Cell Intrinsic and Extrinsic Mechanisms of Caveolin-1-Enhanced Metastasis

Abstract

Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure.

Keywords: caveolae; cholesterol transport; exosomes; metastasis promoter; tumor suppressor.

Figure 1

Time line summarizing the evolution of our understanding of Caveolin-1 (CAV1) function. (1) Early studies indicated at the onset of the time line centered on the structural role of the protein and its function in cholesterol transport. (2) Then, several studies emerged relating CAV1 presence to suppression of oncogenic signaling and correlating cell transformation with loss of CAV1 expression. (3) In later stages of cancer, elevated CAV1 protein levels are often detected and associated with a more malignant (metastatic) cell phenotype, indicating that in this context, CAV1 regulates different cellular traits. Mechanisms considered to this point are linked to CAV1 function within the cell, referred to here as being “intrinsic”. (4) CAV1 was then identified as a secreted protein and “extracellular” presentations of the protein are described. (5) Amongst those, one that is gaining enormous interest currently relates to its possible function(s) in extracellular vesicles (EVs), vesicular nanocarriers of cancer disease.

Figure 2

Proposed structure of Caveolin-1 (CAV1). (A) Schematic of CAV1α highlighting different domains and posttranslational modifications, including phosphorylation on tyrosine 14 and serine 80, ubiquitination of N-terminal residues and carboxyterminal palmitoylation sites. Simplified schematic for the β isoform. (B) CAV1α without amino-terminal modifications partially inserted into sphingolipid and cholesterol-enriched regions via hairpin-like membrane insertion domain.