PET and MRI studies applied on characterization of Fisher/F98 rat glioma model

Introduction: Preclinical brain tumor models have provided a wealth of information on the biology, imaging and experimental therapeuticsof brain tumors. The aim of our study is characterized Fisher/F98 rat glioma model using Positron Emission Tomography (PET) and Magnetic Resonance (MR) analysis to set up an experimental model useful to study the efficacy of new colloidal vectors for chemotherapy. Methods: Syngenic rat brain-glioma models (Fisher/F98) was obtained by stereotactic (x=2; y=5; z=3) implantation of different cell concentrations (102, 103, 104 and 105). To monitor tumor growth progression, rats underwent once a week Gadolinium enhanced T1-MRI studies followed by [18F]FDG PET studies, starting from 7 days after surgery. A group of animals performed also [18F]FAZA PET studies to evaluate regional tissue hypoxia. To improve quantification, PET and MRI images were fused using PMOD 2.7 software. Max radiotracers uptake was calculated for tumor,frontal cortex, cerebellum and background using region of interest (ROI) analysis. Radioactivity concentration values expressed in MBq/g were then transformed into percentage of injected dose per gram of tissue (%ID/g). Moreover, histological analysis of proliferation, apoptosis, differentiation, neoangiogenesis and hypoxia markers were performed. Results: Mean survival time of rats injected with 104 and 105 cells was nine days. One week after surgery, MRI revealed a rapid growth that reached 0.11 cm3 mean tumour volume. Animals injected with 103 and 102 cells showed a mean survival time of 18 and 24 days respectively. In rats injected with 103 cells, tumor was revealed 14 days after surgery at MRI and [18F]FDG PET and successively tumors rapidly increased. Disease course in 102 cells injected rats was slower. Tumors were characterized by high [18F]FDG uptake and hypoxic subareas which only partially overlapped. Hypoxic areas were mainly localized in correspondence to Gd-enhanced regions whereas hyper glucose metabolic areas were localized in the outer part of the tumors. At histological analysis tumoral masses showed an infiltrative pattern of growth and moderate neoangiogenesis. Tumors obtained at animals death showed diffused necrotic areas. HIF1 was clearly expressed by glial and neuronal cells in oedematous and hypoxic areas. Conclusions: Our study indicates that Fisher/ F98 rat glioma model reproduces the characteristic of aggressiveness of human glioblastoma. Tumor was characterized by high glucose metabolism and by hypoxic sub-areas. The concentration of 102 cells permits to better monitor disease onset and progression and to plan experiments to test new anti-neoplastic therapies efficacy.