Melanoma Cells Control HA Synthesis in Peritumoral Fibroblasts via PDGF-AA and PDGF-CC: Impact on Melanoma Cell Proliferation

The microenvironment surrounding tumors has an important role in tumor progression. Fibroblasts (Fbs) of the tumor stroma receive signals from tumors and transform the extracellular matrix, thus supporting tumor growth, motility, and metastasis. The matrix component hyaluronan (HA) has a pivotal role in tumor progression. Here we analyzed the cell populations that synthesize HA in human malignant melanoma (MM) cells and studied the regulatory network between MM cells and stromal Fbs controlling HA synthesis. Tissue analysis indicated that Fbs are the main source of HA in the stroma of melanoma, whereas MM themselves synthesize only minute amounts of HA. In vitro, Fb-derived HA is mainly produced by hyaluronan synthase 2 (HAS2) and enhances proliferation of MM. Proteins secreted by MM can further increase HA synthesis in Fbs in a phosphatidylinositol 3/mitogen-activated protein-kinase-dependent manner. Melanoma cell-derived platelet-derived growth factor (PDGF)-AA and PDGF-CC were identified as major mediators that signal through PDGFR-alpha and thus induce HAS2-mediated HA synthesis in Fbs. In conclusion, we have identified a complex interaction of MM with its surrounding microenvironment by demonstrating that MM by the release of PDGF-AA and PDGF-CC upregulate HA synthesis in Fbs, which in turn stimulates MM proliferation in a paracrine manner.