Dosage-Dependent Regulation of Pancreatic Cancer Growth and Angiogenesis by Hedgehog Signaling

Abstract

Summary Pancreatic cancer, a hypovascular and highly desmoplastic cancer, is characterized by tumor expression of Hedgehog (HH) ligands which signal to fibroblasts in the surrounding stroma that in turn promote tumor survival and growth. However, the mechanisms and consequences of stromal HH pathway activation are not well understood. Here we show that the HH co-receptors GAS1, BOC, and CDON are expressed in cancer-associated fibroblasts. Deletion of two co-receptors (Gas1 and Boc) in fibroblasts reduces HH-responsiveness. Strikingly, these fibroblasts promote greater tumor growth in vivo that correlates with increased tumor-associated vascularity. In contrast, deletion of all three co-receptors (Gas1, Boc and Cdon) results in the near complete abrogation of HH signaling and a corresponding failure to promote tumorigenesis and angiogenesis. Collectively, these data identify a novel role for HH-dosage in pancreatic cancer promotion and may explain the clinical failure of HH pathway blockade as a therapeutic approach in pancreatic cancer.

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

“…This cascade of events ultimately results in the regulation of the corresponding target genes (33). Certain components of the Hh signaling pathway such as PTCH1 and GLI1 are direct transcriptional targets, thus establishing a feedback loop that regulates the level of activity of this pathway (34).…”

GAS1 is present in the cerebrospinal fluid and is expressed in the choroid plexus of the adult rat

“…4). Finally, we looked for the expression of GAS1 in fibroblasts since they are present in the stroma of the CP (Emerich et al 2005a), and a previous report indicated that these cells express GAS1 in the pancreas (Mathew et al 2014). However, we could not observe co-localization of GAS1 with a specific marker for fibroblasts (α-SMA) (Fig.…”

Dental Stem Cell Differentiation Toward Endodermal Cell Lineages: Approaches to Control Hepatocytes and Beta Cell Transformation

“…Last but not least, another crucial signalling pathway worth discussing is the Hedgehog signalling pathway which has a dual role in endocrine pancreatic regeneration [ 117 ]. For instance, Hebrok et al [ 118 ] have shown that Indian hedgehog (Ihh), together with Patched-1 (Ptc-1), a receptor and negative regulator of hedgehog activity, is expressed in pancreatic tissue.…”