Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases
Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases
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癌细胞来源的外泌体通过转运功能性受体酪氨酸激酶诱导丝裂原活化蛋白激酶依赖性单核细胞存活
DOI：
10.1074/jbc.m116.716316
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发表时间：
2016-04-15
影响因子：
4.8
通讯作者：
Nie, Guangjun
中科院分区：
文献类型：
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作者：
Song, Xiao;Ding, Yanping;Nie, Guangjun
肿瘤相关巨噬细胞（TAM）在癌症的发生和发展中起着关键作用。单核细胞，TAM的前体，通常在2天内经历自发凋亡，但可以在炎性肿瘤微环境中生存，以连续存活并产生足够的TAM。肿瘤驱动单核细胞存活的机制仍然不清楚。在这里，我们报告说，癌细胞来源的外泌体是炎症小生境中单核细胞存活的关键介质。对单核细胞中的存活促进分子的分析表明，癌细胞来源的外泌体激活了丝裂原活化蛋白激酶（MAPK）途径中的Ras和细胞外信号调节激酶，从而阻止了半胱天冬酶切割。磷酸化受体酪氨酸激酶（RTK），如磷酸化表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER-2），在癌细胞来源的外泌体中大量表达。EGFR或/和HER-2的敲除，或者针对其磷酸化的抑制剂显著干扰了外泌体介导的MAPK途径的活化、半胱天冬酶切割的抑制和单核细胞存活率的增加。此外，由于EGFR和HER-2的无效表达而剥夺的外泌体的生存刺激活性可以通过激活另一种RTK胰岛素受体来恢复。总的来说，我们的研究揭示了肿瘤相关单核细胞存活的机制，并证明癌细胞来源的外泌体可以通过转运功能性RTK刺激单核细胞中的MAPK通路，导致凋亡相关半胱天冬酶失活。这项工作提供了深入了解长期寻求的问题单核细胞生存之前，在肿瘤微环境中形成丰富的TAM。
Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signal-regulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.