Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models

Abstract

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (DR 1 ) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive DR 1 . We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive DR 1 , termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO 2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic.

Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

“…All MRI maps show heterogeneity within tumors in response to carbogen, with a mixture of pixels sensitive and refractory to carbogen challenge, similar to that in data shown in a recent study assessing R 1 in response to an oxygen challenge [13]. In both models, carbogen generated an increment of pO 2 which broadened linewidths of EPR spectra.…”

“…Note that only the pO 2 in 9L-glioma increased beyond 10mmHg. Interestingly, changes in R1s and R2* induced by a rise in pO 2 , observed here by EPR oximetry, match those seen using the OxyLite TM system (fluorescence quenching fiberoptic-based method) by the group of O'Connor [13], showing that changes in MRI parameters are reproducible across different tumor models and laboratories.…”

“…In this work, we used two tumor models with a lower lipid content, and therefore we needed to adapt the type of acquisition (one acquisition for global R 1 , bi-exponential deconvolution of the signal to extract fast and slow components). The fast and slow components are attributed to lipids and water relaxation [13], but we cannot exclude a contribution to the fast component from water linked to macromolecules. In fact, water exists both in blood and tissue, and water R 1 represents the variation of oxygen in both compartments.…”

“…Since each technique assesses tumor hypoxia in different compartments, efforts are being made to combine R 1 and R 2 * in order to better understand tissue oxygenation as well as to make use of the predictive value of these parameters for tumor response to RT [7,8]. Recently, the group of O'Connor validated oxygen-enhanced MRI (a R 1 -based method) for quantifying the spatial variation of hypoxia with pimonidazole staining in three tumor lines with different hypoxic fractions [9,13].…”

Oxygen-Enhanced MRI Is a Major Advance in Tumor Hypoxia Imaging

“…In this issue of Cancer Research, a manuscript from the group of O'Connor validates oxygen-enhanced MRI (OE-MRI) to quantify the spatial variation of hypoxia (33). The principle is based on measurement of R 1 , which is sensitive to the oxygen concentration in interstitial fluid and plasma.…”