UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer.
UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer.
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DOI：
10.1016/j.cancergencyto.2009.08.018
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发表时间：
2010-01-01
影响因子：
--
通讯作者：
Linehan WM
中科院分区：
文献类型：
--
作者：
Yang Y;Valera VA;Padilla-Nash HM;Sourbier C;Vocke CD;Vira MA;Abu-Asab MS;Bratslavsky G;Tsokos M;Merino MJ;Pinto PA;Srinivasan R;Ried T;Neckers L;Linehan WM
能量失调和肿瘤细胞代谢异常是我们认识癌症的关键问题。遗传性平滑肌瘤型肾细胞癌（HLRCC）是一种侵袭性肾细胞癌，其特征是克雷伯斯循环酶、富马酸水合酶（FH）的种系突变，具有高度转移性和异常致死性。这对于建立能量代谢紊乱的临床前细胞和异种移植模型以及开发针对三羧酸（TCA）周期缺陷的人类癌症的新治疗方法具有重要的实用价值。在这里，我们报告了第一个来自侵袭性hhcc相关复发性肾癌患者的永生细胞系，命名为UOK 262。我们研究了基因表达、染色体谱、外排生物能量分析、线粒体超微结构、FH分解代谢活性、侵袭性和体外生长的最佳葡萄糖需求。UOK 262细胞有同工染色体1q [i(1)(q10)]为反复出现的染色体异常；表现出氧化磷酸化受损和体外对厌氧糖酵解的依赖，与HLRCC的临床表现一致。此外，细胞表现出葡萄糖依赖性生长，乳酸外排率升高，葡萄糖转运体Glut 1和乳酸脱氢酶（LDH） 5过度表达。突变的FH蛋白主要存在于水肿的线粒体中，但其催化活性几乎检测不到。uok262异种移植物保留了HLRCC的组织病理学特征。我们的研究结果表明，氧化磷酸化的严重损害和UOK 262的快速糖酵解通量是这种TCA循环酶缺陷型肾癌的基本特征。该肿瘤模型是“Warburg效应”的体现。UOK 262提供了一种独特的体外和体内临床前模式来研究人类癌症中Warburg效应的生物能量学。
Energy deregulation and abnormalities of tumor cell metabolism are critical issues in our understanding of cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of the Krebs cycle enzyme, fumarate hydratase (FH), and is known to be highly metastatic and unusually lethal. There is significant utility in establishing preclinical cell and xenograft models for study of disorder of energy metabolism as well as development of new therapeutic approaches targeting of tricarboxylic acid (TCA) cycle deficient human cancers. Here we report the first immortal cell line derived from a patient having aggressive HLRCC-associated recurring kidney cancer, designated as UOK 262. We investigated gene expression, chromosome profiles, efflux bioenergetic analysis, mitochondrial ultrastructure, FH catabolic activity, invasiveness, and optimal glucose requirements for in vitro growth. UOK 262 cells have isochromosome 1q [i(1)(q10)] as recurring chromosome abnormality; demonstrate compromised oxidative phosphorylation and in vitro dependence on anaerobic glycolysis consistent with the clinical manifestation of HLRCC. Furthermore the cells display glucose-dependent growth, an elevated rate of lactate efflux, over-expression of the glucose transporter Glut 1 and lactate dehydrogenase (LDH) 5. Mutant FH protein was primarily present in edematous mitochondria, but its catalytic activity was nearly undetectable. UOK 262 xenografts retain the characteristics of HLRCC histopathology. Our findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this TCA cycle enzyme deficient form of kidney cancer. This tumor model is the embodiment of the “Warburg effect”. UOK 262 provides a unique in vitro and in vivo preclinical mode to study the bioenergetics of the Warburg effect in human cancer.
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