CAV1 Protein in Skin Cancer Pathogenesis

Caveolins are a class of oligomeric plasma membrane proteins that function to compartmentalize signaling molecules that are involved in several signal transduction processes. Several lines of in vitro and in vivo evidence suggest that Caveolin-1 (Cav1) is implicated in the pathogenesis of oncogenic cell transformation, tumorigenesis, and metastasis. Although previous studies indicate that Cav1 expression is modulated during both melanoma and non melanoma skin cancers, strong experimental evidence that describes the function of Caveolin proteins in skin carcinogenesis (tumor growth and metastasis) is still lacking. Therefore, the work discussed herein aims to examine this issue by determining Cav1 regulated mechanisms in both melanoma cells and/or the surrounding micro-environment that may affect primary tumor growth and metastatic dissemination. We will also describe mechanisms by which Cav1 expression may affect skin carcinogenesis in a two stage carcinogenesis protocol and in a murine model of cutaneous squamous cell carcinoma (cSCC). In melanoma, Cav1 is demonstrated to suppress the metastatic ability of melanoma cells by inhibiting signaling along the Integrin/Src/FAK pathway. Accordingly, Cav1 expression is shown to be significantly reduced in human metastatic lesions indicating that it may function in late stage melanomas. To determine possible functions of Cav1 in the melanoma microenvironment, we used Cav1 KO mice to determine whether loss of stromal Cav1 may affect the growth and the metastatic ability of B16F10 melanoma cells. Our findings demonstrating that loss of stromal Cav1 has a tumor promoting effects in primary melanoma while having a suppressive function for lung metastasis, illustrate the ability of this protein to affect different biological processes in a tissue specific manner. Furthermore, in non melanoma skin cancer, Cav1 is demonstrated to suppress benign tumorigenesis and inhibit epidermal proliferation both in primary keratinocytes in vitro and promoter-treated epidermis in vivo. In addition, Cav1 functions to suppress proliferation, invasion, and metastasis in a murine model of cSCC, attributed in part to its ability to inhibit signaling along the Ras/Erk/AP-1 pathway. In summary, the work described herein provides evidence that Cav1 may function as a suppressor of tumor progression stages in both melanoma and non melanoma skin cancers and is therefore a possible biomarker for tumor aggression and is a potential target for therapeutic intervention in skin cancer.