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      The Role of the Tumor Stroma in Ovarian Cancer

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          Abstract

          The tumor microenvironment, consisting of stromal myofibroblasts, endothelial cells, and leukocytes, is growingly perceived to be a major contributor to the pathogenesis and disease progression in practically all cancer types. Stromal myofibroblasts produce angiogenic factors, proteases, growth factors, immune response-modulating proteins, anti-apoptotic proteins, and signaling molecules, and express surface receptors and respond to stimuli initiated in the tumor cells to establish a bi-directional communication network in the microenvironment to promote tumor cell invasion and metastasis. Many of these molecules are candidates for targeted therapy and the cancer stroma has been recently regarded as target for biological intervention. This review provides an overview of the biology and clinical role of the stroma in ovarian cancer.

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          Most cited references123

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          The Hox genes and their roles in oncogenesis.

          Hox genes, a highly conserved subgroup of the homeobox superfamily, have crucial roles in development, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrations in Hox gene expression have been reported in abnormal development and malignancy, indicating that altered expression of Hox genes could be important for both oncogenesis and tumour suppression, depending on context. Therefore, Hox gene expression could be important in diagnosis and therapy.
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            Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue.

            Neoplastic cells recruit fibroblasts through various growth factors and cytokines. These "cancer-associated fibroblasts" (CAF) actively interact with neoplastic cells and form a myofibroblastic microenvironment that promotes cancer growth and survival and supports malignancy. Several products of their paracrine signaling repertoire have been recognized as tumor growth and metastasis regulators. However, tumor-promoting cell signaling is not the only reason that makes CAFs key components of the "tumor microenvironment," as CAFs affect both the architecture and growth mechanics of the developing tumor. CAFs participate in the remodeling of peritumoral stroma, which is a prerequisite of neoplastic cell invasion, expansion, and metastasis. CAFs are not present peritumorally as individual cells but they act orchestrated to fully deploy a desmoplastic program, characterized by "syncytial" (or collective) configuration and altered cell adhesion properties. Such myofibroblastic cohorts are reminiscent of those encountered in wound-healing processes. The view of "cancer as a wound that does not heal" led to useful comparisons between wound healing and tumorigenesis and expanded our knowledge of the role of CAF cohorts in cancer. In this integrative model of cancer invasion and metastasis, we propose that the CAF-supported microenvironment has a dual tumor-promoting role. Not only does it provide essential signals for cancer cell dedifferentiation, proliferation, and survival but it also facilitates cancer cell local invasion and metastatic phenomena.
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              TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment.

              TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-κB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β-targeted therapy of ovarian cancer.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                28 March 2014
                13 May 2014
                2014
                : 4
                : 104
                Affiliations
                [1] 1Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital , Oslo, Norway
                [2] 2University of Oslo, Faculty of Medicine, Institute of Clinical Medicine , Oslo, Norway
                [3] 3Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital , Oslo, Norway
                [4] 4Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem, Israel
                Author notes

                Edited by: Nicolas Wentzensen, National Cancer Institute, USA

                Reviewed by: Ie-Ming Shih, Johns Hopkins Medical Institutions, USA; Elise Kohn, National Cancer Institute, USA

                *Correspondence: Ben Davidson, Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Montebello, Oslo N-0424, Norway e-mail: bend@ 123456medisin.uio.no

                This article was submitted to Women’s Cancer, a section of the journal Frontiers in Oncology.

                Article
                10.3389/fonc.2014.00104
                4026708
                24860785
                d33f8038-1a63-49b7-938b-9864d8e25f82
                Copyright © 2014 Davidson, Trope and Reich.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 03 February 2014
                : 27 April 2014
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 135, Pages: 11, Words: 10148
                Categories
                Oncology
                Review Article

                Oncology & Radiotherapy
                ovarian carcinoma,stromal myofibroblasts,metastasis,tumor progression,prognosis

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