PRECLINICAL PET IMAGING FOR TUMOUR CHARACTERIZATION: FOCUS ON HYPOXIA AND INFLAMMATION
Imaging molecular techniques including PET, CT, MRI allow to detect and to monitor normal and pathological conditions non-invasively in clinic. The recent development of dedicated small animal instruments together to the availability of appropriate animal models of disease has allowed the use of these methods in preclinical research with the possibility to transfer directly the obtained results in clinic. In this thesis’s work we characterized two preclinical oncology models through the use of an animal PET instrument focusing on two processes correlated to tumour growth such as hypoxia and inflammation. Tissue hypoxia is considered as a negative prognostic factor both for answer to pharmacological and radiant therapy and for tumour progression and invasiveness. Consequently, identification and localization of hypoxic areas within the tumour have an important interest in clinical diagnostic. To this aim, BALB/c nu/nu mice were inoculated with murine cells of mammary adenocarcinoma (EMT-6) and with human cells of prostate adenocarcinoma (PC-3) and pharingeal cancer (FaDu). Animals were monitored using two hypoxic radiopharmaceutical recently developed, [18F]FAZA and [64Cu]ATSM at two different times, using PET and autoradiography. In parallel, an in vitro evaluation of specific hypoxic markers such as carbonic anhydrase IX and cupper transporters (Ctr-1 and ATP7B) was performed. In FaDu model we confirmed the same [64Cu]ATSM distribution at the two analyzed times, that is similar to that of [18F]FAZA. On the contrary, EMT-6 and PC-3 models showed a time-dependent [64Cu]ATSM uptake, with a distribution at late time (24hrs post injection) similar to that of [18F]FAZA. The different distribution of [64Cu]ATSM can be only partially explained by the different cupper pumps localization observed in vitro. Other factors such red-ox and cellular pH may influence [64Cu]ATSM uptake. PET imaging is an interesting method to identify and monitor tumour hypoxia in a non invasive way but it needs further studies that associate metabolic changes to proteomic pattern changes. Positron Emission Tomography (PET) imaging with [18F]2-fluoro-2-deoxy-D-glucose-PET ([18F]FDG-PET) is widely used in neoplastic patients for disease assessment and evaluation of treatment efficacy. Results interpretation must take into account the contribution of inflammatory cells that infiltrate growing tumours for [18F]FDG uptake. In this work, we established a preclinical model of peritoneal carcinomatosis to verify the actual contribution of macrophages to signals obtained with [18F]FDG-PET. Groups of mice with peritoneal carcinosis were longitudinally evaluated with [18F]FDG-PET. Intraperitoneal depletion of macrophages was achieved by an approach that proved to be safe and effective, i.e. administration of clodronate encapsulated into liposomes. Sham-liposomes were used in control animal cohorts. Using [18F]FDG-PET we detected and monitored peritoneal lesions’ growth, with a good correlation between the real neoplastic lesions extension and that measured using [18F]FDG-PET. Macrophage depleted animals showed a substantial drop in tumour growth. In conclusion, [18F] FDG-PET imaging allows the non-invasive detection of peritoneal adenocarcinoma lesions and macrophages are directly and indirectly involved in [18F]FDG uptake by promoting tumour growth and spreading in the peritoneal cavity.
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
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