Subcutaneously implanted patient-derived xenografts (PDX) have become a commonly used tool in the study of cancer; however, these PDX models rarely metastasize from the subcutaneous site – even if the original patient tumors are known to be metastatic. Orthotopic xenograft models, on the other hand, seem to more closely mimic the metastases observed in human prostate cancer patients, according to a 2016 study published in the Journal of Cellular Biochemistry by Zhang, et al.


The results of this study clearly show “very different tumor behavior at the orthotopic and subcutaneous sites of human prostate cancer PC-3 in athymic nude mice,” according to Zhang, et al. “By day-2 after tumor implantation, the orthotopic tumor is already highly vascularized and the cancer cells have begun to migrate out of the tumor. In contrast, the subcutaneous tumor only begins to be vascularized by day-3 and cells to not migrate from the tumor.” Additionally, when observed over a two week period, angiogenesis is much more extensive in the orthotopic tumor when compared to the subcutaneous tumor.


Specifically, the orthotopic PC-3-GFP tumor is observed to grow very rapidly and presents distinct metastases in the lymph nodes by day-3 and evidence of metastases in the abdominal cavity by day-7. Compare this to the PDX model which, after a full 14 days, showed no evidence of invasion or metastasis associated with the subcutaneous tumor, even after the lymph nodes and abdominal cavities of the mouse was extensively explored.


Using orthotopically-implanted PC-3-GFP cells, Zhang et al were also able to observe metastatic cells that migrated from the primary tumor to various organ systems, thereby demonstrating that “PC-3 has multiple metastatic routes similar to hormone-independent advanced-stage prostate cancer in the clinic.” As researchers continue to better understand the process by which metastases occur in PC-3 and other tumor types using orthotopic xenografts, the possibility for clinical implications are tremendous.