结肠癌化疗后肠道毒副作用和复发是肿瘤领域重大科学问题。我们首先报道了趋化因子CXCL4通过激活p38-MAPK导致p53依赖性肠道粘膜上皮细胞凋亡，是化疗性腹泻（CID）的关键启动因子；同时，CXCL4还影响肿瘤免疫功能，促进结肠癌生长；我们制备的抗CXCL4单克隆抗体同时具有防治CID和协同氟尿嘧啶（5-FU）抑制结肠癌生长的双重疗效。阐明CXCL4抑制免疫功能的分子机制，是确认CXCL4为抗肿瘤新药靶点亟待解决的关键问题。为此，我们将开展CXCL4在结肠癌病人标本的表达规律研究；使用改造后不同CXCL4基因型结肠癌细胞株，建立荷瘤小鼠模型，获得CXCL4表达水平、肿瘤生长速率、和细胞毒T细胞（CD8+CTL）产生数量之间的相关性数据；使用CXCL4受体敲除鼠荷瘤模型，通过体内体外实验，确认CXCL4抑制CD8+CTL产生和/或促进CD8+CTL凋亡的作用，发现CXCL4作用的信号通路。

Intestinal cytotoxicity and tumor relapse after chemotherapy is still a major scientitic challenge in onlogy. We firstly reported that activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluouracil (5-FU). Importantly, CXCL4 also mediates tumor regrowth after chemotherapy by suppression of tumor immunity. We have produced anti-CXCL4 monoclonal antibody and demonstrated that it reduced the incidence, severity and duration of chemotherapy-induced diarrhea and suppressed the tumor growth in synergy with 5-FU. Understanding the molecular mechanism of CXCL4 in suppression of tumor immunity holds the key to confirm CXCL4 as a new drug target for cancer therapy. We will carry out the expression analysis of CXCL4 in colon-cancer samples of patients to verify their clinical relevance. In addition, using CXCL4-modified colon-cancer cell lines to generate tumor-bearing mice, we will establish the relavence of expression level of CXCL4, tumor growth rate, and production of cytotoxitic T lymphocyte (CD8+CTL). Furthermore, using CXCL4 receptor knockout mice, we will confirm the inhibitory role of CXCL4 in production of CD8+CTLs and/or stimulation of their apoptosis by combination of in vitro and in vivo design of experiments. The molecular signal pathways of CXCL4 affecting CD8+CTL proliferation and/or apoptosis will be determined by analysis of expression and activation of relevant molecules in the parthways.