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Jensen, Lasse D
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Publications (10 of 34) Show all publications
Vazquez Rodriguez, G., Abrahamsson, A., Jensen, L. D. & Dabrosin, C. (2018). Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8. Frontiers in Immunology, 9, 1-17, Article ID 1767.
Open this publication in new window or tab >>Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8
2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, p. 1-17, article id 1767Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
breast cancer, microdialysis, zebrafish, angiogenesis, inflammation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-150059 (URN)10.3389/fimmu.2018.01767 (DOI)000440193400002 ()
Funder
Swedish Cancer Society, 2015/309Swedish Research Council, 2013-2457
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-30
Gnosa, S., Capodanno, A., Dahl Ejby Jensen, L. & Sun, X.-F. (2016). AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model. OncoTarget, 7(49), 81634-81644
Open this publication in new window or tab >>AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 81634-81644Article in journal (Refereed) Published
Abstract [en]

Background Radiotherapy is a well-established anti-cancer treatment. Although radiotherapy has been shown to significantly decrease the local relapse in rectal cancer patients, the rate of distant metastasis is still very high. Several studies have shown that radiation enhances migration and invasion both in vitro and in vivo. The aim of this study was to evaluate whether AEG-1 is involved in radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model.

Materials and Methods We evaluated the involvement of AEG-1 in migration and invasion and radiation-enhanced migration and invasion by Boyden chamber assay in three colon cancer cell lines and respective AEG-1 knockdown cell lines. Furthermore, we injected the cells in zebrafish embryos and evaluated the amount of disseminated cells into the tail.

Results Migration and invasion was decreased in all the AEG-1 knockdown cell lines. Furthermore, radiation enhanced migration and invasion, while AEG-1 knockdown could abolish this effect. The results from the zebrafish model confirmed the results obtained in vitro. MMP-9 secretion and expression were decreased in AEG-1 knockdown cells.

Conclusion Our results demonstrate that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced migration and invasion. We speculate that this is done via the downregulation of the intrinsic or radiation-enhanced MMP-9 expression. The zebrafish model can be used to study early events in radiation-enhanced invasion.

Place, publisher, year, edition, pages
Impact Journals, 2016
Keywords
AEG-1, MTDH, LYRIC, Colon cancer, Zebrafish, Transwell migration and invasion, Radiation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-121866 (URN)10.18632/oncotarget.13155 (DOI)000389877500121 ()27835571 (PubMedID)
Note

The previous status of this publication was manuscript

Funding agencies: Swedish Cancer Foundation; Swedish Research Council; Health Research Council in South-East Sweden; Onkologiska klinikernas i Linkoping

Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
Folkesson, M., Sadowska, N., Vikingsson, S., Karlsson, M., Carlhäll, C.-J., Länne, T., . . . Jensen, L. (2016). Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models. Biology Open, 5(7), 970-978
Open this publication in new window or tab >>Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models
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2016 (English)In: Biology Open, ISSN 2046-6390, Vol. 5, no 7, p. 970-978Article in journal (Refereed) Published
Abstract [en]

Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

Place, publisher, year, edition, pages
Company of Biologists, 2016
Keywords
Aneurysm; Aorta; Cardiovascular; Snuff; Tobacco; Zebrafish
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-130706 (URN)10.1242/bio.018812 (DOI)000380569100010 ()27334697 (PubMedID)
Note

The Jensen laboratory is supported by grants from Svenska Sallskapet for Medicinsk Forskning [grant F14-0021], Linkopings Universitet, Eva och Oscar Ahrens Stiftelse, Ollie och Elof Ericssons Stiftelse, Carmen och Bertil Ragners Stiftelse, Gosta Fraenkels Stiftelse, Ake Wibergs Stiftelse, Lions Forskningsfond, Karin Sandbergs Stiftelse, Cancerfonden, Karolinska Institutet's Stiftelser och Fonder and Vetenskapsradet [grant 2015-06271].

Available from: 2016-08-21 Created: 2016-08-21 Last updated: 2018-03-19
Jensen, L. (2016). Editorial Material: A circadian prelude to regulation of angiogenesis and thrombosis by prolactin and plasminogen activator inhibitor-1 in TRANSLATIONAL CANCER RESEARCH, vol 5, issue 1, pp 79-82. TRANSLATIONAL CANCER RESEARCH, 5(1), 79-82
Open this publication in new window or tab >>Editorial Material: A circadian prelude to regulation of angiogenesis and thrombosis by prolactin and plasminogen activator inhibitor-1 in TRANSLATIONAL CANCER RESEARCH, vol 5, issue 1, pp 79-82
2016 (English)In: TRANSLATIONAL CANCER RESEARCH, ISSN 2218-676X, Vol. 5, no 1, p. 79-82Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
AME PUBL CO, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-126851 (URN)10.3978/j.issn.2218-676X.2016.01.06 (DOI)000370966500015 ()
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2016-04-05
Savio, M., Ferraro, D., Maccario, C., Vaccarone, R., Jensen, L., Corana, F., . . . Anna Stivala, L. (2016). Resveratrol analogue 4,4 -dihydroxy-trans-stilbene potently inhibits cancer invasion and metastasis. Scientific Reports, 6(19973)
Open this publication in new window or tab >>Resveratrol analogue 4,4 -dihydroxy-trans-stilbene potently inhibits cancer invasion and metastasis
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 19973Article in journal (Refereed) Published
Abstract [en]

We investigated the preventive effects of resveratrol analogue 4,4-dihydroxy-trans-stilbene (DHS) on cancer invasion and metastasis. Two different in vivo approaches of mouse and zebrafish lung cancer invasion models were employed in our study. The in vitro results showed that DHS displays potent inhibition on anchorage-dependent or -independent cell growth of LLC cells, leading to impairment of the cell cycle progression with reduction of cell numbers arresting at the G1 phase, an evident accumulation of pre-G1 events correlated with apoptotic behaviour. In addition, DHS induces a marked inhibition of LLC cell migration and matrigel invasion. In a murine lung cancer model, tumour volume, cell proliferation, and tumour angiogenesis were significantly inhibited by DHS. Importantly, liver metastatic lesions were significantly reduced in DHS-treated mice. Similarly, DHS significantly inhibits lung cancer cell dissemination, invasion and metastasis in a zebrafish tumour model. These findings demonstrate that DHS could potentially be developed as a novel therapeutic agent for treatment of cancer and metastasis.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125145 (URN)10.1038/srep19973 (DOI)000368988600001 ()26829331 (PubMedID)
Note

Funding Agencies|Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale [PRIN 2008PK2WCW_002]

Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2017-11-30
Ochoa-Alvarez, J. A., Krishnan, H., Pastorino, J. G., Nevel, E., Kephart, D., Lee, J. J., . . . Goldberg, G. S. (2015). Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms. OncoTarget, 6(11), 9045-9060
Open this publication in new window or tab >>Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 11, p. 9045-9060Article in journal (Refereed) Published
Abstract [en]

Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2015
Keywords
podoplanin; cancer; cell migration; receptor; lectin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-120753 (URN)000358774600044 ()25826087 (PubMedID)
Note

Funding Agencies|Osteopathic Heritage Foundation; Northarvest Bean Growers Association; New Jersey Health Foundation; Sentrimed; Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Regional Innovation Strategy Support Program from MEXT of Japan; MEXT of Japan

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2018-01-11
Hu, Z., Brooks, S. A., Dormoy, V., Hsu, C.-W., Hsu, H.-Y., Lin, L.-T., . . . Kleinstreuer, N. (2015). Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis. Carcinogenesis, 36, S184-S202
Open this publication in new window or tab >>Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis
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2015 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, p. S184-S202Article, review/survey (Refereed) Published
Abstract [en]

Angiogenesis is an important hallmark of cancer. We reviewed the various pathways controlling angiogenesis, summarized the possible role of specific environmental chemicals disrupting these pathways and listed assays for assessing the effects of low-dose exposures to chemicals in promoting tumor angiogenesis.One of the important hallmarks of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy B - Oxford Open Option B, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120285 (URN)10.1093/carcin/bgv036 (DOI)000357048100010 ()26106137 (PubMedID)
Note

Funding Agencies|Ohio State University College of Medicine; The OSU James Comprehensive Cancer Center (OSUCCC); OSUCCC Translational Therapeutics Program; Ministry of Science and Technology of Taiwan [NSC93-2314-B-320-006, NSC94-2314-B-320-002]; Taipei Medical University [TMU101-AE3-Y19]; INSERM; University of Strasbourg, France; Fondazione Cariplo [2011-0370]; Kuwait Institute for the Advancement of Sciences [2011-1302-06]; Grant University Scheme (RUGS) Ministry Of Education Malaysia [04-02-12-2099RU]; Italian Ministry of University and Research [2009FZZ4XM_002]; University of Florence; US Public Health Service [RO1 CA92306, RO1 CA92306-51, RO1 CA113447]; Department of Science and Technology, Government of India [SR/FT/LS-063/2008]; NIEHS [N01-ES 35504, HHSN27320140003C]

Available from: 2015-07-24 Created: 2015-07-24 Last updated: 2017-12-04
Wang, Z., Dabrosin, C., Yin, X., Fuster, M. M., Arreola, A., Rathmell, W. K., . . . Jensen, L. D. (2015). Broad targeting of angiogenesis for cancer prevention and therapy. Seminars in Cancer Biology, S1044-579X(15), 00002-00004
Open this publication in new window or tab >>Broad targeting of angiogenesis for cancer prevention and therapy
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2015 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. S1044-579X, no 15, p. 00002-00004Article, review/survey (Refereed) Published
Abstract [en]

Deregulation of angiogenesis - the growth of new blood vessels from an existing vasculature - is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Angiogenesis Cancer Phytochemicals Treatment Anti-angiogenic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-115783 (URN)10.1016/j.semcancer.2015.01.001 (DOI)000366619400011 ()25600295 (PubMedID)
Note

Funding agencies: Swedish Society for Medical Research; Goesta Fraenkel Foundation; Ake Wibergs Foundation; Ollie och Elof Ericssons Foundation; Karolinska Institute; Linkoping University; University of Glasgow; Beatson Oncology Center Fund; Cancer Research UK grant

Available from: 2015-03-19 Created: 2015-03-19 Last updated: 2018-04-23
Svensson, S., Abrahamsson, A., Vazquez Rodriguez, G., Olsson, A.-K., Jensen, L., Cao, Y. & Dabrosin, C. (2015). CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer. Clinical Cancer Research, 21(16), 3794-3805
Open this publication in new window or tab >>CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
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2015 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 16, p. 3794-3805Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-122122 (URN)10.1158/1078-0432.CCR-15-0204 (DOI)000361909100027 ()25901081 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2009/799]; Swedish Research Council [2010-3458]; LiU-Cancer; Linkoping University Hospital

Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2018-08-08
Block, K. I., Gyllenhaal, C., Lowe, L., Amedei, A., Ruhul Amin, A. R., Amin, A., . . . Zollo, M. (2015). Designing a broad-spectrum integrative approach for cancer prevention and treatment. Seminars in Cancer Biology, 35, S276-S304
Open this publication in new window or tab >>Designing a broad-spectrum integrative approach for cancer prevention and treatment
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2015 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 35, p. S276-S304Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
Academic Press, 2015
Keywords
Multi-targeted; Cancer hallmarks; Phytochemicals; Targeted therapy; Integrative medicine
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-123767 (URN)10.1016/j.semcancer.2015.09.007 (DOI)000366619400013 ()26590477 (PubMedID)
Note

Funding Agencies|Terry Fox Foundation Grant [TF-13-20]; UAEU Program for Advanced Research (UPAR) [31S118]; NIH [AR47901, R21CA188818, R15 CA137499-01, F32CA177139, P20RR016477, P20GM103434, R01CA170378, U54CA149145, U54CA143907, R01-HL107652, R01CA166348, R01GM071725, R01 CA109335-04A1, 109511R01CA151304CA168997 A11106131R03CA1711326 1P01AT003961RO1 CA100816P01AG034906 R01AG020642P01AG034906-01A1R01HL108006]; NIH NRSA Grant [F31CA154080]; NIH (NIAID) R01: Combination therapies for chronic HBV, liver disease, and cancer [AI076535]; Sky Foundation Inc. Michigan; University of Glasgow; Beatson Oncology Centre Fund; Spanish Ministry of Economy and Competitivity, ISCIII [PI12/00137, RTICC: RD12/0036/0028]; FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion [CTS-6844, CTS-1848]; Consejeria de Salud of the Junta de Andalucia [PI-0135-2010, PI-0306-2012]; ISCIII [PIE13/0004]; FEDER funds; United Soybean Board; NIH NCCAM Grant [K01AT007324]; NIH NCI Grant [R33 CA161873-02]; Michael Cuccione Childhood Cancer Foundation Graduate Studentship; Ovarian and Prostate Cancer Research Trust, UK; West Virginia Higher Education Policy Commission/Division of Science Research; National Institutes of Health; Italian Association for Cancer Research (AIRC) [IG10636, 15403]; GRACE Charity, UK; Breast Cancer Campaign, UK; Michael Cuccione Childhood Cancer Foundation Postdoctoral Fellowship; Connecticut State University; Swedish Research Council; Swedish Research Society; University of Texas Health Science Centre at Tyler, Elsa U. Pardee Foundation; CPRIT; Cancer Prevention and Research Institute of Texas; NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA); Gilead and Shire Pharmaceuticals; NIH/NCI [1R01CA20009, 5R01CAl27258-05, R21CA184788, NIH P30 CA22453, NCI RO1 28704]; Scottish Governments Rural and Environment Science and Analytical Services Division; National Research Foundation; United Arab Emirates University; Terry Fox Foundation; Novartis Pharmaceutical; Aveo Pharmaceutical; Roche; Bristol Myers Squibb; Bayer Pharmaceutical; Pfizer; Kyowa Kirin; NIH/NIAID Grant [A1076535]; Auckland Cancer Society; Cancer Society of New Zealand; NIH Public Service Grant from the National Cancer Institute [CA164095]; Medical Research Council CCU-Program Grant on cancer metabolism; EU Marie Curie Reintegration Grant [MC-CIG-303514]; Greek National funds through the Operational Program Educational and Lifelong Learning of the National Strategic Reference Framework (NSRF)-Research Funding Program THALES [MIS 379346]; COST Action CM1201 `Biomimetic Radical Chemistry; Duke University Molecular Cancer Biology T32 Training Grant; National Sciences Engineering and Research Council Undergraduate Student Research Award in Canada; Charles University in Prague projects [UNCE 204015, PRVOUK P31/2012]; Czech Science Foundation projects [15-03834Y, P301/12/1686]; Czech Health Research Council AZV project [15-32432A]; Internal Grant Agency of the Ministry of Health of the Czech Republic project [NT13663-3/2012]; National Institute of Aging [P30AG028716-01]; NIH/NCI training grants to Duke University [T32-CA059365-19, 5T32-CA059365]; Ministry of Education, Culture, Sports, Science and Technology, Japan [24590493]; Ministry of Health and Welfare [CCMP101-RD-031, CCMP102-RD-112]; Tzu-Chi University of Taiwan [61040055-10]; Svenska Sallskapet for Medicinsk Forskning; Cancer Research Wales; Albert Hung Foundation; Fong Family Foundation; Welsh Government A4B scheme; NIH NCI; University of Glasgow, Beatson Oncology Centre Fund, CRUK [C301/A14762]; NIH Intramural Research Program; National Science Foundation; American Cancer Society; National Cancer Center [NCC-1310430-2]; National Research Foundation [NRF-2005-0093837]; Sol Goldman Pancreatic Cancer Research Fund Grant [80028595]; Lustgarten Fund Grant [90049125, NIHR21CA169757]; Alma Toorock Memorial for Cancer Research; National Research Foundation of Korea (NRF); Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea [2011-0017639, 2011-0030001]; Ministry of Education of Taiwan [TMUTOP103005-4]; International Life Sciences Institute; United States Public Health Services Grants [NIH R01CA156776]; VA-BLR&D Merit Review Grant [5101-BX001517-02]; V Foundation; Pancreatic Cancer Action Network; Damon Runyon Cancer Research Foundation; Childrens Cancer Institute Australia; University Roma Tre; Italian Association for Cancer Research (AIRC-Grant) [IG15221]; Carlos III Health Institute; Feder funds [AM: CP10/00539, PI13/02277]; Basque Foundation for Science (IKERBASQUE); Marie Curie CIG Grant [2012/712404]; Canadian Institutes of Health Research; Avon Foundation for Women [OBC-134038]; Canadian Institutes of Health [MSH-136647, MOP 64308]; Bayer Healthcare System G4T (Grants4Targets); NIH NIDDK; NIH NIAAA; Shire Pharmaceuticals; Harvard-MIT Health Sciences and Technology Research Assistantship Award; Italian Ministry of University; University of Italy; Auckland Cancer Society Research Centre (ACSRC); German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF) [16SV5536K]; European Commission [FP7 259679 "IDEAL"]; Cinque per Mille dellIRPEF-Finanziamento della Ricerca Sanitaria; European Union Seventh Framework Programme (FP7) [278570]; AIRC [10216, 13837]; European Communitys Seventh Framework Program FP7 [311876]; Canadian Institute for Health Research [MOP114962, MOP125857]; Fonds de Recherche Quebec Sante [22624]; Terry Fox Research Institute [1030]; FEDER; MICINN [SAF2012-32810]; Junta de Castilla y Leon [BIO/SA06/13]; ARIMMORA project [FP7-ENV-2011]; European Union; NIH NIDDK [K01DK077137, R03DK089130]; NIH NCI grants [R01CA131294, R21 CA155686]; Avon Foundation; Breast Cancer Research Foundation Grant [90047965]; National Institute of Health, NINDS Grant [K08NS083732]; AACR-National Brain Tumor Society Career Development Award for Translational Brain Tumor Research [13-20-23-SIEG]; Department of Science and Technology, New Delhi, India [SR/FT/LS-063/2008]; Yorkshire Cancer Research; Wellcome Trust, UK; Italian Ministry of Economy and Finance Project CAMPUS-QUARC, within program FESR Campania Region; National Cancer Institute [5P01CA073992]; IDEA Award from the Department of Defense [W81XWH-12-1-0515]; Huntsman Cancer Foundation; University of Miami Clinical and Translational Science Institute (CTSI) Pilot Research Grant [CTSI-2013-P03]; SEEDS You Choose Awards; DoD [W81XVVH-11-1-0272, W81XWH-13-1-0182]; Kimmel Translational Science Award [SKF-13-021]; ACS Scholar award [122688-RSG-12-196-01-TBG]; National Cancer Institute, Pancreatic Cancer Action Network, Pew Charitable Trusts; American Diabetes Association; Elsa U. Pardee Foundation; Scientific Research Foundation for the Returned Oversea Scholars, State Education Ministry and Scientific and Technological Innovation Project, Harbin [2012RFLX5011]; United States National Institutes of Health [ES019458]; California Breast Cancer Research Program [17UB-8708]; National Institutes of Health through the RCMI-Center for Environmental Health [G1200MD007581]; NIH/National Heart, Lung, and Blood Institute Training Grant [T32HL098062]; European FP7-TuMIC [HEALTH-F2-2008-201662]; Italian Association for Cancer research (AIRC) Grant IG [11963]; Regione Campania L.R:N.5; European National Funds [PON01-02388/1 2007-2013]

Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2019-01-21Bibliographically approved
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