疟原虫感染小鼠血浆外泌体抑制肺癌血管生成的机理研究

Cancers are important life-threating diseases, and some pathogen infections could inhibit the cancer progression. In our previous studies, we discovered that the plasma exosomes of Plasmodium Py17XNL (Py) infected mice significantly inhibited Lewis lung cancer (LLC) growth and tumor angiogenesis in the tumor-bearing hosts. Further study indicated that these exosomes affected the signal transduction of angiogenesis in endothelial cells. However we have not yet elucidated three scientific questions: what kind(s) of cells produce these exosomes? What components inhibit the angiogenesis? Why these exosomes and their components inhibit the angiogenesis? In this proposal, we would like to answer these questions through a Py-infected LLC-bearing mouse model study. We will use the following techniques in this study: flowcytometry, deep sequence of mRNA and miRNA, proteomics and experiment confirmation. We will measure the key molecules in angiogenesis signal transduction. On one hand, our effort may clarify the mechanisms of action for malaria inhibiting cancer angiogenesis, providing more laboratory evidence for our clinical study. On the other hand, this work may benefit for the development of new anti-tumor therapies targeting angiogenesis based on the exosome components.

肿瘤是严重威胁健康和生命的重要疾病，某些病原体感染可以抑制肿瘤的发生发展。我们在前期研究中发现约氏疟原虫Py17XNL（Py）感染显著抑制荷瘤小鼠的肿瘤生长，刺激小鼠产生外泌体（exosomes）；而这些exosomes可能通过影响内皮细胞的与血管生成相关的信号通路从而显著抑制肿瘤血管生成。但尚未阐明疟原虫感染小鼠血浆中exosomes抑制内皮细胞血管形成的详细机理及其来源细胞，exosomes的内容物中抑制血管生成的主要成分及其作用机理。本项目拟在Py感染的Lewis肺癌荷瘤小鼠中，利用流式细胞术、高通量测序和蛋白组学方法结合功能验证，并检测影响血管生成的信号通路上的关键分子的表达和活性来回答以上问题。一方面阐明疟原虫感染抑制肿瘤血管生成的机理，为我们正在开展的临床研究提供更充分的实验室研究依据，另一方面为研发模拟此类exosomes的成分和结构为基础的新型抗肿瘤制剂奠定基础。

该项目对疟原虫感染抑制小鼠肺癌的分子机理进行了深入探讨。在体内，我们通过瘤内注射exosomes 的实验发现，Py 感染小鼠血浆exosomes 能够抑制肿瘤血管的生成。体外研究发现，Py 感染小鼠血浆 exosomes 可以有效抑制血管内皮细胞VEGFR2 的表达并导致其不能形成管腔，这一抑制效果是通过miR16-5p/17-5p/322-5p/497-5p的作用来实现的。这项研究揭示疟原虫感染抑制肿瘤血管生成的部分分子机制，加深了我们对疟原虫感染宿主所分泌的exosomes 与血管生成之间的相互作用的认识，为开发疟原虫感染来源的 exosomes 作为一种新型抗肿瘤制剂奠定基础。