Abstract
The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HFDWI) of CSH images correlated strongly (R2 = 0.66; n = 41) with pimonidazole immunoscore (HSPimo); this relationship was validated in a second pimonidazole cohort (R2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HFDWI correlated with tumor stage and lymph node status, consistent with findings for HSPimo Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice.Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4774/F1.large.jpg Cancer Res; 78(16); 4774-85. ©2018 AACR.
Highlights
Tumor hypoxia is associated with metastatic disease and treatment resistance of prostate cancer [1,2,3,4]
We further demonstrated the robustness of consumption and supply-based hypoxia (CSH) imaging by validation in an independent cohort and by showing its transferability to a histopathology assay for cell density (CD) and blood vessel density (BVD)
Pimonidazole staining in wholemount sections from prostatectomy specimens was utilized for the construction and validation of the CSH imaging technique, ensuring that the images reflected a true and clinically relevant hypoxia phenotype
Summary
Tumor hypoxia is associated with metastatic disease and treatment resistance of prostate cancer [1,2,3,4]. A method to assess hypoxia at diagnosis can help to select patients for intensified treatment and to avoid overtreatment of indolent, low-risk disease [5]. This would meet an urgent need for improvement. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Lyng share equal authorship of this article
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