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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Authors: | Kunio Matsumoto Kazuhiko Date Hideo Shimura Toshikazu Nakamura |
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Affiliation: | Division of Biochemistry, Biomedical Research Center, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565;First Department of Surgery, Kyushu University Faculty of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82 |
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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. |
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Keywords: | Gallbladder cancer Hepatocyte growth factor Tumor invasion Tumor-stromal interactions |
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