Human colorectal cancer-derived carcinoma associated fibroblasts promote CD44-mediated adhesion of colorectal cancer cells to endothelial cells by secretion of HGF

摘要

Carcinoma-associated fibroblasts (CAFs) are dominant components of tumor microenvironment, which has been reported to promote development, progression, and metastasis of cancer. However, the role of CAFs during adhesion process remains unknown. It has been hypothesized that CAFs contribute to adhesion to endothelial cells of colorectal cancer (CRC) via HGF/c-Met pathway. Clinical specimen and orthotopic liver metastasis model was used to investigate association between CD44 expression and propensity of metastasis in CRC. Human CRC derived cancer associated fibroblasts was isolated and its effect on migration and adhesion of CRC cells was investigated. We also confirm the conclusion on animal metastasis model. In this study, clinical specimen and orthotopic liver metastatic model indicated that overexpression of CD44 is associated with CRC metastasis, and we found that colorectal cancer-derived CAFs (CC-CAFs) increased the adhesion and migration of CRC cells in vitro through up-regulation of CD44, we also found that CC-CAFs promoted adhesion and liver or lung metastasis in vivo. Mechanistically, we found that the expression of HGF increased tenfolds compared CC-CAFs with adjacent normal fibroblasts, and HGF promoted adhesion through up-regulation of CD44 via HGF/c-MET signal pathway. These results indicated that CC-CAFs-derived HGF induced up-regulation of CD44 which mediated adhesion of CRC cells to endothelial cells, and subsequently resulted in enhancement of metastasis of CRC cells, it could provide a novel therapeutic or preventive target.