Nude mice model of primary human nonseminoma germ cell tumors to study biology and resistance to cisplatin treatment

Abstract

e16143 Testicular germ cell tumors (TGCTs) are the most common malignancy in young men. Recently, our group has reported the development of a model of human nonseminoma (NSE) after orthotopic nude mice implantation (Piulats et al, Amer Assoc Cancer Res. 2006). Pure and mix NSE anatomies were represented and they reproduce the main histological, genetic and epigenetic characteristics of paired primary tumors. Xenografts mimic distal dissemination patterns and cisplatin (CDDP) tumor behavior responses. This model has been useful for the study of antiangiogenic therapies (Piulats et al, ASCO. 2007), furthermore we want to demonstrate it is an useful tool to study the genetic mechanisms related with CDDP adquired resitance. We have generated in vivo five tumors showing increased resistance to CDDP by exposition to repetitive cycles and increasing the dose applied through different passages (1 yolk-sac; 1 choriocarcinoma; 2 embrional carcinoma; 1 mix tumor). A shortness time elipse between pasajes was observed for each tumor through CDDP treatments. To confirm increasin resistance, a parallel assay of chemotherapy response was performed between nontreated and CDDP resistant tumors. Whole genome analysis of tour xenografted tumors and their paired CDDP resistant tumor (#3 and #5 passage) were analyzed by CGH NimbeGen arrays using 60 Kb average windows. Few differential genomic changes were identified some of them were consistent across resistant tumors including gain of 9q21.11–9q33.3, 15q23–15q24.1, and 15q26.3 regions and loss of Xp22.33. In one tumour showing strong CDDP resistance compared with its sensitive counterpart it occur in absence of new genomic changes. No changes in the MSI or mutational TP53 status were observed in resisant tumors. Our data suggest that acquisition of tumor resistance to CDDP in TGCTs may proably depend of a combination of different mechanisms, including cromosomal imbalances. No significant financial relationships to disclose.