Paracrine Hedgehog Signaling Drives Metabolic Changes in Hepatocellular Carcinoma

被引：44

作者：

Chan, Isaac S. ^{[1
,4
]}

Guy, Cynthia D. ^{[2
]}

Chen, Yuping ^{[1
]}

Lu, Jiuyi ^{[1
]}

Swiderska-Syn, Marzena ^{[1
]}

Michelotti, Gregory A. ^{[1
]}

Karaca, Gamze ^{[1
]}

Xie, Guanhua ^{[1
]}

Krueger, Leandi ^{[1
]}

Syn, Wing-Kin ^{[1
,5
]}

Anderson, Blair R. ^{[3
]}

Pereira, Thiago A. ^{[1
]}

Choi, Steve S. ^{[1
]}

Baldwin, Albert S. ^{[4
]}

Diehl, Anna Mae ^{[1
]}

机构：

[1] Duke Univ, Med Ctr, Div Gastroenterol, Dept Med, Durham, NC 27710 USA

[2] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA

[3] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA

[4] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA

[5] Fdn Liver Res, Liver Regenerat & Repair Grp, Inst Hepatol, London, England

来源：

CANCER RESEARCH | 2012年 / 72卷 / 24期

关键词：

TUMOR-GROWTH; CANCER; PATHWAY; CELLS; LIVER; REQUIREMENT; INHIBITION; MODEL;

D O I：

10.1158/0008-5472.CAN-12-1068

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. Cancer Res; 72(24); 6344-50. (c) 2012 AACR.

引用

页码：6344 / 6350

页数：7

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