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  • Review Article
  • Published:

Caveolae and signalling in cancer

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 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.

  • 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.

  • 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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Figure 1: Membrane microdomains.
Figure 2: Examples of regulation of cell signalling by CAV1: eNOS, SRC and dually acylated proteins.
Figure 3: CAV1 expression and the CAF phenotype.
Figure 4: Downstream effects of a loss of CAV1 expression on CAFs and carcinoma cells.
Figure 5: CAV1 and CD36 expression and the transition to malignancy in breast cancer.
Figure 6: Caveolae discovery timeline: from signalling to cancer biomarkers.

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References

  1. Singer, S. J. & Nicolson, G. L. The fluid mosaic model of the structure of cell membranes. Science 175, 720–731 (1972).

    Article  CAS  PubMed  Google Scholar 

  2. Lingwood, D. & Simons, K. Lipid rafts as a membrane-organizing principle. Science 327, 46–50 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Holopainen, J. M., Subramanian, M. & Kinnunen, P. K. Sphingomyelinase induces lipid microdomain formation in a fluid phosphatidylcholine/sphingomyelin membrane. Biochemistry 37, 17562–17570 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Veatch, S. L. & Keller, S. L. Organization in lipid membranes containing cholesterol. Phys. Rev. Lett. 89, 268101 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Rothberg, K. G. et al. Caveolin, a protein component of caveolae membrane coats. Cell 68, 673–682 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Parton, R. G. & Simons, K. The multiple faces of caveolae. Nature Rev. Mol. Cell Biol. 8, 185–194 (2007).

    Article  CAS  Google Scholar 

  8. Pike, L. J. Rafts defined: a report on the Keystone Symposium on lipid rafts and cell function. J. Lipid Res. 47, 1597–1598 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Parton, R. G. & del Pozo, M. A. Caveolae as plasma membrane sensors, protectors and organizers. Nature Rev. Mol. Cell Biol. 14, 98–112 (2013).

    Article  CAS  Google Scholar 

  10. Stuermer, C. A. The reggie/flotillin connection to growth. Trends Cell Biol. 20, 6–13 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Brown, D. A. & London, E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J. Biol. Chem. 275, 17221–17224 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Brown, D. A. & Rose, J. K. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68, 533–544 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Lisanti, M. P., Scherer, P. E., Tang, Z. & Sargiacomo, M. Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol. 4, 231–235 (1994). This is the first paper to propose the hypothesis that caveolae represent signalling microdomains at the plasma membrane.

    Article  CAS  PubMed  Google Scholar 

  14. Garcia-Cardena, G., Oh, P., Liu, J., Schnitzer, J. E. & Sessa, W. C. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc. Natl Acad. Sci. USA 93, 6448–6453 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Galbiati, F. et al. The dually acylated NH2-terminal domain of gi1α is sufficient to target a green fluorescent protein reporter to caveolin-enriched plasma membrane domains. Palmitoylation of caveolin-1 is required for the recognition of dually acylated g-protein α subunits in vivo. J. Biol. Chem. 274, 5843–5850 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Tao, N., Wagner, S. J. & Lublin, D. M. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails. J. Biol. Chem. 271, 22315–22320 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Dietzen, D. J., Hastings, W. R. & Lublin, D. M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270, 6838–6842 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Palade, G. E. Fine structure of blood capillaries. J. Appl. Phys. 24, 1424–1436 (1953).

    Google Scholar 

  19. Yamada, E. The fine structure of the gall bladder epithelium of the mouse. J. Biophys. Biochem. Cytol. 1, 445–458 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Okamoto, T., Schlegel, A., Scherer, P. E. & Lisanti, M. P. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J. Biol. Chem. 273, 5419–5422 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Owen, D. M., Magenau, A., Williamson, D. & Gaus, K. The lipid raft hypothesis revisited—new insights on raft composition and function from super-resolution fluorescence microscopy. Bioessays 34, 739–747 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Schlormann, W. et al. The shape of caveolae is omega-like after glutaraldehyde fixation and cup-like after cryofixation. Histochem. Cell Biol. 133, 223–228 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Sotgia, F. et al. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu. Rev. Pathol. 7, 423–467 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Lajoie, P. & Nabi, I. R. Regulation of raft-dependent endocytosis. J. Cell. Mol. Med. 11, 644–653 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Parat, M. O., Anand-Apte, B. & Fox, P. L. Differential caveolin-1 polarization in endothelial cells during migration in two and three dimensions. Mol. Biol. Cell 14, 3156–3168 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Murata, M. et al. VIP21/caveolin is a cholesterol-binding protein. Proc. Natl Acad. Sci. USA 92, 10339–10343 (1995). This is the first paper to demonstrate that CAV1 is a cholesterol-binding protein.

    Article  CAS  PubMed  Google Scholar 

  27. Sargiacomo, M. et al. Oligomeric structure of caveolin: implications for caveolae membrane organization. Proc. Natl Acad. Sci. USA 92, 9407–9411 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Couet, J., Li, S., Okamoto, T., Ikezu, T. & Lisanti, M. P. Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J. Biol. Chem. 272, 6525–6533 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Li, S., Couet, J. & Lisanti, M. P. Src tyrosine kinases, Gα subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J. Biol. Chem. 271, 29182–29190 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Drab, M. et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293, 2449–2452 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Razani, B. et al. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J. Biol. Chem. 276, 38121–38138 (2001). References 30 and 31 are the first papers to describe the generation and initial phenotypic characterization of Cav1 -knockout mouse models.

    Article  CAS  PubMed  Google Scholar 

  32. Fra, A. M., Williamson, E., Simons, K. & Parton, R. G. De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin. Proc. Natl Acad. Sci. USA 92, 8655–8659 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Vinten, J. et al. A 60-kDa protein abundant in adipocyte caveolae. Cell Tissue Res. 305, 99–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Voldstedlund, M., Thuneberg, L., Tranum-Jensen, J., Vinten, J. & Christensen, E. I. Caveolae, caveolin and cav-p60 in smooth muscle and renin-producing cells in the rat kidney. Acta Physiol. Scand. 179, 179–188 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Hill, M. M. et al. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132, 113–124 (2008). This is the first paper to show that cavin is required for caveolae formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bastiani, M. et al. MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes. J. Cell Biol. 185, 1259–1273 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fairn, G. D. et al. High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. J. Cell Biol. 194, 257–275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hansen, C. G., Shvets, E., Howard, G., Riento, K. & Nichols, B. J. Deletion of cavin genes reveals tissue-specific mechanisms for morphogenesis of endothelial caveolae. Nature Commun. 4, 1831 (2013).

    Article  CAS  Google Scholar 

  39. Shastry, S. et al. Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations. Am. J. Med. Genet. A 152A, 2245–2253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rajab, A. et al. Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations. PLoS Genet. 6, e1000874 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bai, L. et al. Down-regulation of the cavin family proteins in breast cancer. J. Cell Biochem. 113, 322–328 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Zochbauer-Muller, S. et al. Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. Oncogene 24, 6249–6255 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Souto, R. P. et al. Immunopurification and characterization of rat adipocyte caveolae suggest their dissociation from insulin signaling. J. Biol. Chem. 278, 18321–18329 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Daumke, O. et al. Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling. Nature 449, 923–927 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Moren, B. et al. EHD2 regulates caveolar dynamics via ATP-driven targeting and oligomerization. Mol. Biol. Cell 23, 1316–1329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Senju, Y., Itoh, Y., Takano, K., Hamada, S. & Suetsugu, S. Essential role of PACSIN2/syndapin-II in caveolae membrane sculpting. J. Cell Sci. 124, 2032–2040 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Hansen, C. G., Howard, G. & Nichols, B. J. Pacsin 2 is recruited to caveolae and functions in caveolar biogenesis. J. Cell Sci. 124, 2777–2785 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Parton, R. G., Way, M., Zorzi, N. & Stang, E. Caveolin-3 associates with developing T-tubules during muscle differentiation. J. Cell Biol. 136, 137–154 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Parton, R. G., Joggerst, B. & Simons, K. Regulated internalization of caveolae. J. Cell Biol. 127, 1199–1215 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Boucrot, E., Howes, M. T., Kirchhausen, T. & Parton, R. G. Redistribution of caveolae during mitosis. J. Cell Sci. 124, 1965–1972 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. del Pozo, M. A. et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nature Cell Biol. 7, 901–908 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Furuchi, T. & Anderson, R. G. Cholesterol depletion of caveolae causes hyperactivation of extracellular signal-related kinase (ERK). J. Biol. Chem. 273, 21099–21104 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Fielding, C. J., Bist, A. & Fielding, P. E. Caveolin mRNA levels are up-regulated by free cholesterol and down-regulated by oxysterols in fibroblast monolayers. Proc. Natl Acad. Sci. USA 94, 3753–3758 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Feron, O., Dessy, C., Moniotte, S., Desager, J. P. & Balligand, J. L. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J. Clin. Invest. 103, 897–905 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Frank, P. G. et al. Caveolin-1 and regulation of cellular cholesterol homeostasis. Am. J. Physiol. Heart Circ. Physiol. 291, H677–H686 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Bosch, M. et al. Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr. Biol. 21, 681–686 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Martinez-Outschoorn, U. E., Lisanti, M. P. & Sotgia, F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin. Cancer Biol. 25, 47–60 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Witkiewicz, A. K. et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am. J. Pathol. 174, 2023–2034 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sloan, E. K. et al. Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am. J. Pathol. 174, 2035–2043 (2009). References 58 and 59 are the first papers to demonstrate that loss of stromal CAV1 expression is associated with poor clinical outcome in patients with breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Simpkins, S. A., Hanby, A. M., Holliday, D. L. & Speirs, V. Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J. Pathol. 227, 490–498 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Sotgia, F. et al. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res. 13, 213 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Trimmer, C. et al. Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: a new genetically tractable model for human cancer associated fibroblasts. Cancer Biol. Ther. 11, 383–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Williams, T. M. et al. Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo. Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion. J. Biol. Chem. 279, 51630–51646 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Witkiewicz, A. K. et al. Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle 11, 1108–1117 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ayala, G. et al. Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression. J. Pathol. 231, 77–87 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Giatromanolaki, A., Koukourakis, M. I., Koutsopoulos, A., Mendrinos, S. & Sivridis, E. The metabolic interactions between tumor cells and tumor-associated stroma (TAS) in prostatic cancer. Cancer Biol. Ther. 13, 1284–1289 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Di Vizio, D. et al. An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation. Cell Cycle 8, 2420–2424 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jia, Y. et al. Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: a potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis. Ann. Surg. Oncol. 21, 329–336 (2014).

    Article  PubMed  Google Scholar 

  70. Zhao, X. et al. Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer. PLoS ONE 8, e59102 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wu, K. N. et al. Loss of stromal caveolin-1 expression in malignant melanoma metastases predicts poor survival. Cell Cycle 10, 4250–4255 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Chen, D. & Che, G. Value of caveolin-1 in cancer progression and prognosis: Emphasis on cancer-associated fibroblasts, human cancer cells and mechanism of caveolin-1 expression (Review). Oncol. Lett. 8, 1409–1421 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Savage, K. et al. Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis. Clin. Cancer Res. 13, 90–101 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Yang, G., Truong, L. D., Wheeler, T. M. & Thompson, T. C. Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker. Cancer Res. 59, 5719–5723 (1999).

    CAS  PubMed  Google Scholar 

  75. Thompson, T. C., Timme, T. L., Li, L. & Goltsov, A. Caveolin-1, a metastasis-related gene that promotes cell survival in prostate cancer. Apoptosis 4, 233–237 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Sunaga, N. et al. Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. Cancer Res. 64, 4277–4285 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Felicetti, F. et al. Caveolin-1 tumor-promoting role in human melanoma. Int. J. Cancer 125, 1514–1522 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang, H. et al. Restoration of caveolin-1 expression suppresses growth and metastasis of head and neck squamous cell carcinoma. Br. J. Cancer 99, 1684–1694 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Murakami, S. et al. Caveolin-I overexpression is a favourable prognostic factor for patients with extrahepatic bile duct carcinoma. Br. J. Cancer 88, 1234–1238 (2003).

    CAS  PubMed  Google Scholar 

  80. Bender, F. C., Reymond, M. A., Bron, C. & Quest, A. F. Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity. Cancer Res. 60, 5870–5878 (2000).

    CAS  PubMed  Google Scholar 

  81. Wiechen, K. et al. Caveolin-1 is down-regulated in human ovarian carcinoma and acts as a candidate tumor suppressor gene. Am. J. Pathol. 159, 1635–1643 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lin, M. I., Yu, J., Murata, T. & Sessa, W. C. Caveolin-1-deficient mice have increased tumor microvascular permeability, angiogenesis, and growth. Cancer Res. 67, 2849–2856 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Friedrich, T. et al. Deficiency of caveolin-1 in Apcmin/+ mice promotes colorectal tumorigenesis. Carcinogenesis 34, 2109–2118 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Capozza, F. et al. Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation. Am. J. Pathol. 162, 2029–2039 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Capozza, F. et al. Genetic ablation of Cav1 differentially affects melanoma tumor growth and metastasis in mice: role of Cav1 in Shh heterotypic signaling and transendothelial migration. Cancer Res. 72, 2262–2274 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mercier, I. et al. Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. Am. J. Pathol. 181, 278–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Moon, H. et al. PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer. Oncogene 33, 3561–3570 (2013). This paper suggests that loss of stromal cavin 1 expression is associated with poor outcome in patients with prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  88. DeFilippis, R. A. et al. CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues. Cancer Discov. 2, 826–839 (2012). This paper indicates that loss of stromal CD36 expression is associated with aggressive breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Frank, P. G. et al. Stabilization of caveolin-1 by cellular cholesterol and scavenger receptor class B type I. Biochemistry 41, 11931–11940 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Garcia-Cardena, G., Fan, R., Stern, D. F., Liu, J. & Sessa, W. C. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J. Biol. Chem. 271, 27237–27240 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Galbiati, F. et al. Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade. EMBO J. 17, 6633–6648 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Couet, J., Sargiacomo, M. & Lisanti, M. P. Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J. Biol. Chem. 272, 30429–30438 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Song, K. S. et al. Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J. Biol. Chem. 271, 9690–9697 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Garcia-Cardena, G. et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J. Biol. Chem. 272, 25437–25440 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Ariotti, N. et al. Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling. J. Cell Biol. 204, 777–792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee, S. W., Reimer, C. L., Oh, P., Campbell, D. B. & Schnitzer, J. E. Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene 16, 1391–1397 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Galbiati, F. et al. Caveolin-1 expression negatively regulates cell cycle progression by inducing G0/G1 arrest via a p53/p21(WAF1/Cip1)-dependent mechanism. Mol. Biol. Cell 12, 2229–2244 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hulit, J. et al. The cyclin D1 gene is transcriptionally repressed by caveolin-1. J. Biol. Chem. 275, 21203–21209 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Koleske, A. J., Baltimore, D. & Lisanti, M. P. Reduction of caveolin and caveolae in oncogenically transformed cells. Proc. Natl Acad. Sci. USA 92, 1381–1385 (1995).

    Article  CAS  PubMed  Google Scholar 

  100. Engelman, J. A., Zhang, X. L., Razani, B., Pestell, R. G. & Lisanti, M. P. p42/44 MAP kinase-dependent and -independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras-MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. J. Biol. Chem. 274, 32333–32341 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Sherif, Z. A. & Sultan, A. S. Divergent control of Cav-1 expression in non-cancerous Li-Fraumeni syndrome and human cancer cell lines. Cancer Biol. Ther. 14, 29–38 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hayashi, K. et al. Invasion activating caveolin-1 mutation in human scirrhous breast cancers. Cancer Res. 61, 2361–2364 (2001).

    CAS  PubMed  Google Scholar 

  103. Lee, H. et al. Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1−/− null mice show mammary epithelial cell hyperplasia. Am. J. Pathol. 161, 1357–1369 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bonuccelli, G. et al. Caveolin-1 (P132L), a common breast cancer mutation, confers mammary cell invasiveness and defines a novel stem cell/metastasis-associated gene signature. Am. J. Pathol. 174, 1650–1662 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Patani, N. et al. Non-existence of caveolin-1 gene mutations in human breast cancer. Breast Cancer Res. Treat. 131, 307–310 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Joshi, B. et al. Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion. Cancer Res. 68, 8210–8220 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Samarakoon, R. et al. Redox-induced Src kinase and caveolin-1 signaling in TGFβ1-initiated SMAD2/3 activation and PAI-1 expression. PLoS ONE 6, e22896 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhuang, L., Lin, J., Lu, M. L., Solomon, K. R. & Freeman, M. R. Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res. 62, 2227–2231 (2002).

    CAS  PubMed  Google Scholar 

  109. Xia, H. et al. Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. Am. J. Pathol. 176, 2626–2637 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Trimboli, A. J. et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461, 1084–1091 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sumitomo, M. et al. Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN. Cancer Cell 5, 67–78 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Midgley, A. C. et al. Transforming growth factor-β1 (TGFβ1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. J. Biol. Chem. 288, 14824–14838 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Calon, A., Tauriello, D. V. & Batlle, E. TGFβ in CAF-mediated tumor growth and metastasis. Semin. Cancer Biol. 25, 15–22 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Kojima, Y. et al. Autocrine TGFβ and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc. Natl Acad. Sci. USA 107, 20009–20014 (2010).

    Article  PubMed  Google Scholar 

  115. Guido, C. et al. Metabolic reprogramming of cancer-associated fibroblasts by TGFβ drives tumor growth: connecting TGFβ signaling with “Warburg-like” cancer metabolism and L-lactate production. Cell Cycle 11, 3019–3035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rosenthal, E. et al. Elevated expression of TGFβ1 in head and neck cancer-associated fibroblasts. Mol. Carcinog. 40, 116–121 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Calon, A. et al. Dependency of colorectal cancer on a TGFβ-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ting, H. J. et al. Silibinin prevents prostate cancer cell-mediated differentiation of naive fibroblasts into cancer-associated fibroblast phenotype by targeting TGF β2. Mol. Carcinog. http://dx.doi.org/10.1002/mc.22135 (2015).

  119. Razani, B. et al. Caveolin-1 regulates transforming growth factor TGFβ/SMAD signaling through an interaction with the TGFβ type I receptor. J. Biol. Chem. 276, 6727–6738 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Stuelten, C. H. et al. Breast cancer cells induce stromal fibroblasts to express MMP9 via secretion of TNFα and TGFβ. J. Cell Sci. 118, 2143–2153 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGFβ and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).

    PubMed  PubMed Central  Google Scholar 

  122. Grubisha, M. J., Cifuentes, M. E., Hammes, S. R. & Defranco, D. B. A local paracrine and endocrine network involving TGFβ, Cox-2, ROS, and estrogen receptor β influences reactive stromal cell regulation of prostate cancer cell motility. Mol. Endocrinol. 26, 940–954 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Toullec, A. et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol. Med. 2, 211–230 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bailey, K. M. & Liu, J. Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase. J. Biol. Chem. 283, 13714–13724 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Li, L. et al. Caveolin-1 promotes autoregulatory, Akt-mediated induction of cancer-promoting growth factors in prostate cancer cells. Mol. Cancer Res. 7, 1781–1791 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Meyer, C. et al. Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes. Cell Commun. Signal 11, 6 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Asterholm, I. W., Mundy, D. I., Weng, J., Anderson, R. G. & Scherer, P. E. Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell. Metab. 15, 171–185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Martinez-Outschoorn, U. E. et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle 9, 3515–3533 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chiavarina, B. et al. HIF1-α functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle 9, 3534–3551 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shaul, P. W. et al. Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae. J. Biol. Chem. 271, 6518–6522 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Ju, H., Zou, R., Venema, V. J. & Venema, R. C. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J. Biol. Chem. 272, 18522–18525 (1997).

    Article  CAS  PubMed  Google Scholar 

  132. Brouet, A. et al. Antitumor effects of in vivo caveolin gene delivery are associated with the inhibition of the proangiogenic and vasodilatory effects of nitric oxide. Faseb J. 19, 602–604 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Augsten, M. et al. Cancer-associated fibroblasts expressing CXCL14 rely upon Nos1-derived nitric oxide signaling for their tumor supporting properties. Cancer Res. 74, 2999–3010 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Bolanos, J. P., Peuchen, S., Heales, S. J., Land, J. M. & Clark, J. B. Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J. Neurochem. 63, 910–916 (1994).

    Article  CAS  PubMed  Google Scholar 

  135. Riobo, N. A. et al. Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation. Biochem. J. 359, 139–145 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Moncada, S. & Erusalimsky, J. D. Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nature Rev. Mol. Cell Biol. 3, 214–220 (2002).

    Article  CAS  Google Scholar 

  137. Xu, W., Liu, L., Charles, I. G. & Moncada, S. Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nature Cell Biol. 6, 1129–1134 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Galkin, A. & Moncada, S. S-nitrosation of mitochondrial complex I depends on its structural conformation. J. Biol. Chem. 282, 37448–37453 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Peterson, T. E. et al. Opposing effects of reactive oxygen species and cholesterol on endothelial nitric oxide synthase and endothelial cell caveolae. Circ. Res. 85, 29–37 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Parat, M. O., Stachowicz, R. Z. & Fox, P. L. Oxidative stress inhibits caveolin-1 palmitoylation and trafficking in endothelial cells. Biochem. J. 361, 681–688 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Whitaker-Menezes, D. et al. Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 10, 1772–1783 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Whitaker-Menezes, D. et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 10, 4047–4064 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Erez, N., Truitt, M., Olson, P., Arron, S. T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Subramaniam, K. S. et al. Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. PLoS ONE 8, e68923 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Vicent, S. et al. Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo. Cancer Res. 72, 5744–5756 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Erez, N., Glanz, S., Raz, Y., Avivi, C. & Barshack, I. Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumors. Biochem. Biophys. Res. Commun. 437, 397–402 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Martinez-Outschoorn, U. E. et al. Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle 10, 1784–1793 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Sotgia, F. et al. Caveolin-1−/− null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts. Am. J. Pathol. 174, 746–761 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Park, D. S. et al. Caveolin-1 null−/− mice show dramatic reductions in life span. Biochemistry 42, 15124–15131 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Le Lay, S. et al. The lipoatrophic caveolin-1 deficient mouse model reveals autophagy in mature adipocytes. Autophagy 6, 754–763 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Chaudhri, V. K. et al. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol. Cancer Res. 11, 579–592 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Paradis, V. et al. Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum. Pathol. 32, 327–332 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Med. 18, 1359–1368 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Bavik, C. et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 66, 794–802 (2006).

    Article  CAS  PubMed  Google Scholar 

  160. Dimmer, K. S., Friedrich, B., Lang, F., Deitmer, J. W. & Broer, S. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J. 350, 219–227 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ullah, M. S., Davies, A. J. & Halestrap, A. P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J. Biol. Chem. 281, 9030–9037 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Martins, D. et al. Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma: key events in the progression from an in situ to an invasive breast carcinoma. Cell Cycle 12, 2684–2690 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Cowell, C. F. et al. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. Mol. Oncol. 7, 859–869 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Pavlides, S. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8, 3984–4001 (2009). This is the first paper to demonstrate that aerobic glycolysis (the Warburg effect) occurs in CAFs and the tumour stroma.

    Article  CAS  PubMed  Google Scholar 

  165. Shiroto, T. et al. Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium. PLoS ONE 9, e87871 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Martinez-Outschoorn, U. E. et al. Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells. Cell Cycle 11, 3956–3963 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Fiaschi, T. et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 72, 5130–5140 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Brauer, H. A. et al. Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer. Clin. Cancer Res. 19, 571–585 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet. 18, 231–236 (1998).

    Article  CAS  PubMed  Google Scholar 

  170. Bonuccelli, G. et al. Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 9, 3506–3514 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Vegran, F., Boidot, R., Michiels, C., Sonveaux, P. & Feron, O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71, 2550–2560 (2011).

    Article  CAS  PubMed  Google Scholar 

  172. Ramanathan, A., Wang, C. & Schreiber, S. L. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc. Natl Acad. Sci. USA 102, 5992–5997 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Chiavarina, B. et al. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer Biol. Ther. 12, 1101–1113 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Sanita, P. et al. Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC Cancer 14, 154 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med. 17, 1498–1503 (2011).

    Article  CAS  PubMed  Google Scholar 

  176. Kim, H. M., Kim do, H., Jung, W. H. & Koo, J. S. Metabolic phenotypes in primary unknown metastatic carcinoma. J. Transl. Med. 12, 2 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994).

    Article  CAS  PubMed  Google Scholar 

  178. Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R. & Webb, W. W. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305, 99–103 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Wallace, D. C. Mitochondria and cancer. Nature Rev. Cancer 12, 685–698 (2012).

    Article  CAS  Google Scholar 

  180. Birsoy, K. et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508, 108–112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Zhang, X. et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nature Commun. 5, 3295 (2014).

    Article  CAS  Google Scholar 

  182. Ni Chonghaile, T. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129–1133 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Lee, H. et al. Palmitoylation of caveolin-1 at a single site (Cys-156) controls its coupling to the c-Src tyrosine kinase: targeting of dually acylated molecules (GPI-linked, transmembrane, or cytoplasmic) to caveolae effectively uncouples c-Src and caveolin-1 (TYR-14). J. Biol. Chem. 276, 35150–35158 (2001).

    Article  CAS  PubMed  Google Scholar 

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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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