title: Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.
abstract: 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.
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Moran-Jones
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Gloss
authors.affiliation: Department of Pathology and The Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Colvin
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jones
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
authors.forename: Samuel
authors.initials: S
authors.lastname: Yuen
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
authors.forename: Viive M
authors.initials: VM
authors.lastname: Howell
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: FibroGen Inc., San Francisco, CA, USA.
authors.forename: Carol W
authors.initials: CW
authors.lastname: Wong
authors.affiliation: FibroGen Inc., San Francisco, CA, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Spong
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.|School of Environmental & Life Sciences, University of Newcastle, Ourimbah, NSW, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scarlett
authors.affiliation: School of Women's and Children's Health, University of New South Wales, and Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, NSW, Australia.
authors.forename: Neville F
authors.initials: NF
authors.lastname: Hacker
authors.affiliation: Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sue
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.affiliation: Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst, NSW, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Goli
authors.initials: G
authors.lastname: Samimi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C526317:CCN2 protein, human; D055513:Connective Tissue Growth Factor; C560078:pamrevlumab
keywords: CTGF; FG-3019; metastasis; ovarian cancer; tumor microenvironment