Cytokine production and inflammation drive autophagy in the tumor microenvironment Role of stromal caveolin-1 as a key regulator
Cytokine production and inflammation drive autophagy in the tumor microenvironment Role of stromal caveolin-1 as a key regulator
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DOI：
10.4161/cc.10.11.15674
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发表时间：
2011-06-01
期刊：
影响因子：
4.3
通讯作者：
Sotgia, Federica
中科院分区：
文献类型：
--
作者：
Martinez-Outschoorn, Ubaldo E.;Whitaker-Menezes, Diana;Sotgia, Federica
最近，我们提出了一种新的范例来理解肿瘤微环境在乳腺癌发病和进展中的作用。在该模型中，癌细胞在邻近的成纤维细胞中诱导氧化应激。这反过来又导致基质自噬的发生，产生回收的营养物质来“喂养”合成代谢癌细胞。然而，肿瘤微环境中的自噬与炎症（肿瘤发生的另一个关键驱动因素）之间的关系仍不清楚。为了解决这个问题，我们采用了一种特征良好的共培养系统，其中癌细胞通过氧化应激和 NF kappa B 激活诱导相邻成纤维细胞自噬。我们表明，使用这种共培养系统，导致自噬微环境的相同实验条件也会促进多种炎症介质（包括 IL-6、IL-8、IL-10、MIP1 α、IFN γ、RANTE S (CCL5) 和 GMCSF）的产生。此外，我们证明大多数这些炎症介质单独足以直接诱导成纤维细胞自噬的发生。为了进一步验证这些发现的体内相关性，我们评估了 Cav-1 (-/-) 无效乳腺脂肪垫的炎症状态，这是真正的自噬微环境的模型。值得注意的是，我们发现 Cav-1 (-/-) 乳腺脂肪垫受到多种炎症细胞类型的浸润，包括淋巴细胞、T 细胞、巨噬细胞和肥大细胞。综上所述，我们的结果表明细胞因子的产生和炎症是肿瘤微环境中自噬的关键驱动因素。这些结果可以解释为什么基质 Cav-1 的缺失是乳腺癌患者临床结果不佳的有力预测因素，因为它是肿瘤微环境中 (1) 自噬和 (2) 炎症的标志物。最后，成纤维细胞中的缺氧不足以诱导我们在成纤维细胞与癌细胞共培养期间观察到的全面炎症反应，这表明癌细胞和成纤维细胞之间可能需要关键的相互作用。
Recently, we proposed a new paradigm for understanding the role of the tumor microenvironment in breast cancer onset and progression. In this model, cancer cells induce oxidative stress in adjacent fibroblasts. This, in turn, results in the onset of stromal autophagy, which produces recycled nutrients to "feed" anabolic cancer cells. However, it remains unknown how autophagy in the tumor microenvironment relates to inflammation, another key driver of tumorigenesis. To address this issue, here we employed a well-characterized co-culture system in which cancer cells induce autophagy in adjacent fibroblasts via oxidative stress and NF kappa B-activation. We show, using this co-culture system, that the same experimental conditions that result in an autophagic microenvironment, also drive in the production of numerous inflammatory mediators (including IL-6, IL-8, IL-10, MIP1 alpha, IFN gamma, RANTE S (CCL5) and GMCSF). Furthermore, we demonstrate that most of these inflammatory mediators are individually sufficient to directly induce the onset of autophagy in fibroblasts. To further validate the in vivo relevance of these findings, we assessed the inflammatory status of Cav-1 (-/-) null mammary fat pads, which are a model of a bonafide autophagic microenvironment. Notably, we show that Cav-1 (-/-) mammary fat pads undergo infiltration with numerous inflammatory cell types, including lymphocytes, T-cells, macrophages and mast cells. Taken together, our results suggest that cytokine production and inflammation are key drivers of autophagy in the tumor microenvironment. These results may explain why a loss of stromal Cav-1 is a powerful predictor of poor clinical outcome in breast cancer patients, as it is a marker of both (1) autophagy and (2) inflammation in the tumor microenvironment. Lastly, hypoxia in fibroblasts was not sufficient to induce the full-blown inflammatory response that we observed during the co-culture of fibroblasts with cancer cells, indicating that key reciprocal interactions between cancer cells and fibroblasts may be required.