Experimental implication of celiac ganglionotropic invasion of pancreatic-cancer cells bearing c-ret proto-oncogene with reference to glial-cell-line-derived neurotrophic factor (GDNF)

Perineural invasion is a prominent clinical feature of pancreatic cancer wh ich causes difficulty in curative resection. In the present study, the huma n pancreatic cancer cell lines, PaCa-2, AsPC-1, SW1990 and Capan-2, were al l found to express abundant c-ret proto-oncogene mRNA and RET protein, a me mber of the receptor-tyrosine-kinase superfamily, identified as being a rec eptor for glial-cell-line-derived neurotrophic factor (GDNF). In an invasio n assay, the migration of pancreatic cancer cells was markedly induced by c o-cultivation with human glioma cells, T98G or A172, capable of producing a nd secreting GDNF. Anti-GDNF antibody in conditioned media of glioma cells suppressed much of the migratory activity. Checkerboard analysis of the mig ration showed both chemotactic and chemokinetic activity of GDNF. There was no detectable expression of another GDNF receptor component, a glycosyl-ph osphatidylinositol-linked receptor (GFR alpha-1), in pancreatic-cancer cell lines, suggesting that the neural invasion of pancreatic-cancer cells spre ads along a concentration gradient of GDNF produced from peripheral ganglio ns through direct interaction of GDNF with its receptor, the c-ret proto-on cogene product. Immunochemical localization of GDNF in human celiac ganglio nic tissue supported this contention. (C) 1999 Wiley-Liss, Inc.