Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma.
Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma.
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DOI：
10.1158/0008-5472.can-12-1068
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发表时间：
2012-12-15
期刊：
影响因子：
11.2
通讯作者：
Diehl AM
中科院分区：
文献类型：
--
作者：
Chan IS;Guy CD;Chen Y;Lu J;Swiderska-Syn M;Michelotti GA;Karaca G;Xie G;Krüger L;Syn WK;Anderson BR;Pereira TA;Choi SS;Baldwin AS;Diehl AM
肝细胞癌 (HCC) 通常在肝硬化中发生，肝硬化是一种以 Hedgehog (Hh) 通路激活和 Hh 反应性肌成纤维细胞 (MF) 积累为特征的疾病。尽管 Hh 信号传导通常调节支持上皮活力的基质-上皮相互作用，但 Hh 依赖性 MF 在肝癌发生中的作用尚不清楚。在这里，我们使用人类 HCC 样本、小鼠 HCC 模型和肝癌细胞/MF 共培养物来检验 Hh 信号传导调节 MF 代谢以为邻近恶性肝细胞产生燃料的假设。结果确定了一种新的旁分泌机制，恶性肝细胞通过该机制产生 HH 配体来刺激邻近 MF 中的糖酵解，从而释放 MF 衍生的乳酸，恶性肝细胞将其用作能量来源。这一发现揭示了新的诊断和治疗靶点，可用于改善肝硬化肝癌患者的预后。
Hepatocellular carcinoma (HCC) typically develop in cirrhosis, a condition characterized by Hedgehog (Hh) pathway activation and accumulation of Hh-responsive myofibroblasts (MF). Although Hh signaling generally regulates stromal-epithelial interactions that support epithelial viability, the role of Hh-dependent MF in hepatocarcinogenesis is unknown. Here we used human HCC samples, a mouse HCC model, and hepatoma cell/MF co-cultures to examine the hypothesis that Hh signaling modulates MF 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 MF, resulting in release of MF-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 HCC.