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


CONCLUSIONS
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.
Pham
Nhu-An
NA
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. npham@uhnres.utoronto.ca
Schwock
Joerg
J
Iakovlev
Vladimir
V
Pond
Greg
G
Hedley
David W
DW
Tsao
Ming-Sound
MS
D001798:Blood Proteins / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D012016:Reference Values
D001798:Blood Proteins; D036341:Intercellular Signaling Peptides and Proteins; C021001:cytoplasmic activator protein, human