腹水微环境中成纤维细胞分泌的COL1A1促进卵巢癌转移的机制研究

腹腔转移是卵巢癌高致死率的主要原因之一。腹水在卵巢癌转移中起着重要作用，但其机制尚不明了。课题组前期对上皮性卵巢癌患者腹水和正常腹腔液的定量蛋白质组学研究发现癌腹水中的COL1A1显著升高。进一步研究发现升高的COL1A1主要来源于成纤维细胞；COL1A1可能通过激活ITGB1/AKT信号通路促进卵巢癌细胞的迁移侵袭。本项目拟通过对外源COL1A1蛋白以及ITGB1受体进行调控，首先体外实验证实成纤维细胞分泌的COL1A1激活ITGB1/AKT信号通路，促进卵巢癌细胞的迁移、侵袭和EMT的发生；其次证实卵巢癌细胞反向调控成纤维细胞，促进 COL1A1的分泌及癌相关成纤维细胞的转化；最后动物实验进一步确定COL1A1可促进卵巢癌原位移植瘤腹腔转移，而沉默ITGB1可抑制移植瘤的播散。旨在揭示成纤维细胞和卵巢癌细胞相互作用重塑肿瘤微环境促卵巢癌转移的机理，为探索卵巢癌治疗的新途径提供科学依据。

Wide peritoneal metastasis is the cause of the highest lethality of ovarian cancer in gynecologic malignancies. Ascites play a key role in ovarian cancer metastasis, but involved mechanism is uncertain. Preliminarily, we performed a quantitative proteomics analysis of ascites from epithelial ovarian cancer patients and normal peritoneal fluids, and found that collagen type I alpha 1 (COL1A1) was notably elevated in ascites from epithelial ovarian cancer patients, and further study found that this increasing COL1A1 level mainly originated from fibroblasts. COL1A1 may promote the migration and invasion of ovarian cancer cells by activating ITGB1/AKT signaling pathway. In this study, by regulating the exogenous COL1A1 protein and its receptor level, we will confirm that COL1A1 secreted by fibroblasts activates ITGB1/AKT signaling pathway, and promotes the migration, invasion and EMT of ovarian cancer cells; ovarian cancer cells reversely regulate fibroblasts, promoting the secretion of COL1A1 and the transformation of cancer-related fibroblasts. Furthermore, we plan to verify whether COL1A1 promotes peritoneal metastasis of ovarian cancer xenografts, but silencing ITGB1 inhibits intraperitoneal dissemination of xenografts in vivo, by a mouse model of transplanted tumor. The aim is to reveal the mechanism of the interaction between fibroblasts and ovarian cancer cells to reshape the tumor microenvironment and promote ovarian cancer metastasis, and to provide scientific evidence for exploring new approaches for ovarian cancer therapy.