Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth Connecting TGF-β signaling with "Warburg-like" cancer metabolism and L-lactate production
Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth Connecting TGF-β signaling with "Warburg-like" cancer metabolism and L-lactate production
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DOI：
10.4161/cc.21384
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发表时间：
2012-08-15
期刊：
影响因子：
4.3
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
--
作者：
Guido, Carmela;Whitaker-Menezes, Diana;Lisanti, Michael P.
我们先前已经证明，间质Cav-1的缺失是乳腺癌预后不良的生物标志物。从机制上讲，Cav-1的缺失导致基质细胞代谢重编程，自噬/有丝分裂增加，线粒体功能障碍和有氧糖酵解。因此，Cav-1-低CAF产生营养物质(如L乳酸盐)和化学积木，为线粒体新陈代谢和邻近乳腺癌细胞的合成代谢生长提供动力。我们还知道Cav-1的缺失与过度活跃的转化生长因子-β信号有关。然而，目前尚不清楚转化生长因子-β信号通路的过度激活是否参与了Cav-1-low CAF的代谢重编程。为了解决这些问题，我们在间质成纤维细胞和乳腺癌细胞中过表达了转化生长因子-β配体和转化生长因子-β受体I(转化生长因子-β-RI)。在这里，我们表明转化生长因子-β在肿瘤发生中的作用是特定的，转化生长因子-β通过将与癌症相关的成纤维细胞转移到分解代谢来促进肿瘤的发生。重要的是，转化生长因子-β的促肿瘤作用与产生转化生长因子-β的细胞类型无关。因此，间质来源的转化生长因子-β以自分泌方式激活间质细胞中的信号，导致成纤维细胞激活，通过增加肌成纤维细胞标志物的表达来判断，并进行代谢重编程，转向分解代谢和氧化应激。我们还表明，转化生长因子-β激活的成纤维细胞促进邻近癌细胞的线粒体活性，并在异种移植模型中，促进乳腺癌细胞的生长，而不依赖于血管生成。相反，癌细胞中转化生长因子-β途径的激活不会影响肿瘤的生长，但癌细胞衍生的转化生长因子-β配体以旁分泌方式影响基质细胞，导致成纤维细胞激活和促进肿瘤生长。总之，依赖配体或细胞自主激活基质细胞中的转化生长因子-β途径可诱导其代谢重新编程，导致氧化应激、自噬/有丝分裂和糖酵解增加，并下调Cav-1的表达。这些代谢变化可以在邻近的成纤维细胞中传播，并极大地维持乳腺癌细胞的生长。我们的数据为转化生长因子-β途径在乳腺肿瘤发生中的作用提供了新的见解，并在转化生长因子-β信号的促肿瘤作用和肿瘤微环境的代谢重编程之间建立了明确的因果联系。
We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive TGF-beta signaling. However, it remains unknown whether hyperactivation of the TGF-beta signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. To address these issues, we overexpressed TGF-beta ligands and the TGF-beta receptor I (TGF-beta-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of TGF-beta in tumorigenesis is compartment-specific, and that TGF-beta promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumor-promoting effects of TGF-beta are independent of the cell type generating TGF-beta. Thus, stromal-derived TGF-beta activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that TGF-beta-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the TGF-beta pathway in cancer cells does not influence tumor growth, but cancer cell-derived-TGF-beta ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cell-autonomous activation of the TGF-beta pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. These metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of breast cancer cells. Our data provide novel insights into the role of the TGF-beta pathway in breast tumorigenesis, and establish a clear causative link between the tumor-promoting effects of TGF-beta signaling and the metabolic reprogramming of the tumor microenvironment.