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

总结 该项目旨在验证一种新的假设，即癌细胞通过C5 a/C5 aR与宿主进行交流。 诱导全身性SK 1/S1 P，然后促进肿瘤转移，并抑制全身性S1 P/C5 aR 信号传导抑制转移。为了验证这一假设，提出了三个具体目标：目标1是设计 明确癌细胞诱导的血管内皮细胞补体信号传导的作用和机制， 系统性SK 1/S1 P在肿瘤转移调节中的作用。目标2旨在确定下游 癌细胞诱导的系统性SK-1/S1 P促进肿瘤转移的机制。在这方面，我们的 主要目的是检验我们的假设，即癌细胞诱导的系统性SK 1/S1 P抑制了癌细胞的表达。 转移的主要抑制因子（BRMS 1）通过癌细胞中的S1 PR 2信号传导，诱导肿瘤转移。 目的3旨在确定靶向全身性S1 P和/或C5 a信号传导对肿瘤细胞的治疗功效。 肿瘤转移的衰减。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 系统性C5 aR/SK 1/S1 P信号传导将通过激活肿瘤BRMS 1来抑制肿瘤转移。这些研究 将有助于揭示癌细胞如何通过SK 1/S1 P和补体信号传导与宿主沟通， 调节肿瘤转移，从而导致抑制肿瘤的新治疗策略的发展 生长或转移。在本项目中，我们还将确定患者的全身S1 P/C5 a升高是否 晚期实体瘤患者将提供新的血清标志物，用于监测对治疗的反应和/或早期 检测转移进展。

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.