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      Angiogenesis-Related Pathways in the Pathogenesis of Ovarian Cancer

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          Abstract

          Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis in ovarian cancer, among other tumor types, as it leads to new blood vessel formation. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Growth factors have been identified to play key roles in driving angiogenesis and, thus, the formation of new blood vessels that assist in “feeding” cancer. Such molecules include the vascular endothelial growth factor (VEGF), the platelet derived growth factor (PDGF), the fibroblast growth factor (FGF), and the angiopoietin/Tie2 receptor complex. These proteins are key players in complex molecular pathways within the tumor cell and they have been in the spotlight of the development of anti-angiogenic molecules that may act as stand-alone therapeutics, or in concert with standard treatment regimes such as chemotherapy. The pathways involved in angiogenesis and molecules that have been developed in order to combat angiogenesis are described in this paper.

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          Most cited references143

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          Cancer. p53, guardian of the genome.

          D P Lane (1992)
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            Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.

            New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.
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              Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.

              Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible "metastatic conditioning" in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                1422-0067
                August 2013
                30 July 2013
                : 14
                : 8
                : 15885-15909
                Affiliations
                Department of Clinical Therapeutics, Medical School, University of Athens, Alexandra Hospital, 80 Vas. Sofias Avenue, Athens 115 28, Greece; E-Mails: ngavalas@ 123456med.uoa.gr (N.G.G.); mliontos@ 123456gmail.com (L.M.); sp.voula@ 123456yahoo.com (S.-P.T.); tbagratuni@ 123456hotmail.co.uk (T.B.); karapini@ 123456gmail.com (C.A.); liakou@ 123456med.uoa.gr (C.L.); mdimop@ 123456med.uoa.gr (M.A.G.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: abamias@ 123456med.uoa.gr ; Tel.: +30-210-3381-580; Fax: +30-210-3381-511.
                Article
                ijms-14-15885
                10.3390/ijms140815885
                3759892
                23903048
                eee62348-0ddc-4b82-9757-87ec65ee2765
                © 2013 by the authors; licensee MDPI, Basel, Switzerland

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 20 May 2013
                : 13 June 2013
                : 27 June 2013
                Categories
                Review

                Molecular biology
                ovarian,cancer,angiogenesis,pathway,vegf,pdgf,fgf,ang,tie2
                Molecular biology
                ovarian, cancer, angiogenesis, pathway, vegf, pdgf, fgf, ang, tie2

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