136 Distal Esophageal Emptying: A Mechanistic Analysis Using a Novel 3-D High Resolution Manometry (3-D HRM) Coupled With Videofluoroscopy and a Squamocolumnar Junction Endoclip

Abstract

Although Hedgehog signaling pathway components are aberrantly expressed in pancreatic cancers, accumulating evidence from mouse models suggests that the Sonic Hedgehog ligand (Shh) is often not active in pancreatic cancer cells and instead requires a paracrine signaling mechanism. However, it is not known if this paracrine mechanism of Hedgehog signaling can be extended to human stroma. We performed gene expression profiling of human pancreatic cancer associated fibroblasts (CAFs) and non-neoplastic pancreatic fibroblasts to identify differentially expressed genes in CAFs. Among the genes upregulated in cancer associated fibroblasts relative to control fibroblasts was the Hedgehog receptor Smoothened (SMO). We find that CAFs expressing SMO can transduce the Shh signal to activate Gli1 expression, and siRNA knockdown of SMO blocks the induction of Gli1 in these cells. We further find overexpression of Smo in stromal fibroblasts of human primary pancreatic adenocarcinomas compared to normal pancreatic fibroblasts. These findings implicate overexpression of Smo as a mechanism for the activation of Hedgehog signaling in human pancreatic CAFs and suggest that stromal cells may be a therapeutic target for Smo antagonists in pancreatic cancer.