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.

Caveolin-1 (CAV1) enhanced migration, invasion, and metastasis of cancer cells is inhibited by co-expression of the glycoprotein E-cadherin. Although the two proteins form a multiprotein complex that includes β-catenin, it remained unclear how this would contribute to blocking the metastasis promoting function of CAV1. Here, we characterized by mass spectrometry the protein composition of CAV1 immunoprecipitates from B16F10 murine melanoma cells expressing or not E-cadherin. The novel protein tyrosine phosphatase PTPN14 was identified by mass spectrometry analysis exclusively in coimmunoprecipitates of CAV1 with E-cadherin. Interestingly, PTPN14 is implicated in controlling metastasis, but only few known PTPN14 substrates exist. We corroborated by western blotting experiments that PTPN14 and CAV1 coinmunoprecipitated in the presence of E-cadherin in B16F10 melanoma and other cancer cells. Moreover, the CAV1(Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine-14, as well as suppressed CAV1-enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29(US)] and breast cancer (MDA-MB-231) cell lines. Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo. In summary, we identify here CAV1 as a novel substrate for PTPN14 and show that overexpression of this phosphatase suffices to reduce CAV1-induced metastasis.

Cancer remains a leading cause of death worldwide despite decades of intense efforts to understand the molecular underpinnings of the disease. To date, much of the focus in research has been on the cancer cells themselves and how they acquire specific traits during disease development and progression. However, these cells are known to secrete large numbers of extracellular vesicles (EVs), which are now becoming recognized as key players in cancer. EVs contain a large number of different molecules, including but not limited to proteins, mRNAs, and miRNAs, and they are actively secreted by many different cell types. In the last two decades, a considerable body of evidence has become available indicating that EVs play a very active role in cell communication. Cancer cells are heterogeneous, and recent evidence reveals that cancer cell-derived EV cargos can change the behavior of target cells. For instance, more aggressive cancer cells can transfer their “traits” to less aggressive cancer cells and convert them into more malignant tumor cells or, alternatively, eliminate those cells in a process referred to as “cell competition”. This review discusses how EVs participate in the multistep acquisition of specific traits developed by tumor cells, which are referred to as “the hallmarks of cancer” defined by Hanahan and Weinberg. Moreover, as will be discussed, EVs play an important role in drug resistance, and these more recent advances may explain, at least in part, why pharmacological therapies are often ineffective. Finally, we discuss literature proposing the use of EVs for therapeutic and prognostic purposes in cancer.