Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis

Abstract

Activation of sonic hedgehog (Shh) signaling occurs in the majority of pancreatic ductal adenocarcinomas. Here we investigate the mechanisms by which Shh contributes to pancreatic tumorigenesis. We find that Shh expression enhances proliferation of pancreatic duct epithelial cells, potentially through the transcriptional regulation of the cell cycle regulators cyclin D1 and p21. We further show that Shh protects pancreatic duct epithelial cells from apoptosis through the activation of phosphatidylinositol 3-kinase signaling and the stabilization of Bcl-2 and Bcl-X L. Significantly, Shh also cooperates with activated K-Ras to promote pancreatic tumor development. Finally, Shh signaling enhances K-Ras-induced pancreatic tumorigenesis by reducing the dependence of tumor cells on the sustained activation of the MAPK and phosphatidylinositol 3-kinase/Akt/mTOR signaling pathways. Thus, our data suggest that Shh signaling contributes to tumor initiation in the pancreas through at least two mechanisms and additionally enhances tumor cell resistance to therapeutic intervention. Collectively, our findings demonstrate crucial roles for Shh signaling in multiple stages of pancreatic carcinogenesis.K-ras ͉ mouse model ͉ pancreatic cancer ͉ Shh P ancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, with Ϸ30,000 new cases annually (1, 2). Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions called pancreatic intraepithelial neoplasia (PanIN), which are believed to be induced by the transformation of the epithelial cells of the small intercalated and intralobular ducts (3). PanIN lesions are characterized by specific histologic changes to the duct epithelium that correlate with the accumulation of alterations in the KRAS2 oncogene and loss of the INK4A (PanIN 1 and 2), TP53 (PanIN 2-3), and MADH4 (PanIN 3)

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…For example, it was shown in orthotopic mouse models that hedgehog signaling is required for tumor metastasis of pancreatic cancer ( (Feldmann et al, 2007) and our unpublished data). In contrast, pancreatic-specific deletion of Smo did not affect PDA formation whereas GLI2 expression resulted in undifferentiated pancreatic tumors (Morton et al, 2007;Nolan-Stevaux et al, 2009). These studies indicate that activation of hedgehog signaling is not sufficient for tumor formation of PDAC.…”

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

“…In the absence of Hh ligands, Patched tonically inhibits Smoothened (Smo) and Hh signaling is silenced. However, interaction of Hh ligands with Patched liberates Smoothened signaling activity, leading to a cascade that ultimately activates members of the Gli transcription factor family (Gli1, Gli2, Gli3) to regulate the transcription of Hh target genes, including cell cycle regulators and anti-apoptotic factors [8][9][10][11]. Interestingly, Gli factors regulate the transcription of Ptch, Gli1 and Gli2, permitting the pathway to auto-regulate its activity [12].…”

Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis

“…Genetic analyses have linked mutations in human KRAS to PDA (1), and the functional role of oncogenic KRAS in both PDA initiation and progression were subsequently confirmed using genetically engineered animal models of pancreatic cancer (2)(3)(4)(5)(6)(7)(8)(9). In addition to KRAS, a number of signaling pathways, including Wnt, TGF␣, TGF␤, Notch, EGF, and most recently, Hedgehog (Hh) have been implicated in PDA (10)(11)(12)(13)(14)(15).…”