ICOSL诱导三阴性乳腺癌转移的机制研究

项目名称： ICOSL诱导三阴性乳腺癌转移的机制研究

项目编号： No.81472479

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王斌

作者单位： 中国人民解放军第二军医大学

项目金额： 68万元

中文摘要： 可诱导共刺激分子配体（ICOSL）在多种肿瘤细胞中表达，它能协助肿瘤细胞逃避机体的免疫监视, 因此有望成为逆转肿瘤免疫耐受的重要靶点。我们前期工作发现，ICOSL在三阴性乳腺癌中表达显著上调，并与预后相关；更重要的是，三阴性乳腺癌ICOSL的表达与其转移及磷酸化p38-MAPK水平呈正相关，并可在体外增强肿瘤细胞的侵袭能力。为此我们提出假设：ICOSL作为共刺激分子，一方面能正向活化T抑制细胞诱导肿瘤免疫耐受，另一方面可反向激活肿瘤细胞的p38-MAPK通路促进肿瘤转移，微转移的乳腺癌细胞因而得以逃避机体的免疫监视并恶性增殖。为了验证这一假说，本研究将分别针对T 细胞和三阴性乳腺癌细胞，通过对大量临床标本、体外混和T 细胞-肿瘤细胞反应、肿瘤侵袭转移实验、小鼠乳腺癌肺转移和人裸鼠乳腺癌高肺转移模型的研究，为阐明ICOSL诱导三阴性乳腺癌转移的机制和发现三阴性乳腺癌潜在的治疗靶点提供依据。

中文关键词： C21_乳腺肿瘤；肿瘤转移；可诱导共刺激分子配体；三阴性乳腺癌

英文摘要： ICOS ligand (ICOSL) is expressed on a some tumor cells. It could help tumor cells escape from the immune surveillance of tumor bearing host and could be used as a promising target to reverse the tumor immune tolerance in future.Our preliminary experiment had shown that ICOSL is expressed on triple-negative breast cancer selectively and the expression are positive correlated with the prognosis. More importantly, we also found that the expression of ICOSL are positive correlated with p-p38 and triple-negative breast cancer metastasis. What,s more,we found that the the expression of ICOSL can enhance the ability of invasiveness of triple-negative breast cancer cells in vitro. On the basis of this,we put forward a hypothesis:as co stimulatory molecules,on the one hand, ICOSL could induce immune tolerance through activating Treg, on the other ICOSL could activate p38-MAPK signaling pathway to promotes tumor metastasis. Sporadic tumor cells then could escape from immune surveillance and begin to grow progressively. Sporadic tumor cells at last become clinically apparent tumor.Focusing on T cells and tumor cells, we would examine this hypothesis through clinical data, allogeneicmixed T lymphocyte-tumor response,tumor invasion and metastasis experiment, mouse breast cancer model and nude model bearing human breast cancer with high pulmonary metastatic potential.Through those work we would examine the mechanisms of ICOSL-induced breast cancer metastasis and provide a new target for diagnosis and treatment of triple-negative breast cancer.

英文关键词： Breast Cancer;Tumor Metastasis;ICOSL;Triple-Negative Breast Cancer