1. ¹Laboratoire de Cancérologie Expérimentale EMI 0359/Laboratoire de Transfert d'Oncologie Biologique, Assistance Publique-Hôpitaux de Marseille (AP-HM), IFR Jean Roche, Faculté de Médecine de Marseille, France
2. ²Service de Radiothérapie, CHU Timone, AP-HM, France
3. ³The Prostate Centre, Jack Bell Research Centre, Vancouver, Canada
4. ⁴Service d'Urologie de l'Hôpital Salvator, AP-HM, France

Correspondence: P Rocchi, E-mail: procchi@vanhosp.bc.ca

⁵These authors contributed equally to this work

Received 29 January 2004; Revised 13 August 2004; Accepted 31 August 2004; Published online 18 October 2004.

Abstract

After therapeutic hormone deprivation, most prostate cancer (PrCa) cells develop androgen-independent (AI) growth. PrCa is highly heterogeneous and multifocal, suggesting that several molecular processes or pathways may be contributing to AI. The human LuCaP 23.1 xenograft model retains clinical hallmarks of PrCa, including heterogeneous growth, PSA production, androgen-responsiveness and progression to AI. In this work, we studied the effect of androgen depletion (castration) on the growth of LuCaP 23.1 xenografts. A total of 100 nude mice were implanted and analysed for their growth profiles before and after castration. By 11 and 15 weeks, tumours were harvested and assessed for molecular marker expression specific for PrCa. Prior to castration we found 37 fast growing (FG) tumours (948.976.9 mm³) and 63 slow growing (SG) tumours (229.618.4 mm³), a previously undescribed result for this PrCa model. Quantitative RT–PCR showed that in comparison to SGs, FGs contained high HER1, uPA and thymidilate synthetase (TS) expression with low levels of 5-reductase 2 mRNA. All FG tumours progressed rapidly to AI growth 5 weeks after castration (FG-P). In SG castrated tumours, 66% of tumours (SG-P) showed retarded progression (by 12 weeks) to AI, whereas 34% responded to castration (SG-R). Molecular analysis permitted us to define distinct molecular profiles integrating different pathways associated with AI progression. FG-P, and a subgroup of SG-P tumours, presented significantly high levels of peptidylglycine -amidating monooxygenase (PAM), HER1, HER2, TS, and uPA mRNA, all of which correlated with AR expression. The second subgroup of SG-P tumours showed overexpression of the antiapoptotic gene Bcl-2. A third subgroup of SG-P tumours showed significant expression of hypoxia-related gene (adrenomedullin) after castration. This work permitted to define distinct molecular profiles related to different AI growth in the LuCaP 23.1 xenograft.