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
Language
- eng
Conference Location
- United States