Project 2: Regulation of Tumor Metastasis by Systemic S1P and Complement Signaling

摘要 该项目旨在检验一种新的假设，即癌细胞通过C5a/C5aR与宿主通信- 诱导全身性SK1/S1P，进而促进肿瘤转移，并抑制全身性S1P/C5aR 信号转导抑制肿瘤转移。为了验证这一假设，提出了三个具体目标：目标1是设计的 目的：明确癌细胞诱导血管内皮细胞补体信号转导途径的作用和机制。 系统的SK1/S1P在肿瘤转移调控中的作用AIM 2旨在确定下游 癌细胞诱导系统SK-1/S1P促进肿瘤转移的机制在这个目标上，我们的 主要目的是验证我们的假设，即癌细胞诱导的系统性SK1/S1P抑制a基因的表达 主控转移抑制因子(BRMS1)通过S1PR2信号在癌细胞中发挥作用，诱导肿瘤转移。 AIM 3旨在确定靶向系统性S1P和/或C5a信号转导系统的治疗效果 肿瘤转移的减弱。在这个目标中，我们的主要目标是测试一个新的假设，即抑制 系统的C5aR/SK1/S1P信号通路将通过激活肿瘤BRMS1来抑制肿瘤转移。这些研究 将有助于揭示癌细胞如何通过SK1/S1P与宿主通信，并补充信号以 调节肿瘤转移，导致开发抑制肿瘤的新治疗策略 生长或转移。在这个项目中，我们还将确定患者系统性S1P/C5a的升高 晚期实体瘤将为监测治疗反应和/或早期提供新的血清标志物 进展到转移的检测。

SUMMARY This project is designed to test a novel hypothesis that cancer cells communicate with the host via C5a/C5aR- induced systemic SK1/S1P, which then promotes tumor metastasis, and that inhibition of systemic S1P/C5aR signaling suppresses metastasis. To test this hypothesis, three Specific Aims are proposed: Aim 1 is designed to define the roles and mechanisms of cancer cell-induced vascular endothelial cell complement signaling and systemic SK1/S1P in the regulation of tumor metastasis. Aim 2 is designed to determine the down-stream mechanisms by which cancer cell-induced systemic SK-1/S1P promotes tumor metastasis. In this Aim, our main goal is to test our hypothesis that cancer cell-induced systemic SK1/S1P inhibits the expression of a master suppressor of metastasis (BRMS1) via S1PR2 signaling in cancer cells, inducing tumor metastasis. Aim 3 is designed to determine the therapeutic efficacy of targeting systemic S1P and/or C5a signaling for the attenuation of tumor metastasis. In this Aim, our main goal is to test a novel hypothesis that inhibition of systemic C5aR/SK1/S1P signaling will inhibit tumor metastasis via activation of tumor BRMS1. These studies will help uncover how cancer cells communicate with the host via SK1/S1P and complement signaling to regulate tumor metastasis, leading to the development of novel therapeutic strategies for the inhibition of tumor growth or metastasis. In this project, we will also determine if the elevation of systemic S1P/C5a in patients with advanced solid tumors will provide novel serum markers for monitoring response to therapy and/or early detection of progression to metastasis.