**3.1 Stroma as a microenvironment to determine behaviors of tumors**

The important roles of stroma during tumor progression are demonstrated through several independent studies. Carcinoma-associated fibroblasts, but not normal fibroblasts, stimulate tumor progression of initiated non-tumorigenic epithelial cells both in an *in vivo* tissue recombination and in an *in vitro* co-culture system (Olumi *et al*., 1999). Transforming growth factor (TGF)-β signaling is critical for down-regulating HGF production (Matsumoto *et al*., 1992). Of note, an inactivation of TGF-β type II receptor gene in stromal fibroblasts leads to the onset of epithelial growth and invasion (Bhowmick *et al*., 2004). In this process, activation of paracrine HGF is a key mechanism for stimulation of epithelial proliferation (Bhowmick *et al*., 2004). Thus, the suppression of HGF production by TGF-β seems to be important for an escape from cancer metastasis (Matsumoto & Nakamura, 2006).
