Pheochromocytomas and Paragangliomas: Bypassing Cellular Respiration

Abstract

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that show the highest heritability of all human neoplasms and represent a paradoxical example of genetic heterogeneity. Amongst the elevated number of genes involved in the hereditary predisposition to the disease (at least nineteen) there are eleven tricarboxylic acid (TCA) cycle-related genes, some of which are also involved in the development of congenital recessive neurological disorders and other cancers such as cutaneous and uterine leiomyomas, gastrointestinal tumors and renal cancer. Somatic or germline mutation of genes encoding enzymes catalyzing pivotal steps of the TCA cycle not only disrupts cellular respiration, but also causes severe alterations in mitochondrial metabolite pools. These latter alterations lead to aberrant accumulation of “oncometabolites” that, in the end, may lead to deregulation of the metabolic adaptation of cells to hypoxia, inhibition of the DNA repair processes and overall pathological changes in gene expression. In this review, we will address the TCA cycle mutations leading to the development of PPGL, and we will discuss the relevance of these mutations for the transformation of neural crest-derived cells and potential therapeutic approaches based on the emerging knowledge of underlying molecular alterations.

Genetic and Clinical Profiles of Pheochromocytoma and Paraganglioma: A Single Center Study

“…Our results revealed that patients under 30 had a high germline variant rate (52.6%), suggesting that it is necessary to screen the genes in young patients. On the other hand, with SDHA and SDHD variants, corresponding tumors tend to affect elderly patients (23). It has been reported that the SDHD variant carrier had a penetrance rate of 86% at the age of 50 (22,24,25).…”

Loss of sdhb in zebrafish larvae recapitulates human paraganglioma characteristics

“…Due to the dual role of SDH in the TCA-cycle and in mitochondrial electron transport, SDH subunit mutations cause dysfunction of oxidative phosphorylation and hence increased production of reactive oxygen species (ROS), severely affecting cellular energy metabolism (Cascon et al 2019, Moosavi et al 2020. On the other hand, increased tissue succinate levels determined in SDH-related PPGLs (Pollard et al 2005, Rao et al 2013, Richter et al 2014 act as an oncometabolite with broad cellular effects.…”

“…The Warburg effect entails a shift of metabolism from oxidative phosphorylation to aerobic glycolysis, as exemplified in PPGL by increased lactate dehydrogenase (LDHA) expression and increased blood lactate levels (Gimenez-Roqueplo et al 2002, Favier et al 2009, Frezza et al 2011. Other pathophysiological mechanisms proposed to play a role in succinate-dependent tumorigenesis are epigenetic dysregulation via altered DNA and histone methylation profiles (Cascon et al 2019), and decreased DNA repair via suppression of the homologous recombination pathway (Sulkowski et al 2018).…”

<p>Therapies targeting the signal pathways of pheochromocytoma and paraganglioma</p>

“…Furthermore, it is a kind of human tumor model that has inherited mutations in a metabolic enzyme gene, succinate dehydrogenase subunit D (SDHD). In addition to classic mutations in the genes encoding for the subunits of SDH, in the past five years more germline or somatic mutations have been found in genes encoding for other enzymes catalyzing pivotal steps of the tricarboxylic cycle acid (TCA), such as fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), glutamic-oxaloacetic transaminase 2 (GOT2), and dihydrolipoamide S-succinyltransferase (DLST), in PCC/PGL 9. In regard to the molecular pathogenetic mechanism of PCC/PGL, the hypoxia-related signal pathway (Figure 1) and the increased kinase signal pathways (Figure 2) are two main pathways involving the tumor 10.…”