Establishment And Treatment Of Prostate Cancer Patient-Derived Xenograft Model

ObjectiveIn this study,we intend to establish the models of prostate cancer(Pca)patient-derived xenograft(PDX)and to analyze its consistency with primary tumors.We further explore the crucial factors of establishment of Pca PDX models and evaluate the anti-tumor effects of different therapeutic strategies in individualized Pca PDX models.Materials and MethodsThe surgical fresh specimens of Pca patients were mixed with Matrigel and transplanted into the severe immunodeficient mice that supplement with androgen subcutaneously.The tumor growth was dynamically monitored and serially passaged.We analyzed the main factors affecting the establishment of PDX model of Pca,including transplant site and androgen level.The changes of testosterone levels in the serum of mice supplemented with exogenous androgens(Testosterone undecanoate soft capsules)were monitored continuously and the corresponding curve of the change trend were draw.We selected the prostate cancer PDX models which were stably transmitted to the third generation(F3)to evaluate the fidelity and the consistency of the primary tumor.The xenograft tumor tissue was collected and divided it into three parts,one part was fixed by 4% paraformaldehyde and embedded as paraffin sections for histopathological examination,the other part was extracted RNA to real-time quantitative PCR to exame the expression level of androgen receptor,and another part was extracted genomic DNA to detect STR(Short Tandem Repeat Profiling)typing.Two different types of tumors(Hormone sensitive-D17225 and Castration-resistant-B45354)from the established prostate cancer PDX model were selected for treatmen.The nude mice-bearing tumor were divided into four groups: 1)Docetaxel(DCTX);2)Castration(CAS);3)Docetaxel combined with Castration(DCTX+CAS);And 4)Control group(CON),5 mice in each group.Tumor volume and mouse body weight were measured during treatment.The total prostate specific antigen(tPSA)concentration in serum of mice was detected by ELISA,and histopathological changes were detected by H&E and Immunohistochemical staining(IHC).ResultsSeven PDX models of Pca were successfully established.It can shortened the growth latency of xenografts and improved the success rate of the PDX model when the patients' prostate tumor tissue was implanted to renal capsule and the mice timely supplemented with testosterone undecanoate soft capsules.Both hormone sensitive type PDX model D17225 and castration resistant type PDX model B45354 better maintained the main features of the patient's primary prostate cancer by histopathological analysis and STR detection.Docetaxel alone or docetaxel combined castration treatment showed good therapeutic effect on the D17225 model.ConclusionThe PDX model of prostate cancer was successfully established and stable passaged.These models accurately simulated the pathological features of clinical prostate cancer.Considering hormone supplementation and transplantation site,the success rate of PDX model of prostate cancer can be improved significantly,so as to establish a variety of heterogeneous PDX models of individualized prostate cancer.Furthermore,docetaxel alone or combinated with castration treatment showd a perfect therapeutic effect on the hormone-sensitive(D17225)prostate cancer PDX model.