ESTABLISHING HUMAN PROSTATE-CANCER CELL XENOGRAFTS IN BONE - INDUCTION OF OSTEOBLASTIC REACTION BY PROSTATE-SPECIFIC ANTIGEN-PRODUCING TUMORS IN ATHYMIC AND SCID BG MICE USING LNCAP AND LINEAGE-DERIVED METASTATIC SUBLINES/

LNCaP lineage-derived human prostate cancer cell lines C4-2 and C4-2B( 4) acquire androgen independence and osseous metastatic potential in v ivo. Using C4-2 and C4-2B(4) the goals of the current investigation we re 1) to establish an ideal bone xenograft model for prostate cancer c ells in intact athymic or SCID/bg mice using an intraosseous route of tumor cell administration and 2) to compare prostate cancer metastasis by administering cells either through intravenous (i.v.) or intracard iac administration in athymic or SCID/bg mice. Subsequent to tumor cel l administration, prostate cancer growth in the skeleton was assessed by radiographic bone density, serum prostate-specific antigen (PSA) le vers, presence of hematogenous prostate cancer cells and histopatholog ic evaluation of tumor specimens in the lymph node and skeleton. Our r esults show that whereas LNCaP cells injected intracardially failed to develop metastasis, C4-2 cells injected similarly had the highest met astatic capability in SCID/bg mice. Retroperitoneal and mediastinal ly mph node metastases were noted in 3/7 animals, whereas 2/7 animals dev eloped osteoblastic spine metastases. Intracardiac injection of C4-2 i n athymic hosts produced spinal metastases in 1/5 animals at 8-12 week s post-injection; PC-3 injected intracardially also metastasized to th e bone but yielded osteolytic responses. Intravenous injection of eith er LNCaP or C4-2 failed to establish tumor colonies. Intrailiac inject ion of C4-2 but not LNCaP nor C4-2B(4) cells in athymic mice establish ed rapidly growing tumors in 4/8 animals at 2-7 weeks after inoculatio n. Intrafemoral injection of C4-2 (9/16) and C4-2B(4) (5/18) but not L NCaP (0/13) cells resulted in the development of osteoblastic bone les ions in athymic mice (mean: 6 weeks, range: 3-12 weeks). In SCID/bg mi ce, intrafemoral injection of LNCaP (6/8), C4-2 (8/8) and C4-2B(4) (8/ 8) cells formed PSA-producing, osteoblastic tumors in the bone marrow space within 3-5 weeks after tumor cell inoculation. A stepwise increa se of serum PSA was detected in all animals. Reverse transcription-pol ymerase chain reaction (RT-PCR) to detect hematogenously disseminated prostate cancer cells could not be correlated to either serum PSA leve l or histological evidence of tumor cells in the marrow space. We have thus established a PSA-producing and osteoblastic human prostate canc er xenograft model in mice, (C) 1998 Wiley-Liss, Inc.