The era of targeted cancer therapies has arrived.However,due to the complexity of biological systems,the current progress is far from enough.From biological network modeling to structural/dynamic network analysis,network systems biology provides unique insight into the potential mechanisms underlying the growth and progression of cancer cells.It has also introduced great changes into the research paradigm of cancer-associated drug discovery and drug resistance.
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。
