Abstract
Tumor hypoxia is a persistent obstacle for traditional therapies in solid tumors. Strategies for mitigating the effects of hypoxic tumor cells have been developed under the assumption that chronically hypoxic tumor cells were the central cause of treatment resistance. In this study, we show that instabilities in tumor oxygenation are a prevalent characteristic of three tumor lines and previous characterization of tumor hypoxia as being primarily diffusion-limited does not accurately portray the tumor microenvironment. Phosphorescence lifetime imaging was used to measure fluctuations in vascular pO(2) in rat fibrosarcomas, 9L gliomas, and R3230 mammary adenocarcinomas grown in dorsal skin-fold window chambers (n = 6 for each tumor type) and imaged every 2.5 minutes for a duration of 60 to 90 minutes. O(2) delivery to tumors is constantly changing in all tumors, resulting in continuous reoxygenation events throughout the tumor. Vascular pO(2) maps show significant spatial heterogeneity at each time point, as well as between time points. The fluctuations in oxygenation occur with a common periodicity within and between tumors, suggesting a common mechanism, but have tumor type-dependent spatial patterns. The widespread presence of fluctuations in tumor oxygenation has broad ranging implications for tumor progression, stress response, and signal transduction, which are altered by oxygenation/reoxygenation events.
Highlights
Tumor hypoxia is one of the most studied physiologic phenomena in cancer research and has been shown to be prognostically significant in many clinical studies, independent of treatment type [1,2,3]
Since the discovery of diffusion limited tumor hypoxia in the 1960s, most strategies for overcoming or targeting hypoxic areas in tumors have been developed using a paradigm of chronically hypoxic areas in tumors or areas of hypoxia that are oxygen-deficient because they are beyond the typical diffusion limit of O2
The median pO2 for a single experiment generally changed only 1 to 2 mm Hg between any 2.5 min measurement interval, plots of randomly selected individual pixel pO2 versus time reflect significant spatial and temporal variability (Fig. 1) in vascular pO2. This spatiotemporal variability strongly suggests that sampling a few spatially or temporally discrete pO2 measurements may not be representative of tumor oxygenation
Summary
Tumor hypoxia is one of the most studied physiologic phenomena in cancer research and has been shown to be prognostically significant in many clinical studies, independent of treatment type [1,2,3]. Because oxidative stress has been shown to cause a differential cellular response for intermittent versus chronic hypoxia in tumor and endothelial cells [18,19,20,21,22,23,24,25], the pervasive presence of fluctuating oxygenation in tumors has consequential implications for our understanding of tumor progression, stress response, and signal transduction; in all studies, intermittent hypoxia has been shown to increase molecular or physiologic responses in a manner consistent with more malignant tumor phenotypes [18,19,20,21,22,23,24,25]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
