Isola Allison L, Eddy Kevinn, Zembrzuski Krzysztof, Goydos James S, Chen Suzie
Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University, Piscataway, NJ 08854, USA.
Joint Graduate Program in Toxicology, Rutgers, The State University, Piscataway, NJ 08854, USA.
Oncotarget. 2017 Dec 19;9(1):1187-1199. doi: 10.18632/oncotarget.23455. eCollection 2018 Jan 2.
Exosomes are naturally occurring membrane-bound nanovesicles generated constitutively and released by various cell types, and often in higher quantities by tumor cells. Exosomes may facilitate communication between the primary tumor and its local microenvironment, supporting cell invasion and other early events in metastasis. A neuronal receptor, metabotropic glutamate receptor 1 (GRM1), when ectopically expressed in melanocytes, induces melanocytic transformation and spontaneous malignant melanoma development in a transgenic mouse model. Our earlier studies showed that genetic modulation in GRM1 expression by siRNA or disruption of GRM1-mediated glutamate signaling interfere with downstream effectors resulting in a decrease in both cell proliferation and tumor progression . In this study, we sought to determine whether exosome formation might play a role in GRM1 mediated melanoma development and progression. To test this, we utilized cultured cells in which GRM1 expression and function could be modulated by pharmacological and genetic means and determined effects on exosome production. We also tested the effects of exosomes from GRM1 expressing melanoma cells on growth, migration and invasion of GRM1 negative cells. Our results show that although GRM1 expression has no influence on exosome quantity, exosomes produced by GRM1-positive cells modulate the ability of the recipient cell to migrate, invade and exhibit anchorage-independent cell growth.
外泌体是天然存在的膜结合纳米囊泡，由各种细胞类型组成性产生并释放，肿瘤细胞通常会释放出更多的外泌体。外泌体可能促进原发性肿瘤与其局部微环境之间的通讯，支持细胞侵袭和转移中的其他早期事件。一种神经元受体，即代谢型谷氨酸受体1（GRM1），当在黑素细胞中异位表达时，会在转基因小鼠模型中诱导黑素细胞转化和自发性恶性黑色素瘤的发展。我们早期的研究表明，通过siRNA对GRM1表达进行基因调控或破坏GRM1介导的谷氨酸信号传导会干扰下游效应器，导致细胞增殖和肿瘤进展均减少。在本研究中，我们试图确定外泌体形成是否可能在GRM1介导的黑色素瘤发展和进展中发挥作用。为了验证这一点，我们利用了可以通过药理学和遗传学方法调节GRM1表达和功能的培养细胞，并确定其对外泌体产生的影响。我们还测试了来自表达GRM1的黑色素瘤细胞的外泌体对GRM1阴性细胞的生长、迁移和侵袭的影响。我们的结果表明，尽管GRM1表达对外泌体数量没有影响，但GRM1阳性细胞产生的外泌体可调节受体细胞迁移、侵袭和表现出非锚定依赖性细胞生长的能力。
