Research article
Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis
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* Corresponding author: Ming-Sound Tsao Ming.Tsao@uhn.on.ca
1 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
3 Department of Biostatistics, Princess Margaret Hospital, Toronto, ON, Canada
4 Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada
5 Department of Pathology, University Health Network, Toronto, ON, Canada
BMC Cancer 2008, 8:43 doi:10.1186/1471-2407-8-43
Published: 6 February 2008Abstract
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-NFκB (100%, p = 0.05) and S9p-GSK3β (100%, p = 0.05). High levels of PKBβ/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.