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Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance

Nature Medicine volume 16, pages 1414–1420 (2010)Cite this article

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Abstract

The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.

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Figure 1: N-cadherin is upregulated in castration resistant prostate cancer.
Figure 2: N-cadherin causes invasion, migration and EMT of multiple prostate cancer cell lines.
Figure 3: Antibodies against N-cadherin decrease invasion and tumor growth.
Figure 4: Histological and immunohistochemical assessments of PC3 tumors treated without or with 2A9 at 10 or 20 mg per kg body weight.
Figure 5: N-cadherin antibodies inhibit growth of established tumor and block progression to castration resistance in vivo.
Figure 6: Gene expression change in N-cadherin–overexpressing cells.

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Acknowledgements

This work was supported in parts by the US National Cancer Institute Prostate Cancer SPORE at the University of California–Los Angeles (P50CA092131-09 to R.E.R.), US Department of Defense Prostate Cancer Research grants (W81XWH-06-1-0324 to Z.A.W., W81XWH-09-1-0630 to R.E.R. and M.B.R., PC061456 to J.H.), Takeda Pharmaceuticals, the Jean Perkins Foundation and the American Cancer Society (RSG-07-092-01-TBE to J.H.). We also thank S. and L. Resnick, the Prostate Cancer Foundation and the Luskin Foundation for generous support and J. Said and N. Doan for immunohistochemical assessments. LNCaP-CL1 cells were provided by C.L. Tso (University of California–Los Angeles). Plasmid pΔVPR was provided by I. Chen (University of California–Los Angeles).

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  1. Hiroshi Tanaka and Evelyn Kono: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Hiroshi Tanaka, Evelyn Kono, Chau P Tran, Joyce Yamashiro, Tatsuya Shimomura, Robert Wada, Jaibin An, Matthew B Rettig & Robert E Reiter

  2. Jonsson Comprehensive Cancer Center, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Hiroshi Tanaka, Evelyn Kono, Chau P Tran, Joyce Yamashiro, Tatsuya Shimomura, Jiaoti Huang, Matthew B Rettig, Zev A Wainberg & Robert E Reiter

  3. Department of Urology, University of Tokyo, Tokyo, Japan

    Hideyo Miyazaki

  4. Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada

    Ladan Fazli & Martin Gleave

  5. Department of Pathology, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Jiaoti Huang

  6. Department of Urology, University of Washington Medical Center, Puget Sound Veterans Health Care Administration, Seattle, Washington, USA

    Robert L Vessella

  7. Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System–West Los Angeles, Los Angeles, California, USA

    Jaibin An & Matthew B Rettig

  8. Department of Human Genetics, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Steven Horvath

  9. Department of Biostatistics, School of Public Health, University of California–Los Angeles, Los Angeles, California, USA

    Steven Horvath

  10. Division of Hematology and Oncology, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Zev A Wainberg

  11. Molecular Biology Institute, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Robert E Reiter

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Contributions

H.T. and E.K. designed and conducted in vitro and in vivo studies. C.P.T. generated stable N-cadherin–knockdown reagents and prepared the manuscript. H.M. made the N-cadherin–overexpressing cell lines. J.Y. and R.W. performed gene and protein expression analyses. T.S. contributed to the in vivo N-cadherin–knockdown and antibody studies. F.L. and M.G. conducted immunohistochemical evaluation of prostate cancer specimens. J.H. contributed to immunohistochemical analyses of in vivo studies. R.L.V. provided clinical materials for the initial N-cadherin screening in metastases. J.A. and M.B.R. provided data on AKT activity. S.H. performed gene expression analysis for stem cell markers. Z.A.W. generated the monoclonal antibodies. R.E.R. conceived of the study and supervised the project. All authors discussed the results and commented on the manuscript at all stages.

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Correspondence to Robert E Reiter.

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Competing interests

R.E.R. has an equity interest in EMTx Therapeutics, which has an option to license and develop N-cadherin–specific antibodies for cancer therapy.

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Tanaka, H., Kono, E., Tran, C. et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 16, 1414–1420 (2010). https://doi.org/10.1038/nm.2236

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