Microenvironment remodeled by tumor and stromal cells elevates fibroblast-derived COL1A1 and facilitates ovarian cancer metastasis.

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. Here, we performed a quantitative proteomics of ascites, and found that collagen type I alpha 1 (COL1A1) was notably elevated in ascites from epithelial ovarian cancer patients compared to normal peritoneal fluids, and verified that elevated COL1A1 was mainly originated from fibroblasts. COL1A1 promoted migration and invasion of ovarian cancer cells, but such effects were partially eliminated by COL1A1 antibodies. Intraperitoneally injected COL1A1 accelerated intraperitoneal metastasis of ovarian cancer xenograft in NOD/SCID mice. Further, COL1A1 activated downstream AKT phosphorylation by binding to membrane surface receptor integrin β1 (ITGB1). Knockdown or blockage of ITGB1 reversed COL1A1 enhanced migration and invasion in ovarian cancer cells. Conversely, ovarian cancer ascites and fibrinogen promoted fibroblasts to secrete COL1A1. Elevated fibrinogen in ascites might be associated with increased vascular permeability induced by ovarian cancer. Our findings suggest that microenvironment remodeled by tumor cells and stromal cells promotes fibroblasts to secrete COL1A1 and facilitates the metastasis of ovarian cancer, which may provide a new approach for ovarian cancer therapeutics.