LNCaP progression model of human prostate cancer: Androgen-independence and osseous metastasis

BACKGROUND. Clinically, the lethal phenotypes of human prostate cancer are characterized by their progression to androgen-independence and their prope nsity to form osseous metastases. We reported previously on the establishme nt of androgen-independent (AI) human prostate cancer cell lines derived fr om androgen-dependent (AD) LNCaP cells, with androgen independence defined as the capability of prostate cancer cells to grow in castrated hosts. One of the sublines, C4-2, was found to be AI, highly tumorigenic, and metastat ic, having a proclivity for metastasis to the bane. METHODS. We established the AI and bone metastatic cell sublines B2, B3, B4 , and B5 from the parental C4-2 subline, using a previously established coi noculating procedure. We determined the biologic behavior of the parental a nd derivative LNCaP sublines in vivo and in vitro, as well as their molecul ar and cytogenetic characteristics. RESULTS. Unlike other human prostate cancer models, the LNCaP progression m odel shares remarkable similarities with human prostate cancer. We observed a comparable pattern of metastasis from the primary to the lymph node and to the axial skeleton, with a predominant phenotype of osteoblastic reactio n; 25-37.5% of the animals developed paraplegia. Cytogenetic and biochemica l characterizations of LNCaP sublines also indicate close similarities betw een human prostate cancer and the LNCaP progression model. Additional chrom osomal changes were detected in B2-B5 sublines derived from C4-2 bone metas tases. These LNCaP sublines were found to grow faster under anchorage-depen dent but not -independent conditions. The in vitro invasion and in vivo met astatic potential of these LNCaP sublines surprisingly correlated with anch orage-dependent and not -independent growth. The derivative LNCaP sublines when cultured in vitro produced a substantially higher (20-30-fold) amount of basal steady-state concentrations of PSA than that of the parental LNCaP cells. PSA production was high initially, but was markedly reduced when th e derivative cell lines were inoculated and allowed to grow long-term in vi vo for the establishment of tumors and metastasis, suggesting that unknown host factors derived either from the prostate or the bone can effectively d ownregulate PSA expression by prostate tumor epithelium. CONCLUSIONS. The LNCaP model of human prostate cancer progression will help improve our understanding of the mechanisms of androgen-independence and o sseous metastasis, and tumor-host determinants of PSA expression. Prostate 44:91-103, 2000. (C) 2000 Wiley-Liss, Inc.