Departments of Stem Cell Biology and Regenerative Medicine and Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Cancer Biol Ther. 2011 Dec 15;12(12):1101-13. doi: 10.4161/cbt.12.12.18703.
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 NFκB-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).
我们之前的研究表明，肿瘤基质中增强的有氧糖酵解和/或自噬通过分泌高能代谢物来支持上皮癌细胞的生长和侵袭行为。这些营养物质包括乳酸盐和酮体，以及化学构建块，如氨基酸（谷氨酰胺）和核苷酸。乳酸盐和酮体可作为癌细胞氧化代谢的燃料，而构建块则维持着快速增殖的癌细胞的合成代谢需求。我们将这些新的概念称为“反向沃伯格效应”和“肿瘤代谢中的自噬性肿瘤基质模型”。我们还发现基质中窖蛋白-1（Cav-1）的缺失是基质糖酵解和自噬的标志物。本研究的目的是提供遗传证据，证明基质细胞中增强的糖酵解有利于肿瘤发生。为此，我们通过基因工程使正常的人成纤维细胞表达糖酵解途径中的关键酶丙酮酸激酶 M（PKM1 和 PKM2）的两种同工型。在异种移植模型中，表达 PKM1 或 PKM2 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，而肿瘤血管生成没有增加。有趣的是，PKM1 和 PKM2 通过不同的机制促进了肿瘤发生。PKM1 的表达增强了基质细胞的糖酵解能力，乳酸盐的产量增加。对肿瘤异种移植的分析表明，PKM1 成纤维细胞通过 CD45 染色极大地诱导了肿瘤炎症。相比之下，PKM2 不会导致乳酸盐积累，但会引发基质细胞中的“假性饥饿”反应，诱导 NFκB 依赖性自噬程序，并增加酮体 3-羟基丁酸的产量。引人注目的是，对肿瘤异种移植中复合物 IV 活性的原位评估表明，基质中 PKM2 的表达特异性地驱动肿瘤细胞中的线粒体呼吸。最后，对缺乏基质 Cav-1 的人类乳腺癌样本进行免疫组织化学分析显示，肿瘤基质中存在 PKM1 和 PKM2 的表达。因此，我们的数据表明，一部分失去基质 Cav-1 的人类乳腺癌患者在肿瘤微环境中表现出明显的代谢变化。因此，这组患者可能从针对糖酵解、自噬和/或线粒体活性的强效抑制剂治疗中获益（如二甲双胍）。
Plast Reconstr Surg Glob Open. 2023-8-16
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