Caveolin-1 Modulates the Ability of Ewing's Sarcoma to Metastasize

Abstract

Metastasis is the final stage of tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors. Caveolin-1 (CAV1) regulates multiple cancer-associated processes related to malignant tumor progression. In the present study we tested the hypothesis that CAV1 modulates the metastatic ability of ESFT cells. First, we analyzed the expression of CAV1 by immunostaining a tissue microarray containing 43 paraffin-embedded ESFT tumors with known EWS translocations. Even though no evidence was found for a significant association between CAV1 expression and stage, size or tumor site, all metastatic samples (10/10) had significantly high CAV1 expression, suggesting that high CAV1 content could positively contribute to enhance ESFT metastasis. To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells by stably transfecting a previously validated shRNA construct. In vitro, migration and invasion assays showed that, for both cell lines CAV1 knocked-down cells migrated and invaded significantly less (p≤0.01) than control cells. Moreover, control A673 cells introduced into Balb/c nude mice by tail vein injection strongly colonized the lungs. In contrast, animals injected with CAV1 knocked-down cells showed either no incidence of metastasis or developed lung metastases after a significant delay (P<0.0001). Finally, we show that the molecular mechanisms by which CAV1 carries out its key role in regulating ESFT metastasis involve MMP production and activation as well as the control of the expression of SPARC, a known determinant of lung colonization.

Extracellular matrix-specific Caveolin-1 phosphorylation on tyrosine 14 is linked to augmented melanoma metastasis but not tumorigenesis

“…The function of CAV1 in metastasis is associated with its ability to promote cell migration, which requires phosphorylation on tyrosine-14 [42, 72]. We have previously determined the importance of CAV1 in promoting lung metastasis using a B16F10 melanoma model in syngeneic C57BL/6 mice and reported that overexpression of CAV1 in B16F10 cells led to increased lung metastasis compared with control cells [28].…”

Actin-related protein 2/3 complex subunit 5 (ARPC5) contributes to cell migration and invasion and is directly regulated by tumor-suppressive microRNA-133a in head and neck squamous cell carcinoma

“…CAV1 is not an actin-binding protein, but is the main structural component of caveolae, which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events (15). CAV1 is deeply involved in invadopodia which form actin-rich protrusions into the extracellular matrix (16) and its mediation of cell migration and invasion was revealed in several reports (17,18), including our studies of HNSCC (7).…”

Auto-stimulatory action of secreted caveolin-1 on the proliferation of Ewing's sarcoma cells

“…In a subsequent study, we have shown that the expression levels of CAV1 are related to the resistance of EWS cells to chemotherapeutic agents, as a decrease in CAV1 concentration sensitizes EWS cells to drug treatment (19). Most recently, we also showed that CAV1 is a key regulator of the ability of EWS cells to metastasize (20). However, most of these cellular processes and activities have been related to the endogenous cellular levels of CAV1, but it was not known whether EWS cells secreted CAV1 and the possible significance of any secreted CAV1 form for EWS pathophysiology.…”

“…Knocking CAV1 down increased the sensitivity of EWS cells to clinically relevant agents such as doxorubicin and cisplatin, with a concurrent induction of apoptosis (19). Most recently, it has been demonstrated that CAV1 plays a key role in regulating the metastatic ability of EWS cells (20). …”