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Diverse Effects of Hypoxia on Tumor Progression pp 1–20Cite as

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 345))

Abstract

Cellular adaptation to diminished tissue oxygen tensions, hypoxia, is largely governed by the hypoxia inducible transcription factors, HIF-1 and HIF-2. Tumor hypoxia and high HIF protein levels are frequently associated with aggressive disease. In recent years, high tumor cell levels of HIF-2 and the oxygen sensitive subunit HIF-2α have been associated with unfavorable disease and shown to be highly expressed in tumor stem/initiating cells originating from neuroblastoma and glioma, respectively. In these cells, HIF-2 is active under nonhypoxic conditions as well, creating a pseudo-hypoxic phenotype with clear influence on tumor behavior. Neuroblastoma tumor initiating cells are immature with a neural crest-like phenotype and downregulation of HIF-2α in these cells results in neuronal sympathetic differentiation and the cells become phenotypically similar to the bulk of neuroblastoma cells found in clinical specimens. Knockdown of HIF-2α in neuroblastoma and glioma tumor stem/initiating cells leads to reduced levels of VEGF and poorly vascularized, highly necrotic tumors. As high HIF-2α expression further correlates with disseminated disease as demonstrated in neuroblastoma, glioma, and breast carcinoma, we propose that targeting HIF-2α and/or the pseudo-hypoxic phenotype induced by HIF-2 under normoxic conditions has great clinical potential.

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Acknowledgments

This work was supported by the Swedish Cancer Society, the Children’s Cancer Foundation of Sweden, the Swedish Research Council, the SSF Strategic Center for Translational Cancer Research – CREATE Health, Gunnar Nilsson’s Cancer Foundation and the research funds of Malmö University Hospital.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, University Hospital MAS, Entrance 78, 205 02, Malmö, Sweden

    Alexander Pietras, A. Sofie Johnsson & Sven Påhlman

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  1. Alexander Pietras
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  2. A. Sofie Johnsson
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  3. Sven Påhlman
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Correspondence to Sven Påhlman .

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  1. Medicine, University of Pennsylvania School of, Philadelphia, 19104-6160, Pennsylvania, USA

    M. Celeste Simon

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Pietras, A., Johnsson, A.S., Påhlman, S. (2010). The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization. In: Simon, M. (eds) Diverse Effects of Hypoxia on Tumor Progression. Current Topics in Microbiology and Immunology, vol 345. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_72

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