Molecular mechanisms of hypoxia in cancer

Abstract

Purpose: Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers.

Methods: A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016.

Results: A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels.

Conclusion: Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.

Keywords: Hypoxia; Hypoxia radiotracers; MRI; Positron emission tomography.

Fig. 1

Regulation of HIF1alpha in normoxic and hypoxic conditions and biological consequences of hypoxia

Fig. 2

Structures of clinically used [¹⁸F]-labelled nitroimidazole compounds

Fig. 3

Schematic representation of FMISO uptake in hypoxic conditions

Fig. 4

Hypoxia imaging with radiolabelled 2-nitroimidazole. a Chemical structure of [¹⁸F]fluoroetanidazole. The nitro moiety is necessary for hypoxia selective retention. b Cellular uptake of [¹⁸F]fluoroetanidazole in RIF-1 cell line culture grown under normoxia or hypoxia (nitrogen gas). The amount of radioactivity bound to cells was counted. c Imaging of [¹⁸F]fluoroetanidazole by PET showing tracer localisation in HT1080 (subclone 1-3C) xenograft. A 0.5-mm transverse slice of the 30–60 min image acquired in a small animal PET scanner is shown. Arrow, tumour. Courtesy of EOA Published in Br J Cancer 2004 (Barthel et al.) (Color figure online)

Fig. 5

Structure of [⁶⁴Cu]Cu-ATSM

Fig. 6

Schematic representation of proposed mechanism of [⁶⁴Cu]Cu-ATSM