乳铁蛋白调控肿瘤微环境的机制研究

申请人的前两个国自项目发现了天然免疫分子乳铁蛋白具有抑癌基因的特征，能够抑制EB病毒感染，具有抗炎、抗肿瘤转移的功能，并构建了乳铁蛋白基因敲除小鼠。利用肿瘤转移小鼠模型，我们新近发现乳铁蛋白敲除小鼠的肿瘤转移灶明显增多，转移部位中性粒细胞浸润增多，B细胞增殖受到影响；基因表达谱分析：差异基因主要与中性粒、B细胞的功能相关，以及转移相关基因Gpnmb。肿瘤微环境对肿瘤转移产生重要影响，我们在本项目中将利用乳铁蛋白基因敲除小鼠，通过肿瘤转移模型，分析乳铁蛋白缺失之后如何影响肿瘤微环境中的中性粒细胞、B细胞功能，以及Gpnmb-SD4通路对T细胞功能的抑制。本项目将有助于回答：乳铁蛋白作为天然免疫分子，参与肿瘤微环境的调控机制；乳铁蛋白的临床检测和转化对于肿瘤转移防治的价值。

Lactoferrin (LF) is a key component of innate immune defense. Based on the supporting from the NSFC, we previously reported that lactoferrin has anti-tumor and anti-metastatic activities in different cancers as well anti-inflammation function. We have constructed an Lf gene knockout mouse model to fulfill the in vivo functional study. By employing a tumor metastasis mouse model, we recently discovered that Lf knockout mice are more susceptibility for tumor metastasis comparing to the wild type mice. We also noticed there are more infiltration neutrophils existed in the metastasis loci, and the B-cell related function is also compromised in the Lf knockout mouse compared with wild type mice. Gene expression profiling revealed that the differential expressed genes induced by Lf knockout are mainly related to the neutrophils and B-cell functions, as well a few of metastasis associated genes such as Gpnmb. Tumor microenvironment has a crucial impact on the tumor metastasis. In this proposal, we will employ the Lf knockout mouse to making tumor metastasis model and to studying the effect of Lf deficiency (1) on the infiltration neutrophils, and (2) the B-cell function, and (3) the inhibition of T-cell function induced by Gpnmb-SD-4 axis. We believe our proposal will identify new mechanisms that are used by lactoferrin to modulate tumor microenvironment. This study will pave the way to understand the lactoferrin’s role in tumor metastasis translational medicine.