Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth
Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth
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DOI：
10.4161/cbt.12.12.18703
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发表时间：
2011-12-15
影响因子：
3.6
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
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作者：
Chiavarina, Barbara;Whitaker-Menezes, Diana;Lisanti, Michael P.
我们先前已经证明，肿瘤间质中增强的有氧糖酵解和/或自噬通过分泌高能代谢物支持上皮癌细胞生长和侵袭行为。这些营养素包括乳酸盐和酮，以及化学结构单元，如氨基酸（谷氨酰胺）和核苷酸。乳酸盐和酮是癌细胞氧化代谢的燃料，而构建块维持快速增殖的癌细胞的合成代谢需求。我们将这些新概念称为“反向瓦尔堡效应”和“肿瘤代谢的自噬肿瘤基质模型”。“我们还确定了基质小窝蛋白-1（Cav-1）的缺失作为基质糖酵解和自噬的标志物。本研究的目的是提供遗传学证据，即基质细胞中糖酵解的增强有利于肿瘤发生。为此，对正常人成纤维细胞进行基因工程改造，使其表达丙酮酸激酶M的两种亚型（PKM 1和PKM 2），这是糖酵解途径中的关键酶。在异种移植模型中，表达PKM 1或PKM 2的成纤维细胞极大地促进了共注射的MDA-MB-231乳腺癌细胞的生长，而没有增加肿瘤血管生成。有趣的是，PKM 1和PKM 2通过不同的机制促进肿瘤发生。PKM 1的表达增强了基质细胞的糖酵解能力，增加了乳酸的输出。肿瘤异种移植物的分析表明，PKM 1成纤维细胞极大地诱导肿瘤炎症，如通过CD 45染色所判断的。相比之下，PKM 2不导致乳酸盐积累，但引发基质细胞中的“假饥饿”反应，诱导NF κ B依赖性自噬程序，并增加酮体3-羟基-丁酸盐的输出。引人注目的是，在肿瘤异种移植物中复合物IV活性的原位评价表明基质PKM 2表达特异性地驱动肿瘤细胞中的线粒体呼吸。最后，缺乏间质Cav-1的人乳腺癌样品的免疫组织化学分析揭示了PKM 1和PKM 2在肿瘤间质中的表达。因此，我们的数据表明，一个亚组的人乳腺癌患者与基质Cav-1的损失显示出深刻的代谢变化的肿瘤微环境。因此，该患者亚组可能在治疗上受益于靶向糖酵解、自噬和/或线粒体活性的有效抑制剂（例如二甲双胍）。
We have previously demonstrated that enhanced aerobic glycolysis and/or autophagy in the tumor stroma supports epithelial cancer cell growth and aggressive behavior, via the secretion of high-energy metabolites. These nutrients include lactate and ketones, as well as chemical building blocks, such as amino acids (glutamine) and nucleotides. Lactate and ketones serve as fuel for cancer cell oxidative metabolism, and building blocks sustain the anabolic needs of rapidly proliferating cancer cells. We have termed these novel concepts the "Reverse Warburg Effect," and the "Autophagic Tumor Stroma Model of Cancer Metabolism." We have also identified a loss of stromal caveolin-1 (Cav-1) as a marker of stromal glycolysis and autophagy. The aim of the current study was to provide genetic evidence that enhanced glycolysis in stromal cells favors tumorigenesis. To this end, normal human fibroblasts were genetically-engineered to express the two isoforms of pyruvate kinase M (PKM1 and PKM2), a key enzyme in the glycolytic pathway. In a xenograft model, fibroblasts expressing PKM1 or PKM2 greatly promoted the growth of co-injected MDA-MB-231 breast cancer cells, without an increase in tumor angiogenesis. Interestingly, PKM1 and PKM2 promoted tumorigenesis by different mechanism(s). Expression of PKM1 enhanced the glycolytic power of stromal cells, with increased output of lactate. Analysis of tumor xenografts demonstrated that PKM1 fibroblasts greatly induced tumor inflammation, as judged by CD45 staining. In contrast, PKM2 did not lead to lactate accumulation, but triggered a "pseudo-starvation" response in stromal cells, with induction of an NF kappa B-dependent autophagic program, and increased output of the ketone body 3-hydroxy- buryrate. Strikingly, in situ evaluation of Complex IV activity in the tumor xenografts demonstrated that stromal PKM2 expression drives mitochondrial respiration specifically in tumor cells. Finally, immuno-histochemistry analysis of human breast cancer samples lacking stromal Cav-1 revealed PKM1 and PKM2 expression in the tumor stroma. Thus, our data indicate that a subset of human breast cancer patients with a loss of stromal Cav-1 show profound metabolic changes in the tumor microenvironment. As such, this subgroup of patients may benefit therapeutically from potent inhibitors targeting glycolysis, autophagy and/or mitochondrial activity (such as metformin).