Rab27a Supports Exosome-Dependent and -Independent Mechanisms That Modify the Tumor Microenvironment and Can Promote Tumor Progression
Rab27a Supports Exosome-Dependent and -Independent Mechanisms That Modify the Tumor Microenvironment and Can Promote Tumor Progression
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DOI：
10.1158/0008-5472.can-12-0925
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发表时间：
2012-10-01
期刊：
影响因子：
11.2
通讯作者：
Thery, Clotilde
中科院分区：
文献类型：
--
作者：
Bobrie, Angelique;Krumeich, Sophie;Thery, Clotilde
在从单个癌细胞发展为肿瘤团块及发生转移的过程中，肿瘤细胞会发出能够改变其组织微环境的信号。这些信号涉及可溶性分子以及各种细胞外囊泡，包括一种被称为外泌体的特殊类型。然而，肿瘤微环境中分泌的外泌体的具体作用尚不明确。小GTP酶RAB27A和RAB27B在人类HeLa细胞中调节多囊泡内体的胞吐作用，从而导致外泌体的分泌。在此，我们利用小鼠模型表明，在乳腺癌细胞中阻断Rab27a会减少以内吞标志物为特征的外泌体的分泌，同时也会减少基质金属蛋白酶9的分泌，而基质金属蛋白酶9与外泌体并无关联。阻断Rab27a会导致原发性肿瘤生长减缓以及转移性癌（4T1）的肺转移减少，但对非转移性癌（TS/A）无此作用。4T1肿瘤的局部生长需要动员一群中性粒细胞免疫细胞，这是由依赖于Rab27a的外泌体分泌以及细胞因子和/或金属蛋白酶的特定组合所诱导的。我们的研究结果在体内验证了外泌体分泌在肿瘤形成和进展过程中可发挥关键病理生理作用这一概念，但也凸显了肿瘤环境的特异性。《癌症研究》；72(19)；4920 - 30。（C）2012美国癌症研究协会。
During progression from single cancer cells to a tumor mass and metastases, tumor cells send signals that can subvert their tissue microenvironment. These signals involve soluble molecules and various extracellular vesicles, including a particular type termed exosomes. The specific roles of exosomes secreted in the tumor microenvironment, however, is unclear. The small GTPases RAB27A and RAB27B regulate exocytosis of multivesicular endosomes, which lead to exosome secretion, in human HeLa cells. Here, we used mouse models to show that Rab27a blockade in mammary carcinoma cells decreased secretion of exosomes characterized by endocytic markers, but also of matrix metalloproteinase 9, which is not associated with exosomes. Rab27a blockade resulted in decreased primary tumor growth and lung dissemination of a metastatic carcinoma (4T1), but not of a nonmetastatic carcinoma (TS/A). Local growth of 4T1 tumors required mobilization of a population of neutrophil immune cells induced by Rab27a-dependent secretion of exosomes together with a specific combination of cytokines and/or metalloproteinases. Our findings offer in vivo validation of the concept that exosome secretion can exert key pathophysiologic roles during tumor formation and progression, but they also highlight the idiosyncratic character of the tumor context. Cancer Res; 72(19); 4920-30. (C)2012 AACR.