Functional Expression of HGF and Its Receptor in Human Colorectal Cancer

Abstract

Background: Hepatocyte growth factor (HGF) stimulates proliferation, migration and morphogenesis of epithelial cells by specific binding to its receptor c-met. Overexpression of HGF or c-met has been reported for human gastric or pancreatic cancer. In colorectal cancer overexpression of c-met but not HGF has been shown. However, elevated HGF serum levels have been detected in colorectal cancer patients. Therefore, the present study was performed to investigate expression patterns of both c-met and HGF in colorectal cancers and metastasis in comparison to normal mucosa. Furthermore, the mitogenic actions of HGF on colorectal cancer cells were studied in vitro. Methods: Expression of c-met and HGF were analyzed by RT-PCR and Western blotting and localized in the tissues utilizing immunohistochemistry. Mitogenic effects of HGF were determined in four human colon cancer cell lines by ³H-thymidine incorporation studies. Results: C-met and HGF mRNA were detectable in 60% of the normal specimen, but in the majority of cancer samples, and in just 33% of the liver metastasis. In cancer samples a coexpression of c-met and HGF was detected in 77% of the specimens. The extent of protein expression of receptor and ligand correlated with the mRNA expression. Moreover, c-met protein expression was increased 2- to 3-fold in colorectal cancers. C-met was detected in cells of epithelial origin, whereas HGF was expressed by mesenchymal cells. In vitro, HGF significantly stimulated cell growth in all four cell lines. Conclusion: Overexpression of c-met protein in colorectal cancers is combined with an expression of HGF in the majority of cases suggesting a paracrine manner of growth enhancement, while only a weak expression of c-met or HGF was detected in metastatic tissues.

Quantification of MET and hepatocyte growth factor/scatter factor expression in colorectal adenomas, carcinomas and non-neoplastic epithelia by quantitative laser scanning microscopy

“…When interpreting these data, several aspects regarding HGF-MET interactions are of interest. Whereas MET was expressed in cells of epithelial origin, HGF expression was mostly confined to mesenchymal cells suggesting paracrine effects on the tumor cells (16), as confirmed by our results. On the other hand, HGF bioactivity may be controlled by tumor-cell derived factors such as HGF activator (HGFA) and its inhibitor HGFA inhibitor type 1 (HAI-1), which are both detected in colorectal mucosa as well as neoplasms (45).…”

“…HGF/SF levels vary in many pathologic and physiologic processes (15) and are especially important in injury, differentiation and growth. Otte et al described the functional expression of HGF and MET in colorectal cancers and suggested a paracrine mechanism of growth enhancement (16). The multiple features and properties of MET and HGF have been described in great detail in the review by Birchmeier et al (17).…”

Involvement of Arp2/3 complex in the process of colorectal carcinogenesis

“…28,29 Many studies have reported overexpression of cMet or an HGF receptor by colorectal cancer. [30][31][32][33] Increased cell movement induced by HGF requires activation of Rho protein, and Rac and Rho are involved in cell membrane ruffling during the cell movement caused by HGF. 34 HGF controls the WASP family protein N-WASP, and is related to cell movement and invasion.…”

Systems and Network-Centric Understanding of Pancreatic Ductal Adenocarcinoma Signalling

“…Even though c-MET mRNA is present at very small amounts in normal human exocrine pancreas, it is upregulated in a majority of PDAC. Interestingly overexpression of c-MET has been observed in regenerative tissue affected by acute pancreatitis (Otte et al 2000), and has been linked to early events in PDAC carcinogenesis. HGF is a primary ligand of c-MET.…”