Apport de l'imagerie multimodale à l'étude de l'angiogenèse et du métabolisme des tumeurs liées aux mutations SDHB

Abstract : Pheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumours that arise from chromaffin cells of the adrenal medulla, sympathetic and parasympathetic paraganglia respectively. Around 15% of PCC are malignant. SDHB mutations are associated with malignancy and poor prognosis. SDH deficiency leads to succinate accumulation that induces a cellular pseudohypoxic phenotype, promoting in particular VEGF and GLUT-1 expression and increasing angiogenesis and glucose metabolism. The high malignancy hazard associated with SDHB and the absence of curative treatment of metastatic forms of the disease make it essential to develop a mouse model for preclinical trials launching. The quest for a predisposed mouse model of Sdhb-deficient tumors being unsuccessful, Sdhb-/- and wild-type (WT) immortalized mouse chromaffin cells previously generated in the laboratory were propagated in the fat pad of NMRI nude mice, thereby providing the first pattern of Sdhb- deficient tumors. These mice were compared to a control group receiving non-mutated imCC (WT) and characterization was performed in vivo by multimodality imaging. Optical imaging assessing the tumor angiogenesis with Angiostamp®, an RGD fluorescent peptide, found an increased expression of integrins αvβ3 in the Sdhb-/- group 12 h after tracer injection. Dynamic contrast enhanced MRI (DCE-MRI) showed an overall tumor enhancement significantly higher in the Sdhb-/- model secondary to an increase of the tumor blood flow (F) and of the intratumoral capillary volume fraction (Vb) (compartmental analysis using PhysioD3D software). Metabolic imaging assessed by 18FDG-PET confirmed the expected high glucose consumption by Sdhb-/- tumors. Finally, magnetic resonance spectroscopy (1H-MRS) detected succinate accumulation in Sdhb-/- tumors and not in WT tumors. This result was confirmed by mass spectrometry and this innovative procedure for in vivo detection of succinate was translated into patients suffering from PCC/PGL. A succinate peak was specifically observed in SDHx-related PCC/PGL patients. In conclusion, these results show strong differences between Sdhb-/- and WT allografts and suggest that preclinical therapeutic studies could be implemented in this unique model of Sdhb-deficient tumour. Our noninvasive, highly sensitive and specific method allowing in vivo detection of succinate, the major biomarker of SDHx-mutated tumors was translated into clinical imaging.
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Charlotte Lussey. Apport de l'imagerie multimodale à l'étude de l'angiogenèse et du métabolisme des tumeurs liées aux mutations SDHB. Imagerie médicale. Université Sorbonne Paris Cité, 2015. Français. ⟨NNT : 2015USPCB151⟩. ⟨tel-01721829⟩

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