ECE2017 Eposter Presentations: Adrenal and Neuroendocrine Tumours Adrenal medulla (21 abstracts)
Role of microenvironment on metabolic control of murine pheochromocytoma SDHB silenced cells
Vanessa D’Antongiovanni 1 , Susan Richter 3, , Serena Martinelli 1 , Letizia Canu 1 , Tonino Ercolino 1 , Graeme Eisenhofer 3, , Karel Pacak 5 , Elena Rapizzi 2 & Massimo Mannelli 1
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, MD, 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. Tumor microenvironment plays a pivotal role in modifying the metabolism and the functional characteristics of tumor cells, becoming a potential therapeutic target. To obtain an experimental model resembling the in vivo conditions of the SDHB-mutated PHEO, we evaluated the effects of SDHB silencing and microenvironment on metabolism in the mouse tumor tissue-derived cell line (MTT), cultured alone or in association with mouse primary fibroblasts (here representing the tumor microenvironment). SDHB silenced cells showed a significant increase of both glucose and lactate uptake, and an increase of intracellular lactate compared with control. This increase was even more evident when SDHB silenced cells was co-cultured with mouse primary fibroblasts. The expression levels of monocarboxilase transporter 4 (MCT4), responsible for the transport of lactate from the intracellular to the extracellular space, was found upregulated in fibroblasts in co-culture with tumor cells. Consequently, in co-cultures, primary fibroblasts showed an increase of extracellular lactate. Surprisingly, SDHB silenced cells in co-culture showed a reduction of ATP levels compared to SDHB cultured alone and control cells in co-cultures. Our data demonstrate that SDHB silencing strongly affects tumor metabolism, and these changes are more evident in co-cultures. The comprehension of the mechanisms driving these changes in tumor metabolism may suggest new therapeutic targets.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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