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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives

“…Mechanistically, CAFs facilitated liver metastasis by supporting CRC cells’ adhesion and promoting CRC cell stemness and drug resistance. CAFs secreted hepatocyte growth factor (HGF) to induce CD44 expression on CRC cells via HGF/MET/AKT signaling, which promoted adhesion and migration of CRC cells [ 50 ]. Moreover, TGFβ1 induced adhesion of CRC cells to CAFs, and co-migration of CAFs and CRC cells remarkably enhanced liver metastasis [ 51 ].…”

Pre-metastatic niche drives breast cancer invasion by modulating MSC homing and CAF differentiation

“…Our results of increased adhesion and shear resistance of SMF 2 spheroids are consistent with this study. The prominent expression of CD44 observed in CTC clusters may not only contribute to maintaining cohesion of CTC clusters, but also mediate endothelial adhesion [72]. In addition to CD44, endothelial adhesion may also be mediated by β 1/β 3 integrins via binding to the fibronectin on the surface of endothelial cells [73, 74].…”

A 3D View of Colorectal Cancer Models in Predicting Therapeutic Responses and Resistance

“…Mesenchymal cells are an important cellular component in the TME and can be recruited as resident MSCs and bone marrow MSCs [ 55 , 58 , 59 , 60 , 61 ]. They include multiple cell types including MSCs, fibroblasts, smooth muscle cells, and pericytes which each have diverse subtypes expressing a variety of different cell markers [ 53 , 59 , 60 ].…”