The study of the mechanisms of perineural invasion for pancreatic cancer cell

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Perineural invasion is a prominent clinical feature of pancreatic cancer which causes difficulty in curative resection. In the present study, the human pancreatic cancer cell lines, PaCa-2, AsPC-1, SW1990 and Capan-2, were all found to express abundant c-ret proto-oncogene mRNA and RET protein, a member of receptor tyrosine kinase superfamily identified to be a receptor for glial cell line-derived neurotrophic factor (GDNF). In an invasion assay, the migration of pancreatic cancer cells was markedly induced by cocultivation with human glioma cells, T98G or A172, capable of producing and secreting GDNF. Anti GDNF antibody in conditioned media of glioma cells suppressed much of the migratory activity. Checker board analysis of the migration showed both chemotactic and chemokinetic activity of GDNF. There was no detectable expression of another GDNF receptor component, a glycosyl-phoshatidylinositol-linked receptor (GFR_-1), in pancreatic cancer cell lines, suggesting that the neural invasion of pancreatic cancer cell spreads along a concentration gradient of GDNF produced from peripheral ganglions through direct interaction of GDNF with its receptor, the c-ret proto-oncogene product. Immunochemical localization of GDNF in human celiac ganglionic tissue supported this contention.