Direct cancer–stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells

BACKGROUND: Scirrhous-type gastric carcinoma (SGC) exhibits an extensive submucosal fibrosis and extremely poor patient prognosis. We investigated the importance of the cancer–stromal interaction in the histogenesis of SGC. METHODS: Gastric fibroblasts NF-25 and intestinal fibroblasts NF-j2 were co-cultured with SGC-derived (HSC-39) or non-SGC-derived (HSC-57 and HSC-64) cells. To identify genes that are up- or downregulated in NF-25, complementary DNA (cDNA) microarray analysis was performed. The antibody against vascular-cell adhesion molecule-1 (VCAM-1) was used for cell growth test and immunohistochemistry. Moreover, the impact of interaction with NF-25 fibroblasts on HSC-39 cells was investigated using western blot and reverse transcription-polymerase chain reaction. RESULTS: HSC-39 cells stimulated growth of NF-25 but not NF-j2 when co-cultured. Induction of VCAM-1 in NF-25 fibroblasts was identified, which was specific when co-cultured with HSC-39 but not with non-SGC-derived HSC-57 and HSC-64 cells. Neutralising antibody to VCAM-1 suppressed NF-25 growth in dose-dependent manners. In tissue samples, positive immunoreactivity of VCAM-1 in SGC-derived fibroblasts was significantly higher than that in non-SGC-derived fibroblasts. Furthermore, interaction with NF-25 fibroblasts not only induced the epithelial–mesenchymal transition-like change, but also expressions of matrix metalloproteinase- related genes in HSC-39 cells. CONCLUSION: Direct interaction between SGC cells and gastric fibroblasts establishes the tumour microenvironment and reinforces the aggressiveness of SGC.