ACQUISITION OF INVASIVE PHENOTYPE IN GALLBLADDER CANCER-CELLS VIA MUTUAL INTERACTION OF STROMAL FIBROBLASTS AND CANCER-CELLS AS MEDIATED BYHEPATOCYTE GROWTH-FACTOR

Growth and motility of carcinoma cells are regulated through their int eractions with host stromal cells, i.e., tumor-stromal interactions. H epatocyte growth factor (HGF), a ligand for c-Met tyrosine kinase, is a stromal-derived regulator of growth, motility, and morphogenesis. HG F stimulated proliferation and motility of GB-d1 gallbladder carcinoma cells from a patient with gallbladder cancer. HGF induced in vitro in vasion of GB-d1 cells into a collagen gel matrix, and this potent, inv asive effect was not seen with epidermal growth factor, transforming g rowth factor-beta 1, basic fibroblast growth factor, or platelet-deriv ed growth factor. Although GB-d1 did not produce HGF, the cells did pr oduce a factor which enhances HGF production in human skin fibroblasts , and this factor proved to be interleukin-1 beta (IL-1 beta). When GB -d1 cells were co-cultured with fibroblasts such that a collagen gel m atrix was layered between the GB-d1 cells and fibroblasts, GB-d1 cells invaded the gel, but invasion of the cells in the co-culture system w as inhibited by antibodies against HGF and partially inhibited by anti bodies against IL-1 beta. Thus, GB-d1 cell-derived IL-1 beta stimulate s HGF production in stromal fibroblasts and HGF up-regulated in the fi broblasts induces invasion of GB-d1 cells, The looped interaction of c arcinoma cells and stromal fibroblasts mediated by HGF and a HGF-induc er such as IL-1 beta may be one mechanism which would explain the acqu isition of malignant phenotype through tumor-stromal interactions.