Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer
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Kim Moran-Jones1,2, Brian S. Gloss1,2, Rajmohan Murali3, David K. Chang1, Emily K. Colvin4, Marc D. Jones1, Samuel Yuen4, Viive M. Howell4, Laura M. Brown1, Carol W. Wong5, Suzanne M. Spong5, Christopher J. Scarlett1,6, Neville F. Hacker7, Sue Ghosh8, Samuel C. Mok9, Michael J. Birrer10, Goli Samimi1,2
1Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia
2St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
3Department of Pathology and The Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
4Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
5FibroGen Inc., San Francisco, CA, USA
6School of Environmental & Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
7School of Women's and Children's Health, University of New South Wales, and Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, NSW, Australia
8Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
9Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
10Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA, USA
Goli Samimi, e-mail: firstname.lastname@example.org
Michael J. Birrer, e-mail: email@example.com
Keywords: CTGF, FG-3019, metastasis, ovarian cancer, tumor microenvironment
Received: July 08, 2015 Accepted: October 31, 2015 Published: November 11, 2015
Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.
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