For almost a decade, HGF has been widely referred to as a motogen, mitogen and morphogen, in recognition of its profound impact on the motility, mitogenesis and morphogenesis in cells including cancer cells (Fig. 1). These roles have been firmly endorsed in recent studies. In addition, HGF has also been shown to be a factor that induces invasiveness of cancer cells and induces angiogenesis both in vitro and in vivo.
figure1: HGF roles in Cancer (Photocredit:Wen G. Jianga, Tracey A. Martina. 2005)
One of the most profound biological effects of HGF on cancer cells is its motility induction. Stimulation of cancer cells with HGF will result in increased migration over a number of matrices. Most cancer cells and indeed normal cells (including normal epithelial, endothelial, and neuronal cells) respond to HGF. The motility signals mediated by the HGF receptor, cMET, are multifold. Some of the key signalling pathways downstream of cMET that contribute to the migratory events in cancer cells can be seen in figure 2.
figure2: HGF signaling in cancer (Photocredit:Wen G. Jianga, Tracey A. Martina. 2005)
Disruption of cell–cell adhesion mechanism is key to HGF-induced cell scattering and dissociation, by way of phosphorylating ß-catenin [and by the shedding of cadherin from cell surface, and redistribution of E-cadherin to non-adhesion areas. Disruption of E-cadherin-mediated cell adhesion by HGF, may result in reduction of the cell cycle regulatory protein of the p27kip1 molecule, rendering cells to develop rapid growth without being affected by the cell–cell contact inhibition.
HGF has been shown to increase the invasiveness of a number of cancer cells. This is likely to be via a number of mechanisms including the direct increase in the migration of cancer cells (already discussed in earlier sections), increase in adhesion to matrix and to endothelium, and most notably increase in expression/secretion of proteolytic enzymes from cancer cells including MMP2, MMP7, MMP9, and uPA. It has shown that HGF dependent invasive growth is dependent upon the effective interaction between MET andα6β4 integrin in the cells. Loss of this type of integrin results in cell being not responsive to HGF. MET-induced phosphorylation of the integrin to allow integrins to interact with Shc and PI3K, which in turn enhances ras and PI3K signals. It has been recently reported that the semaphorin 4D (Sema 4D) receptor, Plexin B1, is able to form a complex with MET. Interaction of SEMA4D with Plexin B1, can rapidly induce the phosphorylation of cMET, and elicits migration and invasion of cancer cells.
In general, HGF has been reported to act as an antiapoptotic agent for renal epithelial cells (by activating Bad and inducing the Bcl-xL), gastric epithelial cells, podocytes, myocytes, cerebellar granule neurons, hair follicles, plasma cells, endothelial cells, and hepatocytes. HGF, however, increases apoptosis in ovarian surface epithelial cells. In cancer cells, HGF is anti-apoptotic in lung cancer and glioblastoma cells (both via MAPK/Akt), in colon cancer cells (activate Bcl-W), breast cancer cells (Bcl-Xl), squamous cell carcinoma of head and neck, and myeloma cells.
HGF and its receptor are co-expressed in multiple myeloma cells and may have value in both targeting and monitoring treatment response. Patients with higher levels of HGF in their blood are associated with poor survival and patients with good therapeutic response to treatment have a rapid decline in HGF levels. HGF was found to be higher in sera of patients with non-Hodgkin's lymphoma, in liver tumour, gastric cancer in which some reports failed to show a decrease following surgery and is an indicator to the clinical response. The fall of serum level of HGF has not been seen in hepatocelluar carcinoma. As already discussed earlier, the rise of HGF in cancer may be the result production from cancer cells and stromal cells and that leukemic cell-secreted. HGF may contribute to the development of other forms of cancer in the same patient although this is rare. The transient rise of serum HGF following surgery may be stimulatory to cancer cells. In biliary tract caricinoma, bile levels of HGF may be an indicator for liver function failure, although this has no direct bearing to tumour debulking or progress.