Acquisition of Invasive Phenotype in Gallbladder Cancer Cells via Mutual Interaction of Stromal Fibroblasts and Cancer Cells as Mediated by Hepatocyte Growth Factor

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Abstract
Growth and motility of carcinoma cells are regulated through their interactions with host stromal cells, i. e., tumor‐stromal interactions. Hepatocyte growth factor (HGF), a ligand for c‐Met tyrosine kinase, is a stromal‐derived regulator of growth, motility, and morphogenesis. HGF stimulated proliferation and motility of GB‐d1 gallbladder carcinoma cells from a patient with gallbladder cancer. HGF induced in vitro invasion of GB‐d1 cells into a collagen gel matrix, and this potent, invasive effect was not seen with epidermal growth factor, transforming growth factor‐β1, basic fibroblast growth factor, or platelet‐derived growth factor. Although GB‐d1 did not produce HGF, the cells did produce a factor which enhances HGF production in human skin fibroblasts, and this factor proved to be interleuldn‐1β (IL‐1β). When GB‐d1 cells were co‐cultured with fibroblasts such that a collagen gel matrix 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 was inhibited by antibodies against HGF and partially inhibited by antibodies against IL‐1β. Thus, GB‐d1 cell‐derived IL‐1β stimulates HGF production in stromal fibroblasts and HGF up‐regulated in the fibroblasts induces invasion of GB‐d1 cells. The looped interaction of carcinoma cells and stromal fibroblasts mediated by HGF and a HGF‐inducer such as IL‐1β may be one mechanism which would explain the acquisition of malignant phenotype through tumor‐stromal interactions.