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Molecular and functional imaging insights into the role of hypoxia in cancer aggression

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Abstract

Hypoxia in cancers has evoked significant interest since 1955 when Thomlinson and Gray postulated the presence of hypoxia in human lung cancers, based on the observation of necrosis occurring at the diffusion limit of oxygen from the nearest blood vessel, and identified the implication of these observations for radiation therapy. Coupled with discoveries in 1953 by Gray and others that anoxic cells were resistant to radiation damage, these observations have led to an entire field of research focused on exploiting oxygenation and hypoxia to improve the outcome of radiation therapy. Almost 65 years later, tumor heterogeneity of nearly every parameter measured including tumor oxygenation, and the dynamic landscape of cancers and their microenvironments are clearly evident, providing a strong rationale for cancer personalized medicine. Since hypoxia is a major cause of extracellular acidosis in tumors, here, we have focused on the applications of imaging to understand the effects of hypoxia in tumors and to target hypoxia in theranostic strategies. Molecular and functional imaging have critically important roles to play in personalized medicine through the detection of hypoxia, both spatially and temporally, and by providing new understanding of the role of hypoxia in cancer aggressiveness. With the discovery of the hypoxia-inducible factor (HIF), the intervening years have also seen significant progress in understanding the transcriptional regulation of hypoxia-induced genes. These advances have provided the ability to silence HIF and understand the associated molecular and functional consequences to expand our understanding of hypoxia and its role in cancer aggressiveness. Most recently, the development of hypoxia-based theranostic strategies that combine detection and therapy are further establishing imaging-based treatment strategies for precision medicine of cancer.

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Acknowledgments

We gratefully acknowledge valuable discussions with Dr. R. J. Gillies over the past two decades.

Funding

Support from NIH R01 CA82337, R01 CA136576, R01 CA193365, and R35 CA209960 is gratefully acknowledged.

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  1. Samata Kakkad and Balaji Krishnamachary contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Rm 208C Traylor Building, Baltimore, MD, 21205, USA

    Samata Kakkad, Balaji Krishnamachary, Desmond Jacob, Jesus Pacheco-Torres, Eibhlin Goggins, Santosh Kumar Bharti, Marie-France Penet & Zaver M. Bhujwalla

  2. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Marie-France Penet & Zaver M. Bhujwalla

  3. Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Zaver M. Bhujwalla

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  1. Samata Kakkad
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Kakkad, S., Krishnamachary, B., Jacob, D. et al. Molecular and functional imaging insights into the role of hypoxia in cancer aggression. Cancer Metastasis Rev 38, 51–64 (2019). https://doi.org/10.1007/s10555-019-09788-3

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