Endocrine Abstracts (2016) 40 L13 | DOI: 10.1530/endoabs.40.L13

Cellular and animal models in pheochromocytoma/paragangliomas research: role of microenvironment

M Mannelli, E Rapizzi, L Canu, T Ercolino & V Giachè


Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Italy.


Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors. About 30-40% of these tumors are due to e germ-line mutation in one of the 13 main susceptibility genes which include: the tumor-suppressor gene VHL; the proto-oncogene RET; the tumor-suppressor gene Nf1; the genes encoding the four subunits of the succinate dehydrogenase (SDH); the SDHAF2/SDH5 gene that is responsible for the flavination of the SDHA subunit; TMEM127; MAX; HIF2α; the gene encoding the fumarate-hydratase (FH) and, the gene encoding the TCA cycle enzyme malate-dehydrogenase type 2 (MDH2).

PHEO/PGL are mostly benign and in such cases they are cured by surgical removal. On the contrary, 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 tissue, obtained at surgery, does not permit dynamic studies that can be performed only in vitro on living cells or in vivo in animal models. Unfortunately, the research on malignant PHEO/PGL is made difficult by the limited research models so far available.

In fact, at present no SDH knockdown animal models nor suitable human neural crest-derived cell lines are at disposal. The cell lines most widely utilized for the study of PHEO/PGL tumorigenesis are: PC12, derived from an irradiated rat PHEO; MPC, derived from an irradiated heterozygous Nf1 knockout mouse; MTT, a MPC-derived more aggressive cell line. The only human PHEO cell line (hPheo1), obtained by immortalizing sporadic PHEO primary cultures by hTERT, apart from not being commercially available, appears to be minimally or not at all functional. A surrogate model is offered by human neuroblastoma cell lines, such as SK-N-AS, that share with PHEO/PGL the same embryologic origin.

An additional factor to be considered when studying tumorigenesis is the role of microenvironment. Solid tumors are in fact very complex tissues comprising not only cancer cells, but also non-malignant stromal cells such as endothelial cells, fibroblasts, immune cells and extracellular matrix. It is becoming more and more evident that a continue interplay between cancer and stromal cells generates a positive loop that leads cancer cells to survive the hostile environment, to grow and spread metastases to healthy tissues.

At this aim, co-cultures of stromal cells (fibroblasts) along with cancer cells (SK-N-AS, MPC or MTT control or SDHB silenced) have been performed in an attempt to recreate an in vitro cellular microenvironment as close as possible to the in vivo tissue conditions.

Either SDHB silencing or the fibroblasts were able to modify the metabolism and the functional characteristics of tumor cells. Silencing and fibroblasts caused additional effects.

The comprehension of the mechanisms by which SDHB mutations cause mitochondrial impairment, cell metabolic reprogramming and tumor development as well as the comprehension of the mechanisms driving the cross-talk between tumor cells and microenvironment might possibly represent the first step towards the development of potential novel pharmacological approaches aimed at limiting the proliferative effect and the tumor invasive/metastasizing potential of malignant PHEO/PGL.

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