Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained... Show moreDespite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of reactive oxygen species (ROS) but ROS are inhibited by rising succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of succinate dehydrogenase to fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified succinate threshold model of tumor initiation. Truncating SDH variants cause high succinate accumulation and likely initiate tumorigenesis via disruption of 2-oxoglutarate-dependent enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower succinate accumulation and thus initiate tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of succinate. Show less
This review describes human and rodent-derived cell lines and xenografts developed over the last five decades that are suitable or potentially suitable models for paraganglioma-pheochromocytoma... Show moreThis review describes human and rodent-derived cell lines and xenografts developed over the last five decades that are suitable or potentially suitable models for paraganglioma-pheochromocytoma research. We outline the strengths and weaknesses of various models and emphasize the recurring theme that, despite the major challenges involved, more effort is required in the search for valid human and animal cell models of paraganglioma-pheochromocytoma, particularly those relevant to cancers carrying a mutation in one of the succinate dehydrogenase genes. Despite many setbacks, the recent development of a potentially important new model, the RSO cell line, gives reason for optimism regarding the future of models in the paraganglioma-pheochromocytoma field. We also note that classic approaches to cell line derivation such as SV40-mediated immortalization and newer approaches such as organoid culture or iPSCs have been insufficiently explored. As many existing cell lines have been poorly characterized, we provide recommendations for reporting of paraganglioma and pheochromocytoma cell lines, including the strong recommendation that cell lines are made widely available via the ATCC or a similar cell repository. Basic research in paraganglioma-pheochromocytoma is currently transition ing from the analysis of genetics to the analysis of disease mechanisms and the clinically exploitable vulnerabilities of tumors. A successful transition will require many more disease-relevant human and animal models to ensure continuing progress. Show less
Berkel, A. van; Vriens, D.; Visser, E.P.; Janssen, M.J.R.; Gotthardt, M.; Hermus, A.R.M.M.; ... ; Timmers, H.J.L.M. 2019
