Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
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.
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Acknowledgements
The authors apologize that they were unable to cite many primary references owing to space limitations. U.E.M.-O. was supported, in part, by funding from the US National Cancer Institute of the National Institutes of Health under Award Number K08 CA175193-01A1. M.P.L. and F.S. were supported, in part, by funding from the European Union (ERC Advanced Grant), Breakthrough Breast Cancer and the Manchester Cancer Research Centre (MCRC).
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Martinez-Outschoorn, U., Sotgia, F. & Lisanti, M. Caveolae and signalling in cancer. Nat Rev Cancer 15, 225–237 (2015). https://doi.org/10.1038/nrc3915
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DOI: https://doi.org/10.1038/nrc3915
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