Non-Invasive Characterization of Experimental Bone Metastasis in Obesity Using Multiparametric MRI and PET/CT

SIMPLE SUMMARY: The bone marrow microenvironment, particularly adipocytes, plays a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. In this prospective longitudinal study, we used multimodal and multiparametric imaging from magnetic resonance (MRI) and hybrid imaging (positron emission tomography and computed tomography; PET/CT) to non-invasively characterize the pathophysiologic processes of experimental bone metastases in obese and non-obese individuals. Obesity was induced by a high-fat diet (HFD) in rats and mice, resulting in enhanced glucose metabolism and angiogenic activity in metastatic bone lesions, as shown by significantly increased dynamic contrast-enhanced MRI and [(18)F]fluorodeoxyglucose PET/CT parameters in HFD-fed animals. These results were validated with immunohistochemistry and gene expression analysis. In conclusion, pathophysiological processes can be non-invasively assessed by MRI and PET/CT, opening novel avenues for quantitative assessment of follow-up and monitoring of treatment response in skeletal lesions. ABSTRACT: The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and µPET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [(18)F]fluorodeoxyglucose-PET/CT([(18)F]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [(18)F]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [(18)F]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [(18)F]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [(18)F]FDG-PET/CT.