The Hgf Regulatory Factors

Interactions between tumour cells and their surrounding stromal environment play a key role in modulating the aggressive nature of tumour invasion and metastasis (82-84). HGF is synthesised and released by stromal fibroblasts as an inactive single chain precursor, known as pro-HGF, and requires site-specific cleavage to function as a biologically active cytokine (85, 86). A number of proteases have been proposed as possessing HGF-converting properties, however, the initial factor reported to convert inactive pro-HGF to active HGF was a serine protease known as HGF activator (HGFA) (87). Additional factors which possess pro-HGF converting ability include the pro-metastatic factors known as matriptase, hepsin, and uPA (88-90). It is the activation of HGF that forms a key step in governing the influence of HGF in cancer metastasis. Recent studies have also described two serine protease inhibitors with the ability to bind to the HGF activators, and block the pro-HGF conversion properties. These inhibitors were termed HGFA inhibitor type-1 and type-2 (HAI-1 and HAI-2) (91, 92). HAI-1 and HAI-2 are regulators of HGF action, and may therefore limit the pro-metastatic effects of HGF on tumour cells (Figure 3). We report that the degree to which HGF, c-Met, HGFA, matriptase, HAI-1 and HAI-2 are expressed within breast

Figure 3. The HGFA and matriptase serine proteases convert inactive HGF into the active form of HGF. HAI-1 and HAI-2 are two Kunitz-type inhibitors that suppress the proteolytic activation of HGF, through inhibition of HGFA and matriptase action.

cancer tissues determines the biological activity of HGF (26). Therefore, these factors have direct bearing on the metastatic spread of cancer cells.

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