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.
Highlights
Ovarian cancer is the most common cause of death among women with gynecologic cancer, responsible for 5% of cancer-related deaths [1]
To investigate whether connective tissue growth factor (CTGF) mediates its effect on High grade serous ovarian cancers (HGSOC) cells via α5β1, we examined the effect of blocking the activity of integrin α5β1 on peritoneal adhesion of OVCAR3 and SKOV3 cells (Figure 3E). recombinant human CTGF (rhCTGF)-stimulated peritoneal adhesion was significantly hindered upon treatment with anti-integrin α5β1 antibody compared to rhCTGF-treated cells
Gery et al first demonstrated that CTGF is overexpressed in epithelial ovarian tumors, and that expression correlates with stage of disease [37], similar to our studies showing that highest stromal CTGF expression in a subset of HGSOC was associated with a poor outcome
Summary
Ovarian cancer is the most common cause of death among women with gynecologic cancer, responsible for 5% of cancer-related deaths [1]. Patients diagnosed with early stage disease have a 5-year survival rate of 80%, the majority of women are diagnosed at late stage, when the disease has already metastasized to multiple organs within the peritoneal cavity, resulting in a reduced 5-year survival rate of < 30% [2]. Recent molecular investigations, such as those performed by The Cancer Genome Atlas [3], have led to an increased understanding of the pathogenesis of ovarian cancer. The stromal components of the tumor, which are relatively genomically stable and essential for progression and metastasis [8], have been increasingly targeted by newly developed anti-cancer therapies [9]
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