The Role of HGFA in Cancer

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We have previously reported that HGFA is expressed in a number of human cancer cell lines, including breast, colon, prostate, lung, and liver (106). In addition, we have also demonstrated that the expression of HGFA is upregulated in human breast cancer tissues compared with normal background breast tissues, whereas the levels of the HGFA inhibitors are reduced in breast cancer tissues (26) (Figure 5). This observation is also reported in colorectal carcinomas, where an upregulation of HGFA is accompanied by a downregulation of HAI-1 (105). Plasminogen activator, which shows significant homology to the HGFA precursor, also displays enhanced expression in breast cancer cells and correlates with tumour progression (139). In addition to the changes of HGFA in tumour and tumour cells, recent studies also reveal that serum HGFA was elevated in patients with advanced stage prostate cancer (140). The study, although in small scale, is interesting and indicated that a systemic rise of the HGFA may be a feature in these patients. A large-scale study would be important. The forced expression of HGFA within human glioblastoma cell lines resulted in significantly enhanced tumour growth with increased vascular density when these cells were implanted in nude mouse brain (140, 141). These elevated HGFA levels lead to enhanced HGF activity and in turn may promote tumour metastasis.

Figure 5. HGF, c-MET and HGF regulators in human breast cancer. Top panel - Quantitative analysis of the HGF system. Graphs show the mean number of respective transcripts comparing normal background tissue and tumour tissues. Bottom panel - Immunohisto-chemical staining of breast specimens (Top = background breast tissue from breast cancer patient; bottom = tumour tissue from breast cancer patient). HGF (A,B), c-Met (C,D), and HGFA (E,F) all displayed a low degree of staining in the background specimens, however, the level of these influential factors in the breast cancer tissues was dramatically increased. In contrast, HAI-1 (G,H) and HAI-2 (I,J) showed intense staining in the normal tissue, but the breast cancer tissues displayed far lower levels of these inhibitory factors. (Adapted from Parr et al., 2004. Clin Cancer Res; 10: 202-11).

Figure 5. HGF, c-MET and HGF regulators in human breast cancer. Top panel - Quantitative analysis of the HGF system. Graphs show the mean number of respective transcripts comparing normal background tissue and tumour tissues. Bottom panel - Immunohisto-chemical staining of breast specimens (Top = background breast tissue from breast cancer patient; bottom = tumour tissue from breast cancer patient). HGF (A,B), c-Met (C,D), and HGFA (E,F) all displayed a low degree of staining in the background specimens, however, the level of these influential factors in the breast cancer tissues was dramatically increased. In contrast, HAI-1 (G,H) and HAI-2 (I,J) showed intense staining in the normal tissue, but the breast cancer tissues displayed far lower levels of these inhibitory factors. (Adapted from Parr et al., 2004. Clin Cancer Res; 10: 202-11).

These reports suggest that the HGFA serine protease is a target for inhibition. Serine protease inhibitors have previously been employed in an attempt to examine the possible methods of decreasing HGFA activity. The serine protease inhibitors examined were naturally present in human serum and included antithrombin III, c-1 inhibitor and a2-antiplasmin. The HGF-converting ability of Factor XIIa and HGFA was examined in the presence of these protease inhibitors. The inhibitors suppressed the influence of Factor XIIa, but none of these inhibitors could prevent HGFA converting pro-HGF to HGF (96). This suggests that the HAI inhibitors may be crucial to controlling the pro-metastatic influence of HGF in breast cancer.

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