Expression of hepatocyte growth factor/scatter factor, its activator, inhibitors and the c-Met receptor in human cancer cells

Hepatocyte growth factor/scatter factor (HGF/SF), a cytokine associated with cancer cell migration and invasion, is synthesised as pro-HGF/SF and requires activation by factors such as the HGF activator (HGFA). The present study examined the expression of HGF/SF, HGFA, the two inhibitors to HGFA action known as hepatocyte growth factor activator inhibitors type 1 and 2 (HAI-1 and HAI-2), and the HGF/SF receptor, c-Met. We examined a variety of normal and cancer cells, which included breast, prostate, colon, bladder, liver, lung, and pancreatic cancer cell lines. The cell lines all displayed different patterns of expression, and in some of the cancer cell lines the concomitant expression of the HGF/SF, c-Met, HGFA and HAI genes was observed. The only cell line to produce a significant amount of HGF/SF was the human fibroblasts (MRC-5) which also co-expressed the c-Met and HGFA genes to allow autocrine regulation of HGF/SF stimulation, and importantly displayed little or no inhibitor presence to suppress the biological function of HGF/SF. The highly invasive breast cancer cells (MDA MB-231) expressed large amounts of both c-Met and HGFA, to enable maximum influence from HGF/SF and did not express the HAI-1 gene at all, which suggests a shift in the activation-inhibition balance to enhance metastatic potential. In contrast, the breast cancer cells of low invasive nature (MCF-7) displayed a low level of c-Met and HGFA expression, while expressing the HAI genes to a high degree. However, there was no correlation between HAI-1 and HAI-2 expression. Interestingly, there appeared to be an inverse correlation between the degree of HGFA and HAI-1 expression, which may influence the metastatic ability of the cancer cells. This study has shown that c-Met, HGF/SF and its activator and inhibitors are expressed in different patterns in cancer cells and in normal cells. The balance between HGF/SF activation and HGFA inhibition is critical to the metastatic potential of the tumour cells, and the invasive nature of the cancer cell lines correlated to the degree of c-Met and/or HGFA presence along with HAI-1 expression