Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer
Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer
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DOI：
10.1002/ijc.20657
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发表时间：
2005-02-20
影响因子：
6.4
通讯作者：
Ratajczak, MZ
中科院分区：
文献类型：
--
作者：
Janowska-Wieczorek, A;Wysoczynski, M;Ratajczak, MZ
血小板在肿瘤进展和转移中的作用已被认识，但其作用机制尚不清楚。5种人肺癌细胞系(A549、CRL 2066、CRL 2062、HTB 183、HTB 177)和小鼠Lewis肺癌(LCC)细胞系(用于体内转移模型)被用来研究血小板衍生微囊泡(PMV)和血小板α颗粒释放的外切体如何促进转移扩散。我们发现PMV将血小板衍生的整合素CD41转移到大多数被测试的肺癌细胞系中，并刺激丝裂原活化蛋白激酶P42/44和丝氨酸/苏氨酸激酶的磷酸化以及膜类型1-基质金属蛋白酶(MT1-MMPs)的表达。PMV化疗吸引了5个细胞系中的4个，其中高转移的A549细胞表现出最强的反应。在A549细胞中，PMV能刺激细胞增殖，上调细胞周期蛋白D2的表达，增加细胞的跨Matrigel化学侵袭。此外，在这些细胞中，PMV刺激血管生成因子如基质金属蛋白酶-9、血管内皮生长因子、白介素8和肝细胞生长因子的mRNA表达，以及与纤维蛋白原和人脐静脉内皮细胞的黏附。同基因小鼠静脉注射PMV包被的LLC细胞后，肺转移灶和骨髓LLC细胞的转移灶明显多于未包被PMV的LCC细胞对照组。基于这些发现，我们认为PMV在肺癌的肿瘤进展/转移和血管生成中起重要作用。(C)2004年Wiley-Liss公司
The role of platelets in tumor progression and metastasis has been recognized but the mechanism of their action remains unclear. Five human lung cancer cell lines (A549, CRL 2066, CRL 2062, HTB 183, HTB 177) and a murine Lewis lung carcinoma (LCC) cell line (for an in vivo model of metastasis) were used to investigate how platelet-derived microvesicles (PMV), which are circular fragments shed from the surface membranes of activated platelets, and exosomes released from platelet alpha-granules, could contribute to metastatic spread. We found that PMV transferred the platelet-derived integrin CD41 to most of the lung cancer cell lines tested and stimulated the phosphorylation of mitogen-activated protein kinase p42/44 and serine/threonine kinase as well as the expression of membrane type 1-matrix metalloproteinase (MT1-MMP). PMV chemoattracted 4 of the 5 cell lines, with the highly metastatic A549 cells exhibiting the strongest response. In A549 cells, PMV were shown to stimulate proliferation, upregulate cyclin D2 expression and increase trans-Matrigel chemoinvasion. Furthermore, in these cells, PMV stimulated mRNA expression for angiogenic factors such as MMP-9, vascular endothelial growth factor, interleukin-8 and hepatocyte growth factor, as well as adhesion to fibrinogen and human umbilical vein endothelial cells. Intravenous injection of murine PMV-covered LLC cells into syngeneic mice resulted in significantly more metastatic foci in their lungs and LLC cells in bone marrow than in control animals injected with LCC cells not covered with PMV. Based on these findings, we suggest that PMV play an important role in tumor progression/metastasis and angiogenesis in lung cancer. (C) 2004 Wiley-Liss, Inc.