| Summary: | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 <sup>S2448</sup>p-mTOR (100%, p = 0.05), <sup>T389</sup>p-S6K (100%, p = 0.02 and <sup>S235/236</sup>p-S6 (86%, p = 0.005). Additionally, <sup>T389</sup>p-S6K correlated with <sup>S727</sup>p-STAT3 (86%, p = 0.005). Advanced tumors with lymph node metastasis were characterized by high levels of <sup>S276</sup>p-NFκB (100%, p = 0.05) and <sup>S9</sup>p-GSK3β (100%, p = 0.05). High levels of PKBβ/AKT2, EGFR, as well as nuclear <sup>T202/Y204</sup>p-ERK and <sup>T180/Y182</sup>p-p38 were observed in normal ducts adjacent to PDAC compared with non-cancerous pancreas.</p> <p>Conclusion</p> <p>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.</p>
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