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)

Int J Cancer. 1999 Mar 31;81(1):67-73. doi: 10.1002/(sici)1097-0215(19990331)81:1<67::aid-ijc13>3.0.co;2-v.


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 the receptor-tyrosine-kinase superfamily, identified as being a receptor for glial-cell-line-derived neurotrophic factor (GDNF). In an invasion assay, the migration of pancreatic cancer cells was markedly induced by co-cultivation 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. Checkerboard analysis of the migration showed both chemotactic and chemokinetic activity of GDNF. There was no detectable expression of another GDNF receptor component, a glycosyl-phosphatidylinositol-linked receptor (GFR alpha-1), in pancreatic-cancer cell lines, suggesting that the neural invasion of pancreatic-cancer cells 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement
  • Coculture Techniques
  • Drosophila Proteins*
  • Ganglia, Sympathetic / metabolism
  • Ganglia, Sympathetic / pathology*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Glioblastoma / pathology
  • Humans
  • Immunohistochemistry
  • Neoplasm Invasiveness
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / metabolism*
  • Neuroblastoma / pathology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogenes*
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • Drosophila Proteins
  • GDNF protein, human
  • GFRA1 protein, human
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • MAS1 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila