文章：

癌症中的小泡和信号传导

Caveolae and signalling in cancer

原文发布日期：2015-03-24

DOI: 10.1038/nrc3915

类型: Review Article

开放获取: 否

要点：

1. Lipid rafts are cell membrane microdomains that are enriched for cholesterol and signalling proteins. Lipid rafts can have a planar or a non-planar configuration. Caveolae are a subset of lipid rafts that are invaginated, non-planar structures. Caveolins are the main integral membrane proteins of caveolae and are required for their formation.
2. Caveolin 1 (CAV1) is a key regulator of cell signalling. The caveolin scaffolding domain binds to many divergent signalling molecules and modulates their activity. In many of these instances CAV1 represses signalling cascades and its downregulation leads to signalling activation. For example, the activity of endothelial nitric oxide synthase (eNOS), G proteins, SRC family tyrosine kinases and members of the RAS family are all repressed by binding to CAV1. Loss of CAV1 frequently leads to the activation of signalling cascades, with tumorigenic effects such as increased cell motility and proliferation.
3. Alterations in caveolae have a strong cancer-specific prognostic value. Three caveolar components have all been shown to be reduced or absent in the tumour stroma of high-risk cancer patients. These caveolar biomarkers are CAV1, cavin 1 and CD36.
4. Loss of CAV1 expression in the tumour microenvironment is consistently associated with poor clinical outcomes in a wide variety of cancers, including breast, prostate, pancreatic, oesophageal and gastric carcinomas, as well as melanomas. By contrast, there is no universal pattern of CAV1 expression in epithelial cancer cells that is associated with clinical outcome.
5. Alterations in caveolae in the tumour microenvironment promote paracrine tumour growth via myofibroblast differentiation, transforming growth factor-β (TGFβ) activation, oxidative stress, autophagy and catabolism, as well as premature senescence.
6. Altered caveolae in the tumour microenvironment induce tumour metabolic heterogeneity. The loss of CAV1 generates a catabolic tumour microenvironment that is characterized by increased glycolysis and the generation of L-lactate, ketone bodies and free amino acids. Conversely, cancer cells have increased oxidative metabolism (OXPHOS) and resistance to apoptosis, when there is a loss of CAV1 in the tumour microenvironment.

要点翻译：

1. 脂筏是细胞膜微区，富含胆固醇和信号蛋白。脂筏可呈现平面或非平面构型。小窝是脂筏的一个亚类，呈内陷型非平面结构。小窝蛋白是小窝的主要整合膜蛋白，是其形成所必需的结构蛋白。
2. 小窝蛋白1（CAV1）是细胞信号传导的关键调节因子。其支架结构域可与多种不同信号分子结合并调节其活性。在多数情况下，CAV1会抑制信号级联反应，其下调则导致信号激活。例如，内皮型一氧化氮合酶（eNOS）、G蛋白、SRC家族酪氨酸激酶及RAS家族成员均通过与CAV1结合而受到抑制。CAV1的缺失常引起信号级联激活，产生促肿瘤效应，如增强细胞运动性和增殖能力。
3. 小窝结构的改变具有显著的癌症特异性预后价值。在高危癌症患者的肿瘤间质中，三种小窝组分均被证实减少或缺失。这些小窝生物标志物包括CAV1、小窝蛋白关联蛋白1和CD36。
4. 在肿瘤微环境中，CAV1表达的缺失与多种癌症的不良临床结局持续相关，包括乳腺癌、前列腺癌、胰腺癌、食管癌、胃癌以及黑色素瘤。相比之下，上皮癌细胞中CAV1的表达模式与临床结局之间未发现普遍关联规律。
5. 肿瘤微环境中小窝结构的改变通过肌成纤维细胞分化、转化生长因子-β（TGFβ）激活、氧化应激、自噬与分解代谢以及早衰等现象促进旁分泌肿瘤生长。
6. 肿瘤微环境中改变的小窝会诱导肿瘤代谢异质性。CAV1的缺失形成分解代谢型肿瘤微环境，其特征为糖酵解增强及L-乳酸、酮体和游离氨基酸的生成增加。反之，当肿瘤微环境中CAV1缺失时，癌细胞的氧化代谢（OXPHOS）会增强并获得抗凋亡能力。

英文摘要：

It has been over 20 years since the discovery that caveolar lipid rafts function as signalling organelles. Lipid rafts create plasma membrane heterogeneity, and caveolae are the most extensively studied subset of lipid rafts. A newly emerging paradigm is that changes in caveolae also generate tumour metabolic heterogeneity. Altered caveolae create a catabolic tumour microenvironment, which supports oxidative mitochondrial metabolism in cancer cells and which contributes to dismal survival rates for cancer patients. In this Review, we discuss the role of caveolae in tumour progression, with a special emphasis on their metabolic and cell signalling effects, and their capacity to transform the tumour microenvironment.

摘要翻译： 

自从发现小窝脂筏作为信号细胞器发挥作用以来，已过去20余年。脂筏造成质膜异质性，而小窝是研究最深入的脂筏亚群。一个新兴观点认为，小窝的变化还会带来肿瘤代谢异质性。小窝的改变营造出分解代谢的肿瘤微环境，支持癌细胞的氧化线粒体代谢，并导致癌症患者生存率极差。在本综述中，我们讨论小窝在肿瘤进展中的作用，特别侧重其代谢与细胞信号效应，以及其改造肿瘤微环境的能力。

原文链接：

Caveolae and signalling in cancer