Paracrine hedgehog signaling drives metabolic changes in hepatocellular carcinoma

Isaac S. Chan, Cynthia D. Guy, Yuping Chen, Jiuyi Lu, Marzena Swiderska-Syn, Gregory A. Michelotti, Gamze Karaca, Guanhua Xie, Leandi Krüger, Wing Kin Syn, Blair R. Anderson, Thiago A. Pereira, Steve S. Choi, Albert S. Baldwin, Anna Mae Diehl

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6344-6350
Number of pages7
JournalCancer research
Volume72
Issue number24
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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