Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells
Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells
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DOI：
10.1073/pnas.1017667108
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发表时间：
2011-03-22
影响因子：
11.1
通讯作者：
Cerione, Richard A.
中科院分区：
文献类型：
--
作者：
Antonyak, Marc A.;Li, Bo;Cerione, Richard A.
肿瘤进展涉及癌细胞之间以及与微环境中邻近正常细胞通讯的能力。源自人类癌细胞的微泡（MV）因其参与癌细胞之间信号蛋白的水平转移并有助于其侵袭活性而受到广泛关注。在这里，我们表明 MV 可能在肿瘤发生中发挥另一个重要作用。特别是，我们证明两种不同的人类癌细胞（MDAMB231乳腺癌细胞和U87神经胶质瘤细胞）脱落的MV能够赋予正常成纤维细胞和上皮细胞癌细胞的转化特征（例如，不依赖贴壁的生长和增强的生存能力），并且这种效果需要蛋白质交联酶组织转谷氨酰胺酶（tTG）的转移。我们进一步证明 tTG 不足以转化成纤维细胞，而是必须与另一种蛋白质合作来介导癌细胞来源的 MV 的转化作用。对来自 MDAMB231 和 U87 细胞的 MV 的蛋白质组学分析表明，这两种囊泡制剂均含有 tTG 结合配偶体和交联底物纤连蛋白 (FN)。此外，我们发现 tTG 与来自癌细胞的 MV 中的 FN 交联，随后 MV 介导的交联 FN 和 tTG 向受体成纤维细胞的转移协同作用，激活有丝分裂信号传导活性并诱导其转化。这些发现强调了 MV 在诱导细胞转化中的作用，并确定 tTG 和 FN 是该过程的重要参与者。
Tumor progression involves the ability of cancer cells to communicate with each other and with neighboring normal cells in their microenvironment. Microvesicles (MV) derived from human cancer cells have received a good deal of attention because of their ability to participate in the horizontal transfer of signaling proteins between cancer cells and to contribute to their invasive activity. Here we show that MV may play another important role in oncogenesis. In particular, we demonstrate that MV shed by two different human cancer cells, MDAMB231 breast carcinoma cells and U87 glioma cells, are capable of conferring onto normal fibroblasts and epithelial cells the transformed characteristics of cancer cells (e. g., anchorage-independent growth and enhanced survival capability) and that this effect requires the transfer of the protein cross-linking enzyme tissue transglutaminase (tTG). We further demonstrate that tTG is not sufficient to transform fibroblasts but rather that it must collaborate with another protein to mediate the transforming actions of the cancer cell-derived MV. Proteomic analyses of the MV derived from MDAMB231 and U87 cells indicated that both these vesicle preparations contained the tTG-binding partner and cross-inking substrate fibronectin (FN). Moreover, we found that tTG cross-links FN in MV from cancer cells and that the ensuing MV-mediated transfers of cross-linked FN and tTG to recipient fibroblasts function cooperatively to activate mitogenic signaling activities and to induce their transformation. These findings highlight a role for MV in the induction of cellular transformation and identify tTG and FN as essential participants in this process.