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Genetic modification of hypoxia signaling in animal models and its effect on cancer

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  • Advances in Translational Oncology
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Abstract

Conditions that cause hypoxemia or generalized tissue hypoxia, which can last for days, months, or even years, are very common in the human population and are among the leading causes of morbidity, disability, and mortality. Therefore, the molecular pathophysiology of hypoxia and its potential deleterious effects on human health are important issues at the forefront of biomedical research. Generalized hypoxia is a consequence of highly prevalent medical disorders that can severely reduce the capacity for O2 exchange between the air and pulmonary capillaries. In recent years, some of the key O2-dependent signaling pathways have been characterized at the molecular level. In particular, the prolyl hydroxylase (PHD)-hypoxia-inducible factor (HIF) cascade has emerged as the master regulator of a general gene expression program involved in cell/tissue/organ adaptation to hypoxia. Hypoxia has emerged as a critical factor in cancer because it can promote tumor initiation, progression, and resistance to therapy. Beyond its role in neovascularization as a mechanism of tumor adaptation to nutrient and O2 deprivation, hypoxia has been linked to prolonged cellular lifespan and immortalization, the generation of “oncometabolites”, deregulation of stem cell proliferation, and inflammation, among other tumor hallmarks. Hypoxia may contribute to cancer through several independent pathways, the inter-connections of which have yet to be elucidated. Furthermore, the relevance of chronic hypoxemia in the initiation and progression of cancer has not been studied in depth in the whole organism. Therefore, we explore here the contributions of hypoxia to the whole organism by reviewing studies on genetically modified mice with alterations in the key molecular factors regulating hypoxia.

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Acknowledgments

The AC lab was supported by grants to from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028), Consejeria de Ciencia e Innovacion (CTS-6844 and CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012). D. A. C. was supported by the grants from the Spanish Ministry of Science and Innovation (SAF2011-26805) and Andalusian Regional Ministry of Science and Innovation (CTS-7478).This work has been also possible thanks to the Grant PIE13/0004 co-funded by the ISCIII and FEDER funds. BFA was funded by an FPU fellowship from the Spanish Ministry of Economy and Competitivity.

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Authors and Affiliations

  1. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, 41013, Seville, Spain

    J. M. García-Heredia, B. Felipe-Abrio & A. Carnero

  2. Servicio de Endocrinología y Nutrición, Hospitales Universitarios Virgen del Rocío, 41013, Seville, Spain

    D. A. Cano

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  1. J. M. García-Heredia
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  2. B. Felipe-Abrio
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  3. D. A. Cano
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  4. A. Carnero
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Correspondence to D. A. Cano or A. Carnero.

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García-Heredia, J.M., Felipe-Abrio, B., Cano, D.A. et al. Genetic modification of hypoxia signaling in animal models and its effect on cancer. Clin Transl Oncol 17, 90–102 (2015). https://doi.org/10.1007/s12094-014-1236-0

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  • DOI: https://doi.org/10.1007/s12094-014-1236-0

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