Breast Cancer Cells Induce Cancer-Associated Fibroblasts to Secrete Hepatocyte Growth Factor to Enhance Breast Tumorigenesis

Abstract

It has been well documented that microenvironment consisting of stroma affects breast cancer progression. However, the mechanisms by which cancer cells and fibroblasts, the major cell type in stroma, interact with each other during tumor development remains to be elucidated. Here, we show that the human cancer-associated fibroblasts (CAFs) had higher activity in enhancing breast tumorigenecity compared to the normal tissue-associated fibroblasts (NAFs) isolated from the same patients. The expression level of hepatocyte growth factor (HGF) in these fibroblasts was positively correlated with their ability to enhance breast tumorigenesis in mice. Deprivation of HGF using a neutralizing antibody reduced CAF-mediated colony formation of human breast cancer cells, indicating that CAFs enhanced cancer cell colony formation mainly through HGF secretion. Co-culture with human breast cancer MDA-MB-468 cells in a transwell system enhanced NAFs to secret HGF as well as promote tumorigenecity. The newly gained ability of these “educated” NAFs became irreversible after continuing this process till fourth passage. These results suggested that breast cancer cells could alter the nature of its surrounding fibroblasts to secrete HGF to support its own progression through paracrine signaling.

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…The H. pylori strain (cagA+vacA+) enhanced mRNA expression for TNC, collagen I and III possibly due to activation of STAT3, NFκB, and HIF‐1α pathways. Moreover, the increased expression of HGF and TGFβ both considered as the essential promigrative growth factors secreted by CAFs35, 40, 72 has been observed in our H. pylori (cagA+vacA+)‐infected fibroblasts. These results indicate that the H. pylori ‐derived cytotoxic antigens cagA and vacA may be essential for fibroblast differentiation and myofibroblast formation and might act as prerequisite for progression of normal fibroblasts into CAFs.…”

“…The CAFs secrete proangiogenic factors, such as IL‐8, SDF‐1, vascular endothelial factor (VEGF), and fibroblast growth factor (FGF), into an environment of other stromal cells including endothelial cells to promote tumor angiogenesis 30, 35, 38, 39. CAFs may enhance invasion of the cancer cells through expression of TGF β, potent EMT inducer, and HGF, which has been shown to promote breast tumorigenesis 39, 40. Since fibroblasts may alter the mRNA expression of structural and cell cycle‐associated genes in the presence of H. pylori ,9, 41 we have attempted to determine whether H. pylori can interact with fibroblasts by changing them not only into myofibroblasts, but also into CAFs, further being capable of inducing EMT program in normal RGM‐1 epithelial cell line.…”

Expression of growth-regulated oncogene-1, hepatocyte growth factor, platelet-derived growth factor-AA and soluble E-selectin and their association with high-risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix

“…Overall, detecting the serum levels of GRO-1 in CSCC patients may be useful for predicting the state of tumor load and the progression of the disease. Several studies have indicated that the expression of HGF mainly secreted by stromal cells is elevated in various types of carcinoma (20,21), including cervical cancer (22). Certain studies have demonstrated that overexpression of HGF is associated with the progression and metastasis of hepatocellular carcinoma (20).…”

Sunitinib mesylate inhibits proliferation of human colonic stromal fibroblasts in vitro and in vivo

“…Cancer progression is increasingly recognized as being dependent not only on the cancer cells themselves, but also on stromal fibroblasts in cancer microenvironments (Mueller et al, 2007b;Cui et al, 2010;Henriksson et al, 2011;Tyan et al, 2011;Zhang et al, 2011). Stromal fibroblasts modulate tumorigenic activities of cancer cells, such as proliferation, apoptosis, and angiogenesis (Tomasek et al, 2002;Kalluri, 2003;Micke and Ostman, 2005).…”