Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis

BMC Cancer. 2008 Feb 6;8:43. doi: 10.1186/1471-2407-8-43.

Abstract

Background: The pathogenesis of pancreatic ductal adenocarcinoma (PDAC) involves multi-stage development of molecular aberrations affecting signaling pathways that regulate cancer growth and progression. This study was performed to gain a better understanding of the abnormal signaling that occurs in PDAC compared with normal duct epithelia.

Methods: We performed immunohistochemistry on a tissue microarray of 26 PDAC, 13 normal appearing adjacent pancreatic ductal epithelia, and 12 normal non-PDAC ducts. We compared the levels of 18 signaling proteins including growth factor receptors, tumor suppressors and 13 of their putative downstream phosphorylated (p-) signal transducers in PDAC to those in normal ductal epithelia.

Results: The overall profiles of signaling protein expression levels, activation states and sub-cellular distribution in PDAC cells were distinguishable from non-neoplastic ductal epithelia. The ERK pathway activation was correlated with high levels of S2448p-mTOR (100%, p = 0.05), T389p-S6K (100%, p = 0.02 and S235/236p-S6 (86%, p = 0.005). Additionally, T389p-S6K correlated with S727p-STAT3 (86%, p = 0.005). Advanced tumors with lymph node metastasis were characterized by high levels of S276p-NFkappaB (100%, p = 0.05) and S9p-GSK3beta (100%, p = 0.05). High levels of PKBbeta/AKT2, EGFR, as well as nuclear T202/Y204p-ERK and T180/Y182p-p38 were observed in normal ducts adjacent to PDAC compared with non-cancerous pancreas.

Conclusion: Multiple signaling proteins are activated in pancreatic duct cell carcinogenesis including those associated with the ERK, PKB/AKT, mTOR and STAT3 pathways. The ERK pathway activation appears also increased in duct epithelia adjacent to carcinoma, suggesting tumor micro-environmental effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Proteins / metabolism
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Disease Progression
  • Epithelium / metabolism
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Pancreas / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Reference Values

Substances

  • Blood Proteins
  • Intercellular Signaling Peptides and Proteins
  • cytoplasmic activator protein, human