**3.2 Regulation of HGF production in stroma by tumor cells**

As repeated, a major source of HGF in tumors is stromal cells (including fibroblasts, endothelium, macrophages and neutrophils) (Wislez *et al*., 2003; Matsumoto & Nakamura, 2006; Grugan *et al*., 2010). Thus, how stromal HGF is up-regulated during tumor progression should be discussed. There is now ample evidence that numerous types of carcinoma cells secrete soluble factors that induce HGF production in stromal cells (*i.e*., HGF-inducers). For example, conditioned medium obtained from breast cancer cells enhances HGF production in fibroblasts, along with a raise in prostaglandin-E2 (Matsumoto-Taniura *et al*., 1999). Of note, suppression of prostaglandin-E2 production by indomethacin leads to downregulation of stromal HGF production and suppression of tumor migration *in vitro* (Matsumoto-Taniura *et al*., 1999), indicating that cancer-derived prostaglandins are important for up-regulating HGF in stromal cells (Matsumoto-Taniura *et al*., 1999; Pai *et al*., 2003). Other carcinoma-derived HGF-inducers are interleukin-1β (IL-1β), basic fibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF), and TGF-α (Hasina *et al*., 1999; Matsumoto & Nakamura, 2003). These results indicate a crosstalk between carcinoma and stroma, mediated via a paracrine loop of HGF-inducers produced by carcinoma and HGF secreted from stroma cells, such as fibroblasts (Matsumoto *et al*., 1996a).
