Membrane microvesicles as mediators for melanoma-fibroblasts communication: Roles of the VCAM-1/VLA-4 axis and the ERK1/2 signal pathway

Abstract

Recent studies suggest that microvesicles (MVs) within the tumor microenvironment are emerging as potent mediators for cell–cell communication. In this study, we investigated the MV-mediated transformation of normal fibroblasts to tumor-associated fibroblasts, focusing on the functional regulation of vascular cell adhesion molecule-1 (VCAM-1) expression. After incubation with melanoma-derived MVs, the fibroblasts (NIH/3T3 cells) presented an obvious enhancement of VCAM-1 expression in an ERK1/2-activation-dependent manner, and this enhancement was further increased when the MVs were from highly metastatic melanoma cells. The adhesion analysis showed that the VCAM-1/VLA-4 axis is involved in the preferential attachment of highly metastatic melanoma cells and BMSCs to MV-educated fibroblasts. Hypoxia promoted melanoma-fibroblast interaction by directly upregulating VLA-4 expression in highly metastatic melanoma cells and indirectly provoking VCAM-1 expression in fibroblast cells via melanoma-released MVs. Moreover, MV-educated fibroblasts increased IL-6, fibroblast activation protein and EGF expression simultaneously. Proteomic analysis of MVs suggested that numerous signal pathways in addition to the MAPK signal pathway are regulated by melanoma MVs, which function as tumor messengers that participate in melanoma progression.