**3. Regulation of HGF production by cancer cells**

Several lines of histological evidence indicate that HGF is produced in stroma cells, such as fibroblasts, vascular EC and smooth muscle cells in tumor tissues. In contrast, MET is overexpressed mainly by tumor cells, particular near invasive areas, implying a possible paracrine signal from HGF-producing stroma cells to MET-expressing carcinoma cells

Fig. 1. Various effect of HGF on cancer cells and endothelial cells (EC) during tumor

progression. For example, sequential events during the lung metastasis of hepatic carcinoma are summarized as follows: (A) dissociation and scattering of hepatocellular cancer cells through an HGF-induced endocytosis of cadherins; (B) tumor migration into stromal areas across the basement membrane (BM) is mediated via MMP-dependent matrix degradation and Rho-dependent cell movement; (C) invasion of tumor cells into neighboring vessels (*i.e*., intravasation) where the tight junction between ECs is lost by HGF-MET signaling; (D) inhibition of tumor cell anoikisis by MET-AKT cascades during blood flow, and out-flux of tumor cells across vessel walls (*i.e*., extravasation); and (E) in the lung, HGF supports growth of metastatic nodules via providing vascular beds as an angiogenic factor.

Overall, HGF is shown to take direct action on carcinoma cells: (i) cell spreading via an endocytosis of cadherins; (ii) enhancement of invasion across basement membranes via Rhodependent and MMP-dependent pathways; and (iii) anti-anoikis activity during blood circulation. Toward tumor vessels, HGF elicits vascular and lymphatic EC proliferation and branching angiogenesis, while intravasation and extravasation are achieved through HGFinduced reduction of EC-EC integrity. These HGF-MET-mediated biological functions seem advantageous for invasion and metastasis of malignant tumors, including carcinoma and

**[Note]** Long-term administration of recombinant HGF does not elicit tumor formation in healthy animals, and this result supports a rationale of HGF supplement therapy for treating

Several lines of histological evidence indicate that HGF is produced in stroma cells, such as fibroblasts, vascular EC and smooth muscle cells in tumor tissues. In contrast, MET is overexpressed mainly by tumor cells, particular near invasive areas, implying a possible paracrine signal from HGF-producing stroma cells to MET-expressing carcinoma cells

chronic organ diseases, such as liver cirrhosis, at least in cancer-free patients.

**3. Regulation of HGF production by cancer cells** 

sarcoma (**Fig. 1**).

(Matsumoto *et al*., 1996b). Herein, we will discuss the molecular basis whereby stromal HGF production is up-regulated by tumor cells during cancer invasion and metastasis.
