Selection of highly metastatic variants of different human prostatic carcinomas using orthotopic implantation in nude mice

Abstract

The purpose of this study was to determine whether the implantation of human prostate cancer cells into the prostates of nude mice and their subsequent growth there can be used to select variants with increasing metastatic potential. PC-3M and LNCaP cells were injected into the prostates of athymic mice. Tumors from the prostate or lymph nodes were harvested, and cells were reinjected into the prostate. This cycle was repeated three to five times to yield cell lines PC-3M-Pro4, PC-3M-LN4, LNCaP-Pro3-5, and LNCaP-LN3-4. Parental and variant cells were injected into the prostates of nude mice. PC-3M-LN4 cells produced enhanced regional lymph node and distant organ metastasis as compared to PC-3M-Pro4 or PC-3M cells. After i.v. or intracardiac inoculation, PC-3M-LN4 cells produced a higher incidence of lung metastasis and bone metastasis, respectively, than PC-3M or PC-3M-Pro4 cells. Subsequent to implantation into the prostate, LNCaP-LN3 cells produced a higher incidence of regional lymph node metastases than LNCaP-Pro5 or LNCaP cells. After intrasplenic implantation, LNCaP-LN3 cells also yielded experimental liver metastases. The metastatic LNCaP-LN3 cells exhibited clonal karyotypic abnormalities, were less sensitive to androgen (in vitro and in vivo), and produced high levels of prostate-specific antigen. Collectively, the data show that the orthotopic implantation of human prostate cancer cell lines in nude mice is a relevant model with which to study the biology of prostate cancer metastasis and to select variant cell lines with enhanced metastatic potential.