Common events of two types of gastric cancers, including LOH7q, RUNX3 loss, cyclin E gene amplification, p27 loss, nm23 loss, CD44 aberrant transcripts and telomerase activity, confer invasion and metastasis. However, intestinal and diffuse type gastric cancers exhibit different metastatic potentials to establish invasion and metastasis sites, depending on the scenario of gene signature and the growth factor/cytokine networks between cancer cells and stromal cells. Namely, subpopulations of cancer cells with expression of VEGF andOIL-8 and c-erb2 amplification in primary tumors of intestinal type show liver metastatic activity, whereas populations with c-met or K-sam amplification and bFGF expression in CDH1 negative diffuse type have the propensity to exhibit peritoneal dissemination. Keratinocyte growth factor (KGF) from fibroblasts specifically binds to K-sam on tumor cells, resulting in the development of scirrhous type. VEGF-C expression and mutual interplay between osteopontin and CD44 aberrant transcripts confer nodal metastasis. Importantly, NF-kB activation induced by Helicobacter pylori infection may act as a key player in the up-regulation of the growth factor/cytokine networks in the early stages of tumor progression.
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