title: Genetic ablation of Cav1 differentially affects melanoma tumor growth and metastasis in mice: role of Cav1 in Shh heterotypic signaling and transendothelial migration.
abstract: Both cell-autonomous and non-cell-autonomous factors contribute to tumor growth and metastasis of melanoma. The function of caveolin-1 (Cav1), a multifunctional scaffold protein known to modulate several biologic processes in both normal tissue and cancer, has been recently investigated in melanoma cancer cells, but its role in the melanoma microenvironment remains largely unexplored. Here, we show that orthotopic implantation of B16F10 melanoma cells in the skin of Cav1KO mice increases tumor growth, and co-injection of Cav1-deficient dermal fibroblasts with melanoma cells is sufficient to recapitulate the tumor phenotype observed in Cav1KO mice. Using indirect coculture experiments with fibroblasts and melanoma cells combined with cytokine analysis, we found that Cav1-deficient fibroblasts promoted the growth of melanoma cells via enhanced paracrine cytokine signaling. Specifically, Cav1-deficient fibroblasts displayed increased ShhN expression, which heterotypically enhanced the Shh signaling pathway in melanoma cells. In contrast to primary tumor growth, the ability of B16F10 melanoma cells to form lung metastases was significantly reduced in Cav1KO mice. This phenotype was associated mechanistically with the inability of melanoma cells to adhere to and to transmigrate through a monolayer of endothelial cells lacking Cav1. Together, our findings show that Cav1 may regulate different mechanisms during primary melanoma tumor growth and metastatic dissemination.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Franco.Capozza@jefferson.edu
authors.forename: Franco
authors.initials: F
authors.lastname: Capozza
authors.forename: Casey
authors.initials: C
authors.lastname: Trimmer
authors.forename: Remedios
authors.initials: R
authors.lastname: Castello-Cros
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Crosariol
authors.forename: Gemma
authors.initials: G
authors.lastname: Llaverias
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051243:Caveolin 2 / Q000172:deficiency / Q000378:metabolism; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009362:Neoplasm Metastasis
chemical_list: C495541:Cav1 protein, mouse; C495545:Cav2 protein, mouse; D051242:Caveolin 1; D051243:Caveolin 2; D016207:Cytokines; D053823:Hedgehog Proteins; C465570:Shh protein, mouse