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  • Review Article
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Caveolae: mining little caves for new cancer targets

Nature Reviews Cancer volume 3, pages 571–581 (2003)Cite this article

Key Points

  • Caveolae are dynamic, detergent-resistant microdomains that are enriched in cholesterol and glycosphingolipids. They have a distinct invaginated form that is easily detected by electron microscopy.

  • Caveolae constitute an alternative endocytic pathway to clathrin-coated pits.

  • Caveolae can mediate transcytosis — the transcellular movement of molecules (such as select blood-borne macromolecules) across the endothelial cell.

  • Caveolae contain signalling molecules, such as select heterotrimeric G proteins, non-receptor tyrosine kinases and endothelial nitric oxide synthase (eNOS), and seem to act as organized transducing centres that concentrate key signalling molecules.

  • Angiogenesis depends on nitric oxide produced by eNOS, which is concentrated at the endothelial-cell surface in caveolae. Caveola and its caveolins could be targeted to prevent angiogenesis through inhibition of eNOS.

  • Caveolin seems to act as a tumour suppressor in cultured cells, but might be required for later stages of tumour development in vivo, when it promotes cancer-cell survival, metastasis and chemoresistance.

  • Caveolae with their tissue-specific molecules constitute a trafficking pathway that might be worth targeting — not only for site-directed drug and gene delivery but also to overcome the normally restrictive endothelial-cell barrier to reach underlying tissue or tumour cells.

  • Strategies to target caveolae, and even caveolin-1, might be useful in treating cancer through vascular ablation or functional disruption of metastasis, tumorigenesis, angiogenesis and tumour progression.

Abstract

Caveolae exist at cell surfaces as caveolin-coated invaginations that perform transport and signalling functions influencing cell growth, apoptosis, angiogenesis and transvascular exchange. Caveolin could constitute a key switch in tumour development through its function as a tumour suppressor and as a promoter of metastasis, chemoresistance and survival. Targeting of drugs and gene vectors to tissue-specific proteins in caveolae allows selective delivery into vascular endothelial cells in vivo and might even improve direct access to solid-tumour cells. Therefore, caveolae seem to be rich in potential targets for cancer imaging and therapeutics.

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Figure 1: Caveolar regulation of signalling molecules.
Figure 2: Intracellular trafficking pathways.
Figure 3: Role of caveolin-1 in tumour-cell growth and progression in culture and in vivo.
Figure 4: The strategy of targeting caveolae in the neovasculature of solid tumours.
Figure 5: The amplification effect of targeting tumour endothelium and its caveolae.

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Acknowledgements

Parts of our work presented here were supported by grants from the National Institutes of Health, as well as the California Tobacco Related Diseases Research Program, the California Breast Cancer Research Program and the United States Department of Defense Breast Cancer Research Program. We apologize to the many researchers whose papers could not be cited here because of space limitations.

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Authors and Affiliations

  1. Division of Vascular Biology and Angiogenesis, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, 92121, California, USA

    Lucy A. Carver & Jan E. Schnitzer

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  1. Lucy A. Carver
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Correspondence to Jan E. Schnitzer.

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DATABASES

Cancer.org

breast cancer

prostate cancer

LocusLink

Apc

CAV1

CAV2

eNOS

NSF

PI3K

Rb

SNAP

Trp53

VAMP2

VEGF

FURTHER INFORMATION

Jan Schnitzer's lab

Sidney Kimmel Cancer Center

Glossary

PLASMALEMMAL

Related to the plasma membrane of a cell.

CLATHRIN-COATED PITS

Clathrin-coated vesicles that are involved in membrane transport, both in the endocytic and biosynthetic pathways.

MICRODOMAINS

Specialized small regions of membrane with a unique molecular composition that is organized to optimize specific functions.

MECHANOTRANSDUCTION

The activation of intracellular signal-transduction pathways in cells by mechanical stimuli. For example, endothelial-cell signalling induced by changing haemodynamic forces, such as shear stress and blood pressure.

HAEMODYNAMICS

The study of blood flow and the mechanical forces generated in the cardiovascular system arising from blood being pumped through the vessels by the heart.

ENDOCYTOSIS

Internalization and transport of extracellular material and plasma-membrane proteins from the cell surface to intracellular organelles known as endosomes.

TRANSCYTOSIS

Transport of macromolecules across a cell, consisting of endocytosis of a macromolecule at one side of a monolayer and exocytosis at the other side.

LYSOSOME

A membrane-bounded organelle with a low internal pH (4–5) that contains hydrolytic enzymes and that is the site of the degradation of proteins in both the biosynthetic and the endocytic pathways.

ENDOSOME

Intracellular organelles that transport extracellular material and proteins from the cell surface.

DOMINANT-NEGATIVE PROTEIN

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

GLYCOSPHINGOLIPIDS

Any compound containing residues of a sphingoid and at least one monosaccharide.

ANOIKIS

Induction of programmed cell death by detatchment of cells from the extracellular matrix.

LOSS OF HETEROZYGOSITY

(LOH). Occurs when loss of a particular segment of the genome can be shown by the analysis of a polymorphic marker in that region. If an individual is somatically heterozygous for this marker, but homozygous in the tumour, then there has been 'loss of heterozygosity' in that region. Recurrent LOH of a region indicates the presence of a classical tumour-suppressor gene, although recurrent regional loss is also seen for other reasons (for example, because of the presence of fragile sites).

PROSTAGLANDINS

Any of a class of hormone-like, lipid-soluble regulatory molecules that are constructed from polyunsaturated fatty acids such as arachidonate. These molecules participate in diverse body functions, such as smooth-muscle contraction and relaxation, vasodilation and regulation of kidney function.

INFARCTING

Causing tissue necrosis due to a critical imbalance between the oxygen supply and demand of the tissue.

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Carver, L., Schnitzer, J. Caveolae: mining little caves for new cancer targets. Nat Rev Cancer 3, 571–581 (2003). https://doi.org/10.1038/nrc1146

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