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Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer

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Abstract

Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Once a tumor is established it may attain further characteristics via mutations or hypoxia, which stimulate new blood vessels. Angiogenesis is a hallmark in the pathogenesis of cancer and inflammatory diseases that may predispose to cancer. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatory damage and was previously reported to play a key role in prostate carcinogenesis. To gain insight into the anti-tumoral properties of HO-1, we investigated its capability to modulate PCa associated-angiogenesis. In the present study, we identified in PC3 cells a set of inflammatory and pro-angiogenic genes down-regulated in response to HO-1 overexpression, in particular VEGFA, VEGFC, HIF1α and α5β1 integrin. Our results indicated that HO-1 counteracts oxidative imbalance reducing ROS levels. An in vivo angiogenic assay showed that intradermal inoculation of PC3 cells stable transfected with HO-1 (PC3HO-1) generated tumours less vascularised than controls, with decreased microvessel density and reduced CD34 and MMP9 positive staining. Interestingly, longer term grown PC3HO-1 xenografts displayed reduced neovascularization with the subsequent down-regulation of VEGFR2 expression. Additionally, HO-1 repressed nuclear factor κB (NF-κB)-mediated transcription from an NF-κB responsive luciferase reporter construct, which strongly suggests that HO-1 may regulate angiogenesis through this pathway. Taken together, these data supports a key role of HO-1 as a modulator of the angiogenic switch in prostate carcinogenesis ascertaining it as a logical target for intervention therapy.

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Acknowledgments

This work was supported by grants from the University of Buenos Aires, Argentina, UBACyT (2011- 00179), AGENCIA (PICT RAICES 2006-00367 and 2010-0431). We thank Prof. Gabriel Rabinovich (M. Phil, Ph.D.), Prof. Omar Coso and Dr. Monica Costas for kindly providing us with some reagents used in this paper. We are also very grateful to Pablo Vallecorsa (Instituto de Estudios Oncológicos, Academia Nacional de Medicina) for his technical support in the IHQ analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biological Chemistry, School of Sciences, CONICET, University of Buenos Aires, Intendente Guiraldes 2160, Ciudad Universitaria, Pabellón II, 2do Piso, 1428, Buenos Aires, Argentina

    M. Ferrando, G. Gueron, B. Elguero, A. Salles, F. Coluccio Leskow, A. De Siervi & E. Vazquez

  2. Department of Organic Chemistry, School of Sciences, CIHIDECAR CONICET, University of Buenos Aires, Ciudad Universitaria, Pabellón II, 2do Piso, 1428, Buenos Aires, Argentina

    J. Giudice & E. A. Jares-Erijman

  3. Research Area, Inst of Oncology “A.H.Roffo”, University of Buenos Aires, Buenos Aires, Argentina

    L. Colombo

  4. Department of Pathology, Institute of Oncological Studies, National Academy of Medicine, Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    R. Meiss

  5. Department of Genitourinary Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    N. Navone

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  1. M. Ferrando
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  2. G. Gueron
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  3. B. Elguero
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  6. F. Coluccio Leskow
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  7. E. A. Jares-Erijman
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  8. L. Colombo
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  9. R. Meiss
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  10. N. Navone
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  11. A. De Siervi
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  12. E. Vazquez
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Corresponding author

Correspondence to E. Vazquez.

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M. Ferrando and G. Gueron contributed equally to this work and are co-first authors.

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Ferrando, M., Gueron, G., Elguero, B. et al. Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer. Angiogenesis 14, 467–479 (2011). https://doi.org/10.1007/s10456-011-9230-4

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  • DOI: https://doi.org/10.1007/s10456-011-9230-4

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