Emerging roles of PAR-1 and PAFR in melanoma metastasis.
Emerging roles of PAR-1 and PAFR in melanoma metastasis.
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DOI：
10.1007/s12307-008-0002-7
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发表时间：
2008-12
影响因子：
--
通讯作者：
Bar-Eli, Menashe
中科院分区：
文献类型：
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作者：
Melnikova, Vladislava O;Villares, Gabriel J;Bar-Eli, Menashe
由于募集的炎症细胞和基质细胞分泌高水平的细胞因子和趋化因子，炎症肿瘤微环境强烈促进黑色素瘤的生长、血管生成和转移进展。此外，血小板和促凝血途径的分子成分最近已成为肿瘤生长和转移的关键参与者。特别是凝血酶通过其受体蛋白酶激活受体-1（PAR-1）的活性，调节肿瘤细胞与血小板和内皮细胞的粘附，刺激肿瘤血管生成，促进肿瘤生长和转移。值得注意的是，在包括黑色素瘤在内的许多肿瘤类型中，PAR-1 表达与其转移表型直接相关，并直接导致白细胞介素 8、基质金属蛋白酶 2 (MMP-2)、血管内皮生长因子、血小板源性生长因子和整合素的表达。另一种促炎受体-配体对，血小板激活因子（PAF）及其受体（PAFR），已被证明是肿瘤细胞与内皮细胞粘附、血管生成、肿瘤生长和转移的重要调节剂。 PAF是多种细胞从膜甘油磷脂在释放花生四烯酸的同一反应中产生的生物活性脂质，可由血小板、炎症细胞、角质形成细胞和内皮细胞分泌。我们已经证明，在转移性黑色素瘤细胞中，PAF刺激环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化并激活转录因子1（ATF-1），从而导致MMP-2和膜类型1-MMP（膜类型1-MMP）的过度表达。由于只有转移性黑色素瘤细胞过表达 CREB/ATF-1，我们认为转移性黑色素瘤细胞比非转移性黑色素瘤细胞更能对肿瘤微环境中的 PAF 做出反应。提出并讨论了支持以下假设的证据：两种 G 蛋白偶联受体 PAR-1 和 PAFR 有助于黑色素瘤转移表型的获得。
Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed.