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首页> 外文期刊>Cell cycle >Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the 'reverse Warburg effect': A transcriptional informatics analysis with validation.
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Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the 'reverse Warburg effect': A transcriptional informatics analysis with validation.

机译：基质小窝蛋白-1的缺失会导致氧化应激，模拟缺氧并在肿瘤微环境中引发炎症，从而赋予“逆向Warburg效应”：经过验证的转录信息学分析。

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Cav-1 (-/-) deficient stromal cells are a new genetic model for myofibroblasts and cancer-associated fibroblasts. Using an unbiased informatics analysis of the transcriptional profile of Cav-1 (-/-) deficient mesenchymal stromal cells, we have now identified many of the major signaling pathways that are activated by a loss of Cav-1, under conditions of metabolic restriction (with low glucose media). Our informatics analysis suggests that a loss of Cav-1 induces oxidative stress, which mimics a constitutive pseudo-hypoxic state, leading to (1) aerobic glycolysis and (2) inflammation in the tumor stromal microenvironment. This occurs via the activation of 2 major transcription factors, namely HIF (aerobic glycolysis) and NFkappaB (inflammation) in Cav-1 (-/-) stromal fibroblastic cells. Experimentally, we show that Cav-1 deficient stromal cells may possess defective mitochondria, due to the over-production of nitric oxide (NO), resulting in the tyrosine nitration of the mitochondrial respiratory chain components (such as complex I). Elevated levels of nitro-tyrosine were observed both in Cav-1 (-/-) stromal cells, and via acute knock-down with siRNA targeting Cav-1. Finally, metabolic restriction with mitochondrial (complex I) and glycolysis inhibitors was synthetically lethal with a Cav-1 (-/-) deficiency in mice. As such, Cav-1 deficient mice show a dramatically reduced mitochondrial reserve capacity. Thus, a mitochondrial defect in Cav-1 deficient stromal cells could drive oxidative stress, leading to aerobic glycolysis, and inflammation, in the tumor microenvironment. These stromal alterations may underlie the molecular basis of the "Reverse Warburg Effect", and could provide the key to targeted anti-cancer therapies using metabolic inhibitors. In direct support of these findings, the transcriptional profile of Cav-1 (-/-) stromal cells overlaps significantly with Alzheimer's disease, which is characterized by oxidative stress, NO over-production (peroxynitrite formation), inflammation, hypoxia and mitochondrial dysfunction. We conclude that Cav-1 (-/-) deficient mice are a new whole-body animal model for an activated lethal tumor microenvironment, i.e., tumor stroma animal model for profibrotic disease, our current results may have implications for understanding the pathogenesis of scleroderma (systemic sclerosis) and pulmonary fibrosis, which are also related to abnormal mesenchymal stem cell function.
机译：Cav-1（-/-）缺乏的基质细胞是成肌纤维细胞和癌症相关成纤维细胞的新遗传模型。使用Cav-1（-/-）缺陷间充质基质细胞转录谱的无偏信息学分析，我们现在已经确定了在代谢限制条件下许多Cav-1缺失激活的主要信号通路（低葡萄糖培养基）。我们的信息学分析表明，Cav-1的缺失会诱导氧化应激，该氧化应激模拟本构的假低氧状态，从而导致（1）有氧糖酵解和（2）肿瘤基质微环境中的炎症。这是通过激活Cav-1（-/-）基质成纤维细胞中的2种主要转录因子，即HIF（有氧糖酵解）和NFkappaB（炎症）而发生的。实验上，我们表明缺乏Cav-1的基质细胞可能具有缺陷的线粒体，这是由于一氧化氮（NO）的过量产生，导致线粒体呼吸链成分（如复合物I）的酪氨酸硝化。在Cav-1（-/-）基质细胞中以及通过靶向Cav-1的siRNA的急性敲低都观察到硝基酪氨酸水平升高。最后，线粒体（复合体I）和糖酵解抑制剂的代谢限制在小鼠中具有Cav-1（-/-）缺乏症，是合成致死性的。因此，缺乏Cav-1的小鼠显示出明显降低的线粒体储备能力。因此，在肿瘤微环境中，缺乏Cav-1的基质细胞中的线粒体缺陷可能会驱动氧化应激，导致需氧糖酵解和炎症。这些基质改变可能是“反向Warburg效应”的分子基础，并且可以提供使用代谢抑制剂进行靶向抗癌治疗的关键。这些发现的直接支持是Cav-1（-/-）基质细胞的转录谱与阿尔茨海默氏病显着重叠，该病的特征是氧化应激，NO过度产生（过亚硝酸盐形成），炎症，缺氧和线粒体功能障碍。我们得出的结论是，Cav-1（-/-）缺陷小鼠是活化致死性肿瘤微环境的新型全身动物模型，即纤维变性疾病的肿瘤基质动物模型，我们目前的研究结果可能对理解硬皮病的发病机理具有重要意义。 （全身性硬化）和肺纤维化，也与间充质干细胞功能异常有关。

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