Molecular Imaging of the Tumor Microenvironment Reveals the Relationship between Tumor Oxygenation, Glucose Uptake, and Glycolysis in Pancreatic Ductal Adenocarcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-06, Vol.80 (11), p.2087-2093
• Main Authors: Yamamoto, Kazutoshi, Brender, Jeffrey R, Seki, Tomohiro, Kishimoto, Shun, Oshima, Nobu, Choudhuri, Rajani, Adler, Stephen S, Jagoda, Elaine M, Saito, Keita, Devasahayam, Nallathamby, Choyke, Peter L, Mitchell, James B, Krishna, Murali C
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers, Tumor - metabolism; Carcinoma, Pancreatic Ductal - diagnostic imaging; Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; Electron Spin Resonance Spectroscopy - methods; Fluorodeoxyglucose F18; Glucose - metabolism; Glycolysis; Heterografts; Humans; Mice; Molecular Imaging - methods; Oxygen - metabolism; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - metabolism; Partial Pressure; Positron-Emission Tomography - methods; Radiopharmaceuticals; Tumor Microenvironment
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.can-19-0928

Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic and metabolic aspects of tumors is not fully understood. Here, we developed new hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between F-FDG-PET and lactate production, while pO was inversely related to lactate production and F-2-fluoro-2-deoxy-D-glucose ( F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging. F-FDG uptake negatively correlated with pO in the center of the tumor and positively correlated with pO on the periphery. In contrast to pO and F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. SIGNIFICANCE: Novel multimodal molecular imaging techniques reveal the potential of three interrelated imaging biomarkers to profile the tumor microenvironment and interrelationships of hypoxia, glucose uptake, and glycolysis.