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

Abstract

BACKGROUND.Clinically, the lethal phenotypes of human prostate cancer are characterized by their progression to androgen-independence and their propensity to form osseous metastases. We reported previously on the establishment of androgen-independent (AI) human prostate cancer cell lines derived from 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 metastatic, having a proclivity for metastasis to the bone. 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 coinoculating procedure. We determined the biologic behavior of the parental and derivative LNCaP sublines in vivo and in vitro, as well as their molecular and cytogenetic characteristics. RESULTS. Unlike other human prostate cancer models, the LNCaP progression model 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 reaction; 25-37.5% of the animals developed paraplegia. Cytogenetic and biochemical characterizations of LNCaP sublines also indicate close similarities between human prostate cancer and the LNCaP progression model. Additional chromosomal changes were detected in B2-B5 sublines derived from C4-2 bone metastases. These LNCaP sublines were found to grow faster under anchorage-dependent but not -independent conditions. The in vitro invasion and in vivo metastatic potential of these LNCaP sublines surprisingly correlated with anchorage-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 the derivative cell lines were inoculated and allowed to grow long-term in vivo for the establishment of tumors and metastasis, suggesting that unknown host factors derived either from the prostate or the bone can effectively downregulate 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 osseous metastasis, and tumor-host determinants of PSA expression.

Development of the VCaP androgen-independent model of prostate cancer

“…Similarly, Zhou et al orthotopically injected LNCaP cells into castrated mice and passaged these tumors for 5 generations, each generation resulted in a more aggressive androgen independent tumor [11]. Wu et al developed the C4-2B model of androgen independence from a bone derived subline of LNCaP cells [16][17][18]. Trepper et al developed a CWR22 hormoneindependent variant, CWR22-R, Klein et al generated the LAPC model of AIPCa in SCID mice, Navone et al established the PCa2a and PCa2b model of AIPCa, and Corey et al developed the LuCaP xenograft model of AIPCa [10,12,14,15].…”

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…Addition of androgen to these androgenindependent variants of LNCaP cells suppressed proliferation (Kokontis et al, 1998) and promoted apoptosis (Joly-Pharaboz et al, 2000). Such adaptive changes from growth stimulator to suppressor have also been observed in LNCaP xenografts in vivo after castration of the host (Thalmann et al, 2000;Zhou et al, 2004;Chuu et al, 2006). Down-regulation of AR with anti-sense oligonucleotides (Eder et al, 2000) or siRNA (Ha˚a˚g et al, 2005;Liao et al, 2005) may result in the suppression of cell proliferation or promotion of apoptosis in both androgen-dependent and androgen-independent sublines of LNCaP cells.…”

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…The C4-2 cell line, a subline of LNCaP cells [31,32], is an androgen-independent line that expresses the androgen receptor and mutated PTEN. Cells were maintained under standard tissue culture conditions as previously described.…”