, Denmark.
    Jon Hansen, Anker
    Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark and Novo Nordisk A/S Måløv, Denmark.
    Dissing, Steen
    Department of Cellular and Molecular Medicine, Center for Healthy Aging Panum Institute, University of Copenhagen, Copenhagen, Denmark.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Sweden.
    Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 39, s. 15894-15899Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2-induced lymphangiogenesis. Intriguingly, the VEGFR-3-mediated signaling was required for the lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. Consequently, a VEGFR-3-specific neutralizing antibody markedly inhibited FGF-2-induced lymphangiogenesis. Thus, the VEGFR-3-induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2-stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2- and VEGF-C-induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.

  • 5.
    Cao, Renhai
    et al.
    Karolinska Institute, Sweden.
    Ji, Hong
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, 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.
    Editorial Material: Collaborative effects between the TNF alpha-TNFR1-macrophage axis and the VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis in ONCOIMMUNOLOGY, vol 4, issue 3, pp2015Ingår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 4, nr 3, s. e989777-Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Although inflammation and metastasis are two well-known hallmarks of malignant disease, the relationship between inflammation and lymphatic metastasis is an unexplored research area. We recently elucidated a sophisticated mechanism by which TNF alpha-induced tumor inflammation conscripts macrophage-mediated VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis.

  • 6.
    Cao, Renhai
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Lim, Sharon
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Ji, Hong
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Zhang, Yin
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Yang, Yunlong
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Honek, Jennifer
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Hedlund, Eva-Maria
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Fysiologi. Linköpings universitet, Hälsouniversitetet.
    Mouse corneal lymphangiogenesis model.2011Ingår i: Nature protocols, ISSN 1750-2799, Vol. 6, nr 6, s. 817-26Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This protocol describes a powerful in vivo method to quantitatively study the formation of new lymphatic vessels in the avascular cornea without interference of pre-existing lymphatics. Implantation of 100 ng of lymphangiogenic factors such as vascular endothelial growth factor (VEGF)-A, VEGF-C or fibroblast growth factor-2, together with slow-release polymers, into a surgically created micropocket in the mouse cornea elicits a robust lymphangiogenic response. Newly formed lymphatic vessels are detected by immunohistochemical staining of the flattened corneal tissue with lymphatic endothelial-specific markers such as lymphatic vessel endothelial hyaluronan receptor-1; less-specific markers such as vascular endothelial growth factor receptor 3 may also be used. Lymphatic vessel growth in relation to hemangiogenesis can be readily detected starting at day 5 or 6 after pellet implantation and persists for ∼14 d. This protocol offers a unique opportunity to study the mechanisms underlying lymphatic vessel formation, remodeling and function.

  • 7.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Angiogenesis and Vascular Functions in Modulation of Obesity, Adipose Metabolism, and Insulin Sensitivity2013Ingår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 18, nr 4, s. 478-489Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    White and brown adipose tissues are hypervascularized and the adipose vasculature displays phenotypic and functional plasticity to coordinate with metabolic demands of adipocytes. Blood vessels not only supply nutrients and oxygen to nourish adipocytes, they also serve as a cellular reservoir to provide adipose precursor and stem cells that control adipose tissue mass and function. Multiple signaling molecules modulate the complex interplay between the vascular system and the adipocytes. Understanding fundamental mechanisms by which angiogenesis and vasculatures modulate adipocyte functions may provide new therapeutic options for treatment of obesity and metabolic disorders by targeting the adipose vasculature.

  • 8.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Erythropoietin in cancer: a dilemma in risk therapy2013Ingår i: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 24, nr 4, s. 190-199Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Erythropoietin (EPO) is a frequently prescribed drug for treatment of cancer-related and chemotherapy-induced anemia in cancer patients. Paradoxically, recent preclinical and clinical studies indicate that EPO could potentially accelerate tumor growth and jeopardize survival in cancer patients. In this review I critically discuss the current knowledge and broad biological functions of EPO in association with tumor growth, invasion, and angiogenesis. The emphasis is focused on discussing the complex interplay between EPO and other tumor-derived factors in angiogenesis, tumor growth, invasion, and metastasis. Understanding the multifarious functions of EPO and its reciprocal relation with other signaling pathways is crucial for developing more effective agents for cancer therapy and for minimizing risks for cancer patients.

  • 9.
    Cao, Yihai
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Future options of anti-angiogenic cancer therapy2016Ingår i: CHINESE JOURNAL OF CANCER, ISSN 1000-467X, Vol. 35, nr 21Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    In human patients, drugs that block tumor vessel growth are widely used to treat a variety of cancer types. Many rigorous phase 3 clinical trials have demonstrated significant survival benefits; however, the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients. Currently, it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients. In this article, we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.

  • 10.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis2013Ingår i: Trends in Molecular Medicine, ISSN 1471-4914, E-ISSN 1471-499X, Vol. 19, nr 8, s. 460-473Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are frequently expressed in various tumors and their expression levels correlate with tumor growth, invasiveness, drug resistance, and poor clinical outcomes. Emerging experimental evidence demonstrates that PDGFs exhibit multiple functions in modulation of tumor growth, metastasis, and the tumor microenvironment by targeting malignant cells, vascular cells, and stromal cells. Understanding PDGF PDGFR-mediated molecular signaling may provide new mechanistic rationales for optimizing current cancer therapies and the development of future novel therapeutic modalities.

  • 11.
    Cao, Yihai
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Arbiser, Jack
    Emory University.
    DAmato, Robert J
    Childrens Hospital, Boston.
    DAmore, Patricia A
    Harvard University.
    Ingber, Donald E
    Childrens Hospital, Boston.
    Kerbel, Robert
    Sunnybrook Health Science Centre.
    Klagsbrun, Michael
    Childrens Hospital, Boston.
    Lim, Sharon
    Karolinska Institute.
    Moses, Marsha A
    Childrens Hospital, Boston.
    Zetter, Bruce
    Childrens Hospital, Boston.
    Dvorak, Harold
    Harvard University.
    Langer, Robert
    MIT.
    Forty-Year Journey of Angiogenesis Translational Research2011Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 3, nr 114Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Forty years ago, Judah Folkman predicted that tumor growth is dependent on angiogenesis and that inhibiting this process might be a new strategy for cancer therapy. This hypothesis formed the foundation of a new field of research that represents an excellent example of how a groundbreaking scientific discovery can be translated to yield benefits for patients. Today, antiangiogenic drugs are used to treat human cancers and retinal vascular diseases. Here, we guide readers through 40 years of angiogenesis research and discuss challenges of antiangiogenic therapy.

  • 12.
    Chen, Xiaoyun
    et al.
    Sun Yat Sen University, Peoples R China; Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Yang, Huasheng
    Sun Yat Sen University, Peoples R China.
    Sun, Yuping
    Shandong University, Peoples R China.
    Zhuang, Rujie
    Chinese Medical University, Peoples R China.
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China.
    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.
    Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 10351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.

  • 13.
    Dahl Jensen, Lasse
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Nakamura, Masaki
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Brautigam, Lars
    Karolinska Institute, Sweden .
    Andersson, Patrik
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Wahlberg, Eric
    Linköpings universitet, Institutionen för medicin och hälsa, Kärlkirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Länne, Toste
    Linköpings universitet, Institutionen för medicin och hälsa, Fysiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish2012Ingår i: Cell Reports, ISSN 2211-1247, Vol. 2, nr 2, s. 231-241Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Molecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis.

  • 14.
    Eleonora Hedlund, Eva-Maria
    et al.
    Karolinska Institute, Sweden .
    Yang, Xiaojuan
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Shibuya, Masabumi
    Tokyo Medical and Dent University, Japan .
    Zhong, Weide
    Guangzhou Medical University, Peoples R China .
    Sun, Baocun
    Tianjin Medical University, Peoples R China .
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China .
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 2, s. 654-659Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.

  • 15.
    Honek, Jennifer
    et al.
    Karolinska Institute, Sweden.
    Seki, Takahiro
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Fischer, Carina
    Karolinska Institute, Sweden.
    Li, Jingrong
    Simcere Pharmaceut Research and Dev, Peoples R China.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Samani, Nilesh J.
    University of Leicester, England; Glenfield Hospital, England.
    Zang, Jingwu
    Simcere Pharmaceut Research and Dev, Peoples R China.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden; University of Leicester, England.
    Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 41, s. 14906-14911Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti-VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.

  • 16.
    Hosaka, Kayoko
    et al.
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Seki, Takahiro
    Karolinska Institute, Sweden .
    Nakamura, Masaki
    Karolinska Institute, Sweden .
    Andersson, Patrik
    Karolinska Institute, Sweden .
    Rouhi, Pegah
    Karolinska Institute, Sweden .
    Yang, Xiaojuan
    Karolinska Institute, Sweden .
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Lim, Sharon
    Karolinska Institute, Sweden .
    Feng, Ninghan
    Karolinska Institute, Sweden .
    Xue, Yuan
    Karolinska Institute, Sweden .
    Li, Xuri
    Sun Yat Sen University, Peoples R China .
    Larsson, Ola
    Karolinska Institute, Sweden .
    Ohhashi, Toshio
    Shinshu University, Japan .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden .
    Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis2013Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, nr 2129Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dose-dependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-beta signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-beta and inactivation of the PDGF-beta signalling decreases integrin alpha 1 beta 1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.

  • 17.
    Jensen, Lasse
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Brautigam, Lars
    Karolinska Institute, Sweden.
    Li, Xuri
    Sun Yat Sen University, Peoples R China.
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China.
    Samani, Nilesh J.
    University of Leicester, England; Glenfield Hospital, England.
    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.
    VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 44, s. E5944-E5953Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Physiological functions of vascular endothelial growth factor (VEGF)-B remain an enigma, and deletion of the Vegfb gene in mice lacks an overt phenotype. Here we show that knockdown of Vegfba, but not Vegfbb, in zebrafish embryos by specific morpholinos produced a lethal phenotype owing to vascular and neuronal defects in the brain. Vegfba morpholinos also markedly prevented development of hyaloid vasculatures in the retina, but had little effects on peripheral vascular development. Consistent with phenotypic defects, Vegfba, but not Vegfaa, mRNA was primarily expressed in the brain of developing zebrafish embryos. Interestingly, in situ detection of Neuropilin1 (Nrp1) mRNA showed an overlapping expression pattern with Vegfba, and knockdown of Nrp1 produced a nearly identically lethal phenotype as Vegfba knockdown. Furthermore, zebrafish VEGF-Ba protein directly bound to NRP1. Importantly, gain-of-function by exogenous delivery of mRNAs coding for NRP1-binding ligands VEGF-B or VEGF-A to the zebrafish embryos rescued the lethal phenotype by normalizing vascular development. Similarly, exposure of zebrafish embryos to hypoxia also rescued the Vegfba morpholino-induced vascular defects in the brain by increasing VEGF-A expression. Independent evidence of VEGF-A gain-of-function was provided by using a functionally defective Vhl-mutant zebrafish strain, which again rescued the Vegfba morpholino-induced vascular defects. These findings show that VEGF-B is spatiotemporally required for vascular development in zebrafish embryos and that NRP1, but not VEGFR1, mediates the essential signaling.

  • 18.
    Ji, Hong
    et al.
    Karolinska Institute, Sweden; Nanjing Medical University, Peoples R China.
    Cao, Renhai
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden.
    Sun, Yuping
    Shandong University, Peoples R China.
    Dissing, Steen
    University of Copenhagen, Denmark.
    He, Xia
    Nanjing Medical University, Peoples R China.
    Yang, Xiaojuan
    Karolinska Institute, Sweden.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden; University of Leicester, England.
    TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling2014Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, nr 4944Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-alpha markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-alpha-TNFR1 signalling pathway directly stimulates lymphatic endothelial cell activity through a VEGFR3-independent mechanism. However, VEGFR3-induced lymphatic endothelial cell tips are a prerequisite for lymphatic vessel growth in vivo, and a VEGFR3 blockade completely ablates TNF-alpha-induced lymphangiogenesis. Moreover, TNF-alpha-TNFR1-activated inflammatory macrophages produce high levels of VEGF-C to coordinately activate VEGFR3. Genetic deletion of TNFR1 (Tnfr1(-/-)) in mice or depletion of tumour-associated macrophages (TAMs) virtually eliminates TNF-alpha-induced lymphangiogenesis and lymphatic metastasis. Gain-of-function experiments show that reconstitution of Tnfr1(+/+) macrophages in Tnfr1(+/+) mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-alpha-TNFR1 pathway.

  • 19.
    Keklikoglou, I.
    et al.
    German Cancer Research Centre, Germany; Swiss Federal Institute Technology Lausanne EPFL, Switzerland.
    Hosaka, K.
    Karolinska Institute, Sweden.
    Bender, C.
    German Cancer Research Centre, Germany.
    Bott, A.
    German Cancer Research Centre, Germany.
    Koerner, C.
    German Cancer Research Centre, Germany.
    Mitra, D.
    German Cancer Research Centre, Germany.
    Will, R.
    German Cancer Research Centre, Germany.
    Woerner, A.
    German Cancer Research Centre, Germany.
    Muenstermann, E.
    German Cancer Research Centre, Germany.
    Wilhelm, H.
    German Cancer Research Centre, Germany.
    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.
    Wiemann, S.
    German Cancer Research Centre, Germany.
    MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes2015Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, nr 37, s. 4867-4878Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-kappa B transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF-kappa B-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies.

  • 20.
    Lim, Sharon
    et al.
    Karolinska Institute.
    Honek, Jennifer
    Karolinska Institute.
    Xue, Yuan
    Karolinska Institute.
    Seki, Takahiro
    Karolinska Institute.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Patrik
    Karolinska Institute.
    Yang, Xiaojuan
    Karolinska Institute.
    Hosaka, Kayoko
    Karolinska Institute.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice2012Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 7, nr 3, s. 606-615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure of humans and rodents to cold activates thermogenic activity in brown adipose tissue (BAT). This protocol describes a mouse model to study the activation of BAT and angiogenesis in adipose tissues by cold acclimation. After a 1-week exposure to 4 degrees C, adult C57BL/6 mice show an obvious transition from subcutaneous white adipose tissue (WAT) into brown-like adipose tissue (BRITE). The BRITE phenotype persists after continuous cold exposure, and by the end of week 5 BRITE contains a high number of uncoupling protein-1-positive mitochondria, a characteristic feature of BAT. During the transition from WAT into BRITE, the vascular density is markedly increased owing to the activation of angiogenesis. In BAT, cold exposure stimulates thermogenesis by increasing the mitochondrial content and metabolic rate. BAT and the increased metabolic rate result in a lean phenotype. This protocol provides an outstanding opportunity to study the molecular mechanisms that control adipose mass.

  • 21.
    Lim, Sharon
    et al.
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Cao, Yihai
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Karolinska Institute, Sweden; Nanjing Medical University, Peoples R China; University of Leicester, England; Glenfield Gen Hospital, England.
    Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 25, s. 38282-38291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.

  • 22.
    Lim, Sharon
    et al.
    Karolinska Institute, Sweden.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Zhang, Danfang
    Karolinska Institute, Sweden; Tianjin Medical University, Peoples R China.
    Chen, Fang
    Karolinska Institute, Sweden; Zhejiang Chinese Medical University, Peoples R China.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Feng, Ninghan
    Karolinska Institute, Sweden; Second Hospital Wuxi, Peoples R China.
    Seki, Takahiro
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Li, Jingrong
    Simcere Pharmaceut RandD, Peoples R China.
    Zang, Jingwu
    Simcere Pharmaceut RandD, Peoples R China.
    Sun, Baocun
    Tianjin Medical University, Peoples R China.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden; University of Leicester, England.
    VEGFR2-Mediated Vascular Dilation as a Mechanism of VEGF-Induced Anemia and Bone Marrow Cell Mobilization2014Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 9, nr 2, s. 569-580Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF-and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy.

  • 23.
    Martinez Molina, Daniel
    et al.
    Karolinska Institute, Sweden .
    Jafari, Rozbeh
    Karolinska Institute, Sweden .
    Ignatushchenko, Marina
    Karolinska Institute, Sweden .
    Seki, Takahiro
    Karolinska Institute, Sweden .
    Larsson, E. Andreas
    Nanyang Technology University, Singapore .
    Dan, Chen
    Nanyang Technology University, Singapore .
    Sreekumar, Lekshmy
    Nanyang Technology University, Singapore .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Nordlund, Par
    Karolinska Institute, Sweden Nanyang Technology University, Singapore .
    Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay2013Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 341, nr 6141, s. 84-87Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement.

  • 24.
    Nallapalli, Rajesh K
    et al.
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Ibrahim, Mohamed X
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Zhou, Alex X
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Bandaru, Sashidar
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Naresh Sunkara, Sai
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Redfors, Bjorn
    University of Gothenburg, Sweden .
    Pazooki, David
    University of Gothenburg, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Boren, Jan
    University of Gothenburg, Sweden .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Bergo, Martin O
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Akyurek, Levent M
    University of Gothenburg, Sweden University of Gothenburg, Sweden .
    Targeting filamin A reduces K-RAS-induced lung adenocarcinomas and endothelial response to tumor growth in mice2012Ingår i: Molecular Cancer, ISSN 1476-4598, E-ISSN 1476-4598, Vol. 11, nr 50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. less thanbrgreater than less thanbrgreater thanMethods: First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. less thanbrgreater than less thanbrgreater thanResults: Knockout of Flna significantly reduced K-RAS-induced lung tumor formation and the proliferation of oncogenic K-RAS-expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.

  • 25.
    Religa, Piotr
    et al.
    Karolinska Institute, Sweden .
    Cao, Renhai
    Karolinska Institute, Sweden .
    Religa, Dorota
    Karolinska Institute, Sweden .
    Xue, Yuan
    Karolinska Institute, Sweden .
    Bogdanovic, Nenad
    Karolinska Institute, Sweden .
    Westaway, David
    University of Toronto, Canada .
    Marti, Hugo H.
    Heidelberg University, Germany .
    Winblad, Bengt
    Karolinska Institute, Sweden .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    VEGF significantly restores impaired memory behavior in Alzheimers mice by improvement of vascular survival2013Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The functional impact of amyloid peptides (Abs) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimers patients. Here we show substantial accumulation of Abs 40 and 42 in the brain arterioles of Alzheimers patients and of transgenic Alzheimers mice. PurifiedAbs 1-40 and 1-42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimers patients. VEGF significantly prevented Ab-induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimers. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimers disease.

  • 26.
    Rouhi, Pegah
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Jensen, Lasse D
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Hosaka, Kayoko
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Länne, Toste
    Linköpings universitet, Institutionen för medicin och hälsa, Fysiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärtcentrum, Thorax-kärlkliniken.
    Wahlberg, Eric
    Linköpings universitet, Institutionen för medicin och hälsa, Kärlkirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärtcentrum, Thorax-kärlkliniken.
    Fleng Steffensen, John
    Marine Biological Laboratory, Biological Institute, University of Copenhagen, Helsingor, Denmark.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Hypoxia-induced metastasis model in embryonic zebrafish2010Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, nr 12, s. 1911-1918Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the circulation. However, until recently, animal models and imaging technology did not enable monitoring of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average experimental time for this model is 7 d. Our protocol offers a remarkable opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis.

  • 27.
    Shahul Hameed, L.
    et al.
    Karolinska Institute, Sweden.
    Berg, Daniel A.
    Karolinska Institute, Sweden.
    Belnoue, Laure
    Karolinska Institute, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Karolinska Institute, Sweden.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden; University of Leicester, England.
    Simon, Andras
    Karolinska Institute, Sweden.
    Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain2015Ingår i: eLIFE, E-ISSN 2050-084X, ELIFE SCIENCES PUBLICATIONS LTD, SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND, ISSN 2050-084X, Vol. 4, nr e08422Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate.

  • 28.
    Singleton, D. C.
    et al.
    University of Oxford, England.
    Rouhi, P.
    Karolinska Institute, Sweden.
    Zois, C. E.
    University of Oxford, England.
    Haider, S.
    University of Oxford, England.
    Li, J-L
    University of Oxford, England.
    Kessler, B. M.
    University of Oxford, England.
    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.
    Harris, A. L.
    University of Oxford, England.
    Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis2015Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, nr 36, s. 4713-4722Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1 alpha (HIF1 alpha) in tumours causes transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1 alpha-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.

  • 29.
    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 Cancer2015Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, nr 16, s. 3794-3805Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    Wang, Jian
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Zhang, Xing-Mei
    Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Sun, Meili
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Hartman, Johan
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Harris, Robert A.
    Karolinska Institute, Sweden.
    Sun, Yuping
    Shandong University, Peoples R China.
    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.
    Novel Mechanism of Macrophage-Mediated Metastasis Revealed in a Zebrafish Model of Tumor Development2015Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 2, s. 306-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNF alpha promoted the ability of macrophages to mediate this step. M2 macro-phages were particularly potent when induced by IL4, IL10, and TGF beta. In contrast, IFN gamma-lipopolysaccharide-induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications.

  • 31.
    Xue, Yuan
    et al.
    Karolinska Institute.
    Lim, Sharon
    Karolinska Institute.
    Yang, Yunlong
    Karolinska Institute.
    Wang, Zongwei
    Karolinska Institute.
    Dahl Ejby Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet.
    Hedlund, Eva-Maria
    Karolinska Institute.
    Andersson, Patrik
    Karolinska Institute.
    Sasahara, Masakiyo
    Toyama University.
    Larsson, Ola
    Karolinska Institute.
    Galter, Dagmar
    Karolinska Institute.
    Gao, Renhai
    Karolinska Institute.
    Hosaka, Kayoko
    Karolinska Institute.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells2012Ingår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 18, nr 1, s. 100-110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-beta (PDGFR-beta). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB PDGFR-beta signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.

  • 32.
    Yang, Xiaojuan
    et al.
    Karolinska Institute, Sweden; Tongji University, Peoples R China.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden.
    Tholander, Fredrik
    Karolinska Institute, Sweden.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Morikawa, Hiromasa
    Karolinska Institute, Sweden.
    Tegner, Jesper
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Lim, Sharon
    Karolinska Institute, 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.
    VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 22, s. E2900-E2909Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

  • 33.
    Yang, Yunlong
    et al.
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Cao, Renhai
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Yang, Xiaojuan
    Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden.
    Zhuang, Rujie
    TCM Hospital Zhejiang Prov, Peoples R China.
    Morikawa, Hiromasa
    Karolinska Institute, Sweden.
    Xue, Yuan
    Karolinska Institute, Sweden; MIT, MA 02139 USA.
    Braun, Harald
    University of Ghent, Belgium; Inflammat Research Centre VIB, Belgium.
    Beyaert, Rudi
    University of Ghent, Belgium; Inflammat Research Centre VIB, Belgium.
    Samani, Nilesh
    University of Leicester, England; Glenfield Hospital, England.
    Nakae, Susumu
    University of Tokyo, Japan.
    Hams, Emily
    University of Dublin Trinity Coll, Ireland.
    Dissing, Steen
    University of Copenhagen, Denmark.
    Fallon, Padraic G.
    University of Dublin Trinity Coll, Ireland.
    Langer, Robert
    Karolinska Inst, Stockholm, Sweden, Univ Leicester, Leicester, England, Glenfield Hosp, Leicester, England.
    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.
    The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, nr 11385Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

  • 34.
    Yang, Yunlong
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Karolinska Institute, Stockholm, Sweden.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Ji, Hong
    Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Karolinska Institute, Stockholm, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Länne, Toste
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Sun, Baocun
    Tianjin Medical University, China.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Stockholm, Sweden.
    Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 29, s. 12018-12023Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

  • 35.
    Zhang, Fan
    et al.
    NEI, MD USA .
    Li, Yang
    NEI, MD USA .
    Tang, Zhongshu
    NEI, MD USA .
    Kumar, Anil
    NEI, MD USA .
    Lee, Chunsik
    NEI, MD USA .
    Zhang, Liping
    National Institute Dent and Craniofacial Research, MD 20892 USA .
    Zhu, Chaoyong
    NanTong University, Peoples R China .
    Klotzsche-von Ameln, Anne
    University of Dresden, Germany .
    Wang, Bin
    Binzhou Medical University, Peoples R China .
    Gao, Zhiqin
    Weifang Medical University, Peoples R China .
    Zhang, Shizhuang
    Weifang Medical University, Peoples R China .
    Langer, Harald F.
    University of Tubingen, Germany .
    Hou, Xu
    Fourth Mil Medical University, Peoples R China .
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet.
    Ma, Wenxin
    NEI, MD 20852 USA .
    Wong, Wai
    NEI, MD 20852 USA .
    Chavakis, Triantafyllos
    University of Dresden, Germany .
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China .
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet.
    Li, Xuri
    NEI, MD 20852 USA .
    Proliferative and Survival Effects of PUMA Promote Angiogenesis2012Ingår i: CELL REPORTS, ISSN 2211-1247, Vol. 2, nr 5, s. 1272-1285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The p53 upregulated modulator of apoptosis (PUMA) is known as an essential apoptosis inducer. Here, we report the seemingly paradoxical finding that PUMA is a proangiogenic factor critically required for the proliferation and survival of vascular and microglia cells. Strikingly, Puma deficiency by genetic deletion or small hairpin RNA knockdown inhibited developmental and pathological angiogenesis and reduced microglia numbers in vivo, whereas Puma gene delivery increased angiogenesis and cell survival. Mechanistically, we revealed that PUMA plays a critical role in regulating autophagy by modulating Erk activation and intracellular calcium level. Our findings revealed an unexpected function of PUMA in promoting angiogenesis and warrant more careful investigations into the therapeutic potential of PUMA in treating cancer and degenerative diseases.

  • 36.
    Zhang, Yin
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China; Shandong University, Peoples R China.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Huang, Guichun
    Karolinska Institute, Sweden.
    Zang, Jingwu
    BioSciKin Biopharma, Peoples R China.
    Chen, Fang
    Zhejiang Chinese Medical University, Peoples R China.
    Zhang, Yun
    Karolinska Institute, Sweden; Shandong University, Peoples R China; Shandong University, Peoples R China.
    Samani, Nilesh J.
    University of Leicester, England; Glenfield Gen Hospital, England.
    Cao, Yihai
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Gen Hospital, England; Second Hospital Wuxi, Peoples R China.
    Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 15, s. 4158-4163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Anti-VEGF-based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects.

  • 37.
    Zhao, Chunyan
    et al.
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Qiao, Yichun
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Jonsson, Philip
    University of Houston, Texas, USA.
    Wang, Jian
    Karolinska Institute, Stockholm, Sweden .
    Xu, Li
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Rouhi, Pegah
    Karolinska Institute, Stockholm, Sweden .
    Sinha, Indranil
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Stockholm, Sweden; University of Leicester, Glenfield Hospital, Leicester, UK.
    Williams, Cecilia
    University of Houston, TX, USA .
    Dahlman-Wright, Karin
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer2014Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 14, s. 3983-3994Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.

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