New approaches to study tumor microvesicles

摘要 肿瘤源性微泡（TMV），细胞外基质家族中的一种囊泡亚型， 囊泡（EV），含有生物活性蛋白质和核酸货物，并且已经出现， 肿瘤微环境（TME）中细胞间通讯的重要介质。通过 由于它们在TME中的作用，EV被认为支持转移性肿瘤的扩散， 通过促进肿瘤扩张和肿瘤侵袭活性，抑制免疫反应， 反应，并促进血管生成。因此，鉴定和靶向分子， 控制EV生物发生和/或功能的信号传导途径有可能导致新的 和互补的治疗策略。此外，发现电动汽车是在 这些囊泡作为有前途的诊断和预后的研究引起了人们的极大兴趣 平台尽管在过去的十年里，我们已经了解了很多关于电动汽车功能的知识， 需要更多地了解各种EV亚型是如何形成的， 参与并影响TME中的受体细胞。特别是，迫切需要界定 TMV生物发生的细胞途径和信号机制，以更好地了解 它们的旁分泌特性和功能。相对于肿瘤外泌体，其他突出的EV 我们对TMV的了解明显较少。我们理解 控制TMV形成和货物掺入的分子原理在大范围内仍然是有限的。 部分原因是在分离和精确定义单个EV的分子组成方面存在局限性 人口。为了开始探索TMV形成和释放的分子机制，我们 已经采用了生物化学筛选TMV蛋白质组学研究，旨在识别TMV- 特异性货物和测试TMV生物发生的新调控。由此得出的结论是， 试点研究将成为描绘和测试基本机制框架的基础 TMV在肿瘤进展的临床前模型中的生物发生和功能。根据我们的经验 和专业知识，我们的实验室完全有能力进行这些调查。

ABSTRACT Tumor-derived microvesicles (TMVs), a vesicle subtype in the family of extracellular vesicles (EVs), contain bioactive protein and nucleic acid cargoes and have emerged as important mediators of intercellular communication in the tumor microenvironment (TME). By virtue of their roles in the TME, EVs have been thought to support the spread of metastatic disease by promoting tumor expansion and tumor invasive activity, dampening immune responses, and facilitating angiogenesis. Thus, identifying and targeting molecules and signaling pathways that control EV biogenesis and/or function has the potential to lead to novel and complementary therapeutic strategies. Moreover, the discovery that EVs are found in circulation has heightened interest in these vesicles as promising diagnostic and prognostic platforms. Although we have learned a great deal about EV function over the past decade, there is need to learn much more about how the various EV subtypes are formed and how they engage and affect recipient cells in the TME. In particular, there is a critical need to define the cellular pathways and signaling mechanisms that underlie TMV biogenesis to better understand their paracrine properties and function. Relative to tumor exosomes, the other prominent EV subtype shed by tumor cells, we know significantly less about TMVs. Our understanding of the molecular principles that control TMV formation and cargo incorporation remains limited in large part due to limitations in isolating and precisely defining the molecular makeup of individual EV populations. To begin to explore the molecular mechanisms of TMV formation and release, we have adapted a biochemical screen for TMV proteomic studies aimed at identifying TMV- specific cargo and testing novel regulation of TMV biogenesis. The findings that result from this pilot study will form the basis of delineating and testing a mechanistic framework underlying TMV biogenesis and function in preclinical models of tumor progression. Given our experience and expertise, our laboratory is well position to carry out these investigations.