Impact of macrophage/microglia IL4R-activation on CNS-colonization

巨噬细胞/小胶质细胞 IL4R 激活对中枢神经系统定植的影响

• 批准号: 392615870
• 负责人: Professor Dr. Tobias Pukrop
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392615870?language=en
• 关键词: Impact; macrophage; microglia; IL4R; activation

Brain metastases of breast cancer have not only significant impact on the quality of live (QoL), but also result in a fatal prognosis with a median overall survival (OS) ranging from 4 to 5.5 months. The final step of metastasis itself, the colonization, is a multi-phase process which can be subdivided into; survival of the carcinoma cells upon entry of the metastatic organ; formation of a micro-metastasis; reactivation of growth; macro-metastasis; overtaking the host tissue; the dissemination in the metastatic organ and finally the organ-destruction. Most important, it is the rate-limiting step of the whole metastatic cascade. In the CNS the first-line of defence is composed of microglia and astrocytes; however, its impact during CNS-colonization is barely understood. Up to date we know that after seeding of the brain microglia together with astrocytes immediately get attracted and co-localize with the intruders. This forces the carcinoma cells to adapt to this foreign microenvironment and micro-milieu shortly after arrival. Interestingly, the majority of the arriving cancer cells do not survive the next hours to days and only a few start to regrowth. However, how the carcinoma cells interact with the glial cells, how they communicate and which pathways or signals are involved in this interaction during the colonization are almost unknown. Recently, we identified IL4R-signaling as master regulator of the monocyte-derived macrophages (MDM)/microglia colonization-promoting phenotypes. In line with these findings we aim to investigate the impact of IL4R-signaling in MDM and microglia during colonization of the brain in the framework of the second funding period of the DFG-FOR2127. Therefore we will use MDM/microglia specific IL4rα(-/-) models and study the colonization process of various syngeneic breast cancer cell lines by stereotactical injection. Additionally we will use different co-culture models and will investigate the impact of IL4-signaling in the communication of the macrophages with breast cancer cells. These experiments will lead to a better understanding of this very complex process of CNS-colonization and of the adaption to a foreign microenvironment of the breast cancer cells. Additionally, we will investigate the IL4-signaling as potential therapeutic target during this fatal step of metastasis.

乳腺癌脑转移不仅严重影响患者的生活质量，而且预后不良，中位生存期为4 ~ 5.5个月。转移本身的最后一步，即定殖，是一个多阶段过程，其可以细分为：癌细胞在进入转移器官时的存活;微转移的形成;生长的再激活;宏观转移;超越宿主组织;在转移器官中的扩散以及最终的器官破坏。最重要的是，它是整个转移级联反应的限速步骤。在中枢神经系统中，第一道防线由小胶质细胞和星形胶质细胞组成;然而，其在中枢神经系统定植期间的影响几乎不为人所知。到目前为止，我们知道，在脑内接种后，小胶质细胞和星形胶质细胞立即被吸引并与入侵者共定位。这迫使癌细胞在到达后不久适应这种外来微环境和微环境。有趣的是，大多数到达的癌细胞在接下来的几个小时到几天内无法存活，只有少数开始重新生长。然而，癌细胞如何与神经胶质细胞相互作用，它们如何通信以及在定植期间这种相互作用涉及哪些途径或信号几乎是未知的。最近，我们确定了IL 4 R信号转导作为单核细胞衍生的巨噬细胞（MDM）/小胶质细胞定植促进表型的主调节因子。根据这些发现，我们的目标是在DFG-FOR 2127第二个资助期的框架内研究脑定植期间MDM和小胶质细胞中IL 4 R信号传导的影响。因此，我们将使用MDM/小胶质细胞特异性IL 4 r α（-/-）模型，通过立体定向注射研究各种同基因乳腺癌细胞系的定植过程。此外，我们将使用不同的共培养模型，并将研究IL 4信号转导在巨噬细胞与乳腺癌细胞的通信中的影响。这些实验将使我们更好地理解CNS定植的这一非常复杂的过程，以及乳腺癌细胞对外来微环境的适应。此外，我们将研究IL 4信号传导作为转移的这一致命步骤中的潜在治疗靶点。