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Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo

Oncogene volume 30, pages 4601–4608 (2011)Cite this article

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Abstract

Ionizing radiation is a genotoxic agent and human carcinogen. Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. In vitro, diverse mechanisms involving secreted soluble factors, gap junction intercellular communication (GJIC) and oxidative metabolism are proposed to mediate these indirect effects. In vivo, the mechanisms behind long-range ‘bystander’ responses remain largely unknown. Here, we investigate the role of GJIC in propagating radiation stress signals in vivo, and in mediating radiation-associated bystander tumorigenesis in mouse central nervous system using a mouse model in which intercellular communication is downregulated by targeted deletion of the connexin43 (Cx43) gene. We show that GJIC is critical for transmission of oncogenic radiation damage to the non-targeted cerebellum, and that a mechanism involving adenosine triphosphate release and upregulation of Cx43, the major GJIC constituent, regulates transduction of oncogenic damage to unirradiated tissues in vivo. Our data provide a novel hypothesis for transduction of distant bystander effects and suggest that the highly branched nervous system, similar to the vascular network, has an important role.

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Acknowledgements

This work was supported by Grant 10357 from the Associazione Italiana Ricerca sul Cancro (AIRC) to AS. We are grateful to Maria Pia Toni and Maria Pimpinella for assistance with dosimetry and Monte Carlo simulation. We also thank Alessandro Pannicelli for help with photographs and John Bechberger (University of British Columbia, Canada) for assistance with transfer of Cx43+/− mice.

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Authors and Affiliations

  1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy

    M Mancuso, E Pasquali, S Leonardi, S Rebessi, M Tanori, F Borra, S Pazzaglia, V Di Majo & A Saran

  2. Department of Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy

    E Pasquali & P Giardullo

  3. Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada

    C C Naus

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  1. M Mancuso
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  2. E Pasquali
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  3. S Leonardi
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  4. S Rebessi
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  5. M Tanori
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  7. F Borra
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  8. S Pazzaglia
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  9. C C Naus
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  10. V Di Majo
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  11. A Saran
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Corresponding authors

Correspondence to M Mancuso or A Saran.

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Mancuso, M., Pasquali, E., Leonardi, S. et al. Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo. Oncogene 30, 4601–4608 (2011). https://doi.org/10.1038/onc.2011.176

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