The role of hepatocyte growth factor (scatter factor) in epithelial–mesenchymal transition and breast cancer

Abstract

North American women have a one in eight lifetime risk of developing breast cancer, and approximately one in three women with breast cancer will die of metastases. We, and others, have recently shown that high levels of expression of hepatocyte growth factor (HGF) and its receptor Met are associated with invasive human breast cancer and may be causally linked to metastasis. This high level of HGF and Met expression has been considered as a possible indicator of earlier recurrence and shortened survival in breast cancer patients. In contrast, HGF expression (but not Met) is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention in the treatment of breast cancer. We have recently demonstrated that sustained activation or hyper-activation of c-Src and Stat3, which occurs in invasive breast cancer, can stimulate strong expression of HGF in carcinoma cells. In contrast, transient induction of Stat3 occurs in normal epithelium and promotes mammary tubulogenesis. We hypothesize that increased autocrine HGF-Met signaling is a critical downstream function of c-Src-Stat3 activation in mammary tumorigenesis. Future studies will identify novel Stat3 consensus sites that regulate HGF promoter activity and HGF expression preferentially in carcinoma cells and could lead to novel therapeutic drugs that specifically block HGF expression in mammary carcinoma cells, and which could be used in combined treatments to abrogate metastasis.

Tyrosine kinase receptor RON in human pancreatic cancer

“…Growth factors such as epidermal growth factor and hepatocyte growth factor have been implicated in mediating tumor progression and growth, and these same factors mediate EMT. 22,23 Our studies demonstrated 1) the presence of increased RON expression in pancreatic neoplasia (both invasive cancer and PIN); 2) RON's ability to induce EMT in pancreatic cancer cells; and 3) the ability of a RON MoAb to inhibit tumor cell signaling, migration, invasion, and growth. We demonstrated that RON activation induced EMT and increased migration and invasion of pancreatic cancer cells.…”

Co‐expression of hepatocyte growth factor and c‐Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c‐Met signaling in gastric cancer

“…31 EMT is induced by growth factors implicated in these processes, such as HGF, transforming growth factor b and epidermal growth factors. 32 Clinically, paracrine activation of HGF/c-Met signaling via overexpression of HGF and/or c-Met is well known in many types of carcinoma, 33,34 whereas many studies have demonstrated that HGF/c-Met autocrine signaling is closely related to malignant progression of tumor cells. Indeed, co-expression of HGF and c-Met has been detected in a variety of human tumors.…”

Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells

“…Under these conditions, EMT is defined as the occurrence of a variable proportion of tumor cells that upregulate mesenchymal markers such as vimentin and snail, and that downregulate epithelial markers such as E-cadherin (17,18). The expression of these EMT markers is induced by a number of growth factor/receptor systems such as the hepatocyte growth factor (HGF)/c-met system (19)(20)(21) and the transforming growth factor (TGF)-ß/TGF-ß receptor system (22,23), both of which are associated with a more aggressive phenotype of cancer cells. However, little information is available regarding the type of EMT induced by chemokine system(s), including the SDF-1/CXCR4 system, despite abundant evidence of the diverse malignant behaviors of such systems in cancer cells.…”