ECE2017 Guided Posters Adrenal 3 (12 abstracts)
Tumor microenvironment increases migration/invasion of murine pheochromocytoma SDHB silenced spheroids
Vanessa D’Antongiovanni 1 , Serena Martinelli 1 , Susan Richter 3, , Letizia Canu 1 , Daniele Guasti 2 , Paolo Romagnoli 2 , Karel Pacak 5 , Graeme Eisenhofer 3, , Massimo Mannelli 1 & Elena Rapizzi 2
1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 2Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 3Institute of Clinical Chemistry & Laboratory Medicine, Dresden, Germany; 4Department of Medicine III, Technische Universitat Dresden, Dresden, Germany; 5Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors. About 30-40% of Pheo/PGLs are due to a germ-line mutation in one of the 13 main susceptibility genes which include the genes encoding the four subunits of the succinate dehydrogenase (SDH - mitochondrial complex II). In PHEO/PGL due to SDHB mutations up to 80% of affected patients develop metastatic disease and no successful cure is at present available. To obtain an experimental model resembling the in vivo conditions of the SDHB-mutated PHEO, we used multicellular tumor spheroids (3D culture) of a murine cell line cultured alone or in co-culture with mouse primary fibroblasts, evaluating the effects of SDHB silencing and microenvironment on invasion and migration processes. The growth of spheroids is linear with clear edges. When the spheroids are treated with conditioned medium of cancer-associated fibroblasts (CAFs), we observe an evident detachment of clusters of viable cells in the surrounding space. SDHB silenced cells show a greater migratory capability than negative control (NC) cells. In particular, SDHB silenced cells invade the surrounding space moving collectively, unlike the NC spheroids where cells tend to move individually. This difference was even more evident when spheroids were co-cultured directly with mouse primary fibroblasts. Using electronic microscopy on spheroids, we observed that SDHB silenced cells show swollen mitochondria and, alterations of mitochondrial crests (similarly to mitochondria of patients with SDHB mutations) while SDHB mutated spheroids show borders that are more fraying than those of NC spheroids. In conclusion, SDHB silencing strongly increased the invasion/migration capabilities, and these changes are more evident in SDHB spheroids co-cultured directly with primary fibroblasts. Further studies on these mechanisms may suggest new therapeutic targets.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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