KEY POINTS * 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. * 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

stroma of high-risk cancer patients. These caveolar biomarkers are CAV1, cavin 1 and CD36. * 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. * 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. * 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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support SIMILAR CONTENT BEING VIEWED BY OTHERS CAVEOLIN-1 MEDIATES THE UTILIZATION OF EXTRACELLULAR PROTEINS FOR SURVIVAL IN REFRACTORY GASTRIC CANCER Article Open access 02 November 2023 A

NOVEL TRPM7/_O_-GLCNAC AXIS MEDIATES TUMOUR CELL MOTILITY AND METASTASIS BY STABILISING C-MYC AND CAVEOLIN-1 IN LUNG CARCINOMA Article Open access 20 July 2020 CAVEOLIN-1 SUPPRESSES TUMOR

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276, 35150–35158 (2001). Article  CAS  PubMed  Google Scholar  Download references 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). AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA Ubaldo E. Martinez-Outschoorn * Breakthrough

Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester, M20 4BX, UK Federica Sotgia & Michael P. Lisanti * Manchester Centre for Cellular

Metabolism (MCCM), University of Manchester, M20 4BX, Manchester, UK Federica Sotgia & Michael P. Lisanti Authors * Ubaldo E. Martinez-Outschoorn View author publications You can also

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publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Federica Sotgia or Michael P. Lisanti. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR

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Lisanti, M. Caveolae and signalling in cancer. _Nat Rev Cancer_ 15, 225–237 (2015). https://doi.org/10.1038/nrc3915 Download citation * Published: 24 March 2015 * Issue Date: April 2015 *

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