Melanoma cells control HA synthesis in peritumoral fibroblasts via PDGF-AA and PDGF-CC: impact on melanoma cell proliferation.
Melanoma cells control HA synthesis in peritumoral fibroblasts via PDGF-AA and PDGF-CC: impact on melanoma cell proliferation.
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黑色素瘤细胞通过 PDGF-AA 和 PDGF-CC 控制瘤周成纤维细胞中 HA 的合成：对黑色素瘤细胞增殖的影响
DOI：
10.1038/jid.2011.325
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
U.Anderegg
中科院分区：
文献类型：
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作者：
Willenberg;A.Saalbach;J.C.Simon;U.Anderegg
肿瘤周围的微环境在肿瘤进展中具有重要作用。肿瘤基质的成纤维细胞（Fb）接收来自肿瘤的信号并转化细胞外基质，从而支持肿瘤的生长、运动和转移。基质成分透明质酸 (HA) 在肿瘤进展中发挥着关键作用。在这里，我们分析了人类恶性黑色素瘤 (MM) 细胞中合成 HA 的细胞群，并研究了 MM 细胞和控制 HA 合成的基质 Fb 之间的调控网络。组织分析表明，Fb是黑色素瘤基质中HA的主要来源，而MM本身仅合成微量HA。在体外，Fb来源的HA主要由透明质酸合酶2（HAS2）产生，并增强MM的增殖。 MM 分泌的蛋白质可以以磷脂酰肌醇 3/丝裂原激活蛋白激酶依赖性方式进一步增加 Fb 中 HA 的合成。黑色素瘤细胞衍生的血小板衍生生长因子 (PDGF)-AA 和 PDGF-CC 被确定为通过 PDGFR-α 发出信号的主要介质，从而诱导 Fb 中 HAS2 介导的 HA 合成。总之，我们通过证明 MM 通过释放 PDGF-AA 和 PDGF-CC 上调 Fb 中的 HA 合成，进而以旁分泌方式刺激 MM 增殖，确定了 MM 与其周围微环境的复杂相互作用。
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.