Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma.

Journal Article (Journal Article)

Hepatocellular carcinoma (HCC) typically develops in cirrhosis, a condition characterized by Hedgehog (Hh) pathway activation and accumulation of Hh-responsive myofibroblasts. Although Hh signaling generally regulates stromal-epithelial interactions that support epithelial viability, the role of Hh-dependent myofibroblasts in hepatocarcinogenesis is unknown. Here, we used human HCC samples, a mouse HCC model, and hepatoma cell/myofibroblast cocultures to examine the hypothesis that Hh signaling modulates myofibroblasts' metabolism to generate fuels for neighboring malignant hepatocytes. The results identify a novel paracrine mechanism whereby malignant hepatocytes produce Hh ligands to stimulate glycolysis in neighboring myofibroblasts, resulting in release of myofibroblast-derived lactate that the malignant hepatocytes use as an energy source. This discovery reveals new diagnostic and therapeutic targets that might be exploited to improve the outcomes of cirrhotic patients with HCCs.

Full Text

Duke Authors

Cited Authors

  • Chan, IS; Guy, CD; Chen, Y; Lu, J; Swiderska-Syn, M; Michelotti, GA; Karaca, G; Xie, G; Krüger, L; Syn, W-K; Anderson, BR; Pereira, TA; Choi, SS; Baldwin, AS; Diehl, AM

Published Date

  • December 15, 2012

Published In

Volume / Issue

  • 72 / 24

Start / End Page

  • 6344 - 6350

PubMed ID

  • 23066040

Pubmed Central ID

  • PMC3525764

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-12-1068


  • eng

Conference Location

  • United States