Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.
Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.
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DOI：
10.18632/oncotarget.6082
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发表时间：
2015-12-29
期刊：
影响因子：
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通讯作者：
Samimi G
中科院分区：
文献类型：
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作者：
Moran-Jones K;Gloss BS;Murali R;Chang DK;Colvin EK;Jones MD;Yuen S;Howell VM;Brown LM;Wong CW;Spong SM;Scarlett CJ;Hacker NF;Ghosh S;Mok SC;Birrer MJ;Samimi G
卵巢癌是妇科癌症患者中最常见的死亡原因。我们检查了正常卵巢和高级别浆液性卵巢肿瘤成纤维细胞的分子特征，以确定参与肿瘤进展的新型治疗靶点。我们确定了2,300个在肿瘤相关成纤维细胞中显著差异表达的基因。这些基因之一，结缔组织生长因子（CTGF），成纤维细胞的表达，证实了免疫组织化学。卵巢肿瘤成纤维细胞CTGF蛋白表达与基因表达水平显著相关。CTGF是肿瘤微环境的分泌组分，并且正在被追求作为胰腺癌的治疗靶点。我们在体外和离体卵巢癌模型中检测了其作用，并检测了CTGF表达与患者临床病理特征之间的相关性。CTGF促进卵巢癌细胞的迁移和腹膜粘附。这些作用被FG-3019消除，FG-3019是一种抗CTGF的人单克隆抗体，目前正作为治疗剂进行临床研究。高级别浆液性卵巢肿瘤的免疫组化分析显示，肿瘤间质CTGF表达水平最高与预后最差相关。我们的研究发现CTGF是腹膜粘连的促进剂，可能介导转移，是高级别浆液性卵巢癌的潜在治疗靶点。这些结果保证了进一步研究FG-3019在高级别浆液性卵巢癌中的治疗疗效。
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.