阿帕替尼治疗小鼠人源化胃癌移植瘤模型的疗效观察及CD31的意义

Efficacy of apatinib on patient-derived xenograft mouse model for gastric cancer and the significance of CD31

目的利用人源化胃癌移植瘤(PDX)模型探索阿帕替尼的可能疗效预测标志物及其与紫杉醇联用的可行性。方法选择6例小鼠PDX模型,每例模型分对照组、阿帕替尼组、紫杉醇组以及联合治疗组。测量肿瘤体积及小鼠质量,计算抑瘤率。靶向捕获测序及转录组测序分析PDX肿瘤组织的分子变异及阿帕替尼用药前后的基因表达变化。免疫组化方法检测组织中CD31表达情况。结果阿帕替尼单药组在6例胃癌PDX模型中均具有不同程度的抑瘤作用,其抑瘤率略优于紫杉醇单药;与单药组相比,联合用药组的抑瘤率无明显增加。阿帕替尼用药后,包含FGFR1/2在内的基因显著下调。差异基因主要富集在血管生成、血液循环、炎性反应和蛋白级联激活等生物过程以及补体和凝血级联信号通路。微血管密度相对较高的PDX组织对阿帕替尼的敏感性高于微血管密度较低的组织。结论阿帕替尼在胃癌PDX模型中通过抑制血管生成发挥抑瘤作用,肿瘤组织微血管密度可能预测阿帕替尼的疗效,临床是否应推荐阿帕替尼与紫杉醇联用尚需进一步验证。

Objective Try to identify the predictive biomarker of efficacy of apatinib and its feasibility in combination with paclitaxel on patient-derived xenografts(PDX)for gastric cancer(GC).Methods A total of six GC PDX mouse models were selected.Each model was divided into control group,apatinib group,paclitaxel group and combination group.The tumor volume and the body weight of mice were measured and the tumor growth inhibition(TGI)rate was calculated.Targeted next-generation sequencing and transcriptome sequencing were conducted on tumor tissues of PDX models,respectively.The CD31 expressions of tumor tissues were detected by immunohistochemistry(IHC)assay.Results Apatinib monotherapy showed selective antitumor effects on six GC PDX models,which was superior to paclitaxel.After apatinib treatment,the expression of FGFR1/2 was downregulated.The differentially expressed genes were significantly enriched in biological processes of vasculature development,blood circulation,inflammation response,protein cascade activation and the complement and coagulation cascade signaling pathway.PDX models with relatively high microvessel density were more sensitive to apatinib than that of models with lower microvessel density.Conclusions Apatinib exerted its antitumor effect by inhibiting angiogenesis in GC PDX models.The microvessel density of tumor tissue may predict the efficacy of apatinib,combination of apatinib and paclitaxel should be recommended in clinical practice needs further validation as a potential regiem.