Much evidence now exists demonstrating the diverse effects of HGF/SF on cells in vitro and thus HGF/SF may play an important role in vivo. The motogenic activity of HGF/SF suggests that it may well play a role in both physiological (embryogenesis, wound healing and tissue repair) and pathological (tumour invasion and metastasis, angiogenesis) processes. Modulation of intercellular adhesive interactions in tumour tissues may play a role in the initial events surrounding tumour metastatic spread whilst HGF/SF-stimulated regulation of tumour cell-matrix/endothelium interactions will further aid tumour spread, promoting tumour cell intra and extravasation. The effects of HGF/SF are mediated by c-met proto-oncogene product. Following ligand binding and receptor phosphorylation, activation of several intracellular signalling pathways occurs, ultimately leading to the cellular response. Both autocrine and paracrine regulatory mechanisms have been reported for tumour cell stimulation by HGF/SF, depending upon the type of tumour cell involved. It appears, however, that the most common mechanism of activation of c-met is via a paracrine action since the majority of tumour cells/types do not express or produce the active HGF/SF; it is the stromal cells in the tumour environment that are the main source of HGF/SF ligand in almost all tumours studied so far. Furthermore, the production of HGF/SF from stromal cells can be regulated by a number of tumour-derived factors and cytokines and also some therapeutic agents. This knowledge may prove useful concerning modulation of HGF/SF production in clinical practice. Clearly, HGF/SF and the c-met receptor are of great clinical significance. Many studies have shown that the c-met receptor is overexpressed in numerous tumour types, thus these tumour tissues may have an augmented response to HGF/SF, the serum level of which has also been reported to be elevated in some tumour types. Indeed, several studies have demonstrated a correlation between c-met expression and metastatic development in vivo and in a number of cancer patients, both circulatory levels of HGF/SF and expression of the c-met protein have been found to be good prognostic indicators. The exception is thyroid cancer, where c-met expression is inveresely correlated with tumour stage. The role of the HGF/SF-c-met system in cancers of this type thus presents an interesting area for future research. Presence of mutant forms of c-met that may be constituatively phosphorylated in tumour tissue/cells may also give rise to metastatic development however, studies of this nature are not widely reported at present. Since HGF/SF may play a role as a key regulatory molecule in cancer development, antagonism of this molecule thus presents an important opportunity for anti-cancer treatment/prevention strategies. Inhibitory agents of HGF/SF activity have been reported, including HGF/SF antagonists (NK1, NK2, NK3, NK4), invasion inhibiting factors (IIF-2, IL-12), retinoids and polyunsaturated fatty acids (GLA). However, since most data concerning the effects of these inhibitors of HGF/SF action have been done in vitro, there is clearly much further work to be done concerning inhibition of HGF/SF effects in vivo. Although this review has high-lighted a number of key tumour-promoting functions of HGF/SF as well as discussing current data regarding HGF/SF and its receptor expression in tumour tissues, there is still much to understand concerning both the molecular and cellular events which accompany stimulation by HGF/SF and its role in cancer progression. The prevention of metastatic spread of cancer cells thus remains a long term goal that will have great benefit in the management and treatment of cancer patients.
