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

Abstract

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-α 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.

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

“…This is mediated by platelet-derived growth factor receptor-PI3K-AKT and MAPK pathways (23,24). In this study, we show for the first time that LEF1 was required for the induction of Has2 mRNA expression in fibroblasts.…”

“…It was shown previously (23,24) that melanoma cell conditioned medium induces Has2 mRNA expression in fibroblasts. This is mediated by platelet-derived growth factor receptor-PI3K-AKT and MAPK pathways (23,24).…”

“…Because it has been reported that Has2 mRNA expression in fibroblasts depends on ERK signaling (24,35,36), we additionally addressed the question of whether PD98059, a MEK1 inhibitor, was able to prevent Has2 induction in co-culture. However, Has2 mRNA expression was still increased in the co-culture setting.…”

PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omicsapproach

“…PDGF-AA and PDGFR-alpha are less potent mitogens, with contrasting- even inhibitory-effects in different cells and tissues, including endothelial and melanoma cells, as demonstrated in previous studies by ours and other laboratories [31, 44–46]. A recent study highlighted an inhibitory effect of PDGFR-alpha in ulcer healing, indicating a PDGFR-alpha mediated anti-angiogenesis effect [47].…”

Expression of growth-regulated oncogene-1, hepatocyte growth factor, platelet-derived growth factor-AA and soluble E-selectin and their association with high-risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix

“…Aune et al (25) demonstrated that preoperative serum HGF level is not associated with age, which is consistent with the results from the present study. Several studies have demonstrated that the upregulation of PDGF in numerous carcinomas is able to promote lymph node metastasis and tumor cell proliferation (26,27). Importantly, it can promote the formation of tumor blood vessels and lymph vessels (28,29).…”