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Molecular analysis integrating different pathways associated with androgen-independent progression in LuCaP 23.1 xenograft

Oncogene volume 23, pages 9111–9119 (2004)Cite this article

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 (948.9±76.9 mm3) and 63 slow growing (SG) tumours (229.6±18.4 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 5α-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 α-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.

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Abbreviations

AI:

androgen independent

AM:

adrenomedullin

FG:

fast growing

FG-P:

fast growing/progressing

5α-R2:

5 alpha-reductase 2

PAM:

peptidyl α-amidating monooxygenase

PrCa:

prostate cancer

SG:

slow growing

SG-P:

slow growing/progressing

SG-R:

slow growing/responding

TK:

thymidine kinase

TS:

thymidilate synthetase

uPA:

urokinase plasminogen activator

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Acknowledgements

We thank Dr Robert Vessella's Laboratory, Department of Urology, University of Washington, Seattle for providing with LuCaP 23.1 xenograft. We thank Dr Lisa Valettes, Inserm U419, Nantes, who very kindly carried out Bcl-2 TaqMan analyses.

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Author notes

  1. Palma Rocchi and Xavier Muracciole: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratoire 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

    Palma Rocchi, Frederic Fina, Jacqueline Palmari, L'Haucine Ouafik & Pierre-Marie Martin

  2. Service de Radiothérapie, CHU Timone, AP-HM, France

    Xavier Muracciole

  3. The Prostate Centre, Jack Bell Research Centre, Vancouver, Canada

    Palma Rocchi & Dave J Mulholland

  4. Service d'Urologie de l'Hôpital Salvator, AP-HM, France

    Gilles Karsenty & Franck Bladou

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  1. Palma Rocchi
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Correspondence to Palma Rocchi.

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Rocchi, P., Muracciole, X., Fina, F. et al. Molecular analysis integrating different pathways associated with androgen-independent progression in LuCaP 23.1 xenograft. Oncogene 23, 9111–9119 (2004). https://doi.org/10.1038/sj.onc.1208154

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