Establishment and characterization of human urothelial cancer xenografts in severe combined immunodeficient mice

Abstract

Aim : To establish and characterize a murine xenograft model of human urothelial cancer in severe combined immunodeficient (SCID) mice for therapeutic simulation. Methods : Pieces of 30 freshly resected urothelial tumors (24 obtained from bladder and 6 from ureter or pelvis) were implanted subcutaneously into SCID mice, and xenograft tumors were passed in tumorigenic cases. At each passage, histopathology, TP53 mutational status assessed by yeast p53 functional assay, and the Ki-67 labeling index (LI) were examined to evaluate the preservation of original features. A growth delay assay after single-dose irradiation was performed in four representative xenografts. Results : Tumor growth was observed in 18 mice (60%, 18/30). Histologically, 15 of the 18 were epithelial carcinomas similar to the original tumors, whereas the other 3 were Epstein-Barr virus-associated lymphoproliferative disease, resulting in a 50% (15/ 30) take rate. No correlation was found between the tumor take rate and the clinicopathologic features, TP53 mutational status, or Ki-67 LI of the patients' tumors. Of these 15 xenografts, 11 xenografts were passed from 3 to 10 generations. TP53 mutational status remained stable during the passages, and the Ki-67 LI of eight xenografts was within a range of 50% of the LI of the original tumors, although the other three xenografts increased by over 50%. Specific growth delay after irradiation, independent of the original tumor growth speed and Ki-67 LI, was observed in four xenografts. Conclusions : SCID mice are useful recipients for investigations of human urothelial cancer with a wide biological range. This easy-to-handle xenograft system can help to develop a better in vivo preclinical evaluation system for therapeutic agents as well as the investigation of tumor pathophysiology.

Characterization of in vivo chemoresistant human hepatocellular carcinoma cells with transendothelial differentiation capacities

“…However, the extent of upregulation was not significantly different in chemosensitive and chemoresistant tumors. The detected chemosensitivity of HUH-PAS exclude resistance by unspecific selection processes in vivo , which might change cellular properties independently of therapeutic pressure [12,13]. …”

Patient-derived bladder cancer xenografts: a systematic review

“…When analyzed, P53 expression and mutational status were found concordant between the original tumor and the xenografts. 23,28 On the other hand, Ki-67 index was increased in xenografts comparing with the original tumor, particularly after serial passages in mice. 23,25 These studies found no statistically significant relationship between success take rate and malignant characteristics of the original tumor (P53, Ki-67).…”

“…14,15,22 The studies that evaluated the xenografts after several passages confirmed the histologic stability of the xenografts in later passages. 12,22,23 The xenograft molecular characterization is summarized in Table III. Immunohistochemical assessment of xenografts was reported in 5 studies. The most frequently analyzed markers were P53 and Ki-67.…”

Infiltration of Epstein‐Barr virus‐harboring lymphocytes occurs in a large subset of bladder cancers

“…As far as we know, there were only three reports showing the presence of EBV in bladder tumors, including our previous work that lymphoproliferative disease (LPD) derived from EBV-infected tumorinfiltrating lymphocytes could occur when human bladder cancer materials were transplanted directly into severe combined immunodeficient (SCID) mice. 18 To date, it remains unknown whether EBV has a significant role in bladder cancer carcinogenesis. In the present study, we provide new evidence that there is an association between EBV and bladder cancer and indicate the possible role of EBV in bladder cancer.…”

“…In addition, frozen material was available in 18 EBV‐positive cases. In the experiments, EBV lymphomas occurring in severe combined immunodeficient mouse xenotransplants were used as a positive control 18 …”