Tumor lymphangiogenesis is regulated by lymphangiogenic factors released by tumor cells and stromal cells into the microenvironment of the neoplastic tissue. Of known lymphangiogenic factors, the best-characterized are vascular endothelial growth factor (VEGF)-C and -D, which bind to VEGF receptor-3 on lymphatic endothelial cells. In gastric cancer, tumor cells produce both VEGF-C and -D. Expression of VEGF-C, but not VEGF-D, correlates directly with lymph node metastasis of early-stage gastric cancer. Some gastric cancer cells express VEGF receptor-3 as well as VEGF-C and -D ligands, and VEGF-C and -D can stimulate growth and invasion and inhibit apoptosis of gastric cancer cells in an autocrine manner. We found recently that platelet-derived growth factor (PDGF) receptor-β is expressed in tumor-associated lymphatic endothelial cells and that cancer cells produce PDGF-BB, which also acts as a lymphangiogenic factor for gastric cancer. We review the current understanding of molecular mechanisms involved in lymphangiogenesis and lymph node metastasis of human gastric cancer.
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