中文摘要：

目的研究贝伐珠单抗治疗与结直肠癌肺转移的相关性及机制。方法 BALB/c-nu小鼠脾内注射指数生长期的HCT116细胞,建立小鼠结直肠癌肝转移模型。16只模型小鼠分为贝伐珠单抗治疗组和对照组,每组8只。治疗组ip给予贝伐珠单抗5 mg·kg^-1,对照组给予相同剂量的同型对照Ig G,分别于建模前2 d及建模后2 d各给药1次,之后每5 d给药1次,连续给药4周,共计给药7次。给药结束后处死小鼠,取出肝、肺器官,肉眼观察肝、肺表面转移灶;HE染色法观察小鼠肝、肺组织转移灶;定量RT-PCR检测小鼠肺组织趋化因子受体4（CXCR）及其配体CXCL12 m RNA的表达。结直肠癌细胞HCT116体外与贝伐珠单抗5 mg·L^-1共孵育24 h,Western蛋白印迹法和定量RT-PCR分别检测血管内皮生长因子受体1（VEGFR1）/CXCR4/CXCR7蛋白和CXCR3/4/7 m RNA的表达水平。结果肉眼观察发现,贝伐珠单抗治疗组小鼠2/8出现肝转移,较对照组（6/8肝转移）明显减少（P〈0.05）;贝伐珠单抗治疗组小鼠8/8出现肺转移,较对照组（2/8肺转移）明显增加（P〈0.05）;小鼠肺组织中鼠源CXCR4及人源CXCL12 m RNA表达显著高于对照组（P〈0.05）。HCT116细胞体外经贝伐珠单抗诱导后,VEGFR1蛋白,CXCR4/7 m RNA和蛋白表达显著升高（P〈0.05）,而CXCR3表达无明显变化。结论贝伐珠单抗可能通过上调CXCR4及其配体CXCL12的表达促进结直肠癌的肺转移。

英文摘要：

OBJECTIVE To investigate the effect of bevacizumab,an anti-human vascular endothelial growth factor monoclonal antibody,on pulmonary dissemination of colorectal cancer. METHODS A metastatic colorectal cancer mouse model was established. Mice were randomly divided into two groups（n=8）. The mice in experimental group were administered ip with bevacizumab at the dosage of5 mg·kg- 1,and those in control group were given isotype Ig G at the same dosage. The antibodies were administered on 2 d before initiation of model establishment and 2 d after that,then once every 5 d for4 weeks,for a total of 7 times. Liver and lung metastases were determined by histopathological examination.The chemokine receptor C-X-C receptor 4（CXCR4）and its ligand C-X-C ligand 12（CXCL12）m RNA expression in the lung were detected by quantitative RT-PCR. Human colon cancer cells HCT116 were treated with bevacizumab（5 mg·L^-1）for 24 h. The expression levels of vascular endothelial growth factor receptor 1（VEGFR1）and CXCR4/7 protein as well as CXCR3/4/7 m RNA were examined by Western blotting and quantitative RT-PCR respectively. RESULTS The number of mice（2/8）with liver metastases was reduced,while the number of mice（8/8） with lung metastases increased in experimental group compared with isotype Ig G-treated group（6/8 and 2/8 respectively,P〈0.05）. The m RNA expression level of CXCR4 and CXCL12 in lung tissue was significantly up-regulated in bevacizumab-treated group compared with control group（P〈0.05）. The m RNA and protein expression level of CXCR4 and CXCR7 was dramatical y increased in HCT116 cel s treated with bevacizumab（P〈0.05）. CONCLUSION Bevacizumab can potentially promote lung metastases of colorectal cancer,which may be related to up-regulation of CXCR4 and CXCL12 expression.