Metabolic implications of hypoxia and pseudohypoxia in pheochromocytoma and paraganglioma

Abstract

Hypoxia is a critical driver of cancer pathogenesis, directly inducing malignant phenotypes such as epithelial-mesenchymal transition, stem cell-like characteristics and metabolic transformation. However, hypoxia-associated phenotypes are often observed in cancer in the absence of hypoxia, a phenotype known as pseudohypoxia, which is very well documented in specific tumour types, including in paraganglioma/pheochromocytoma (PPGL). Approximately 40% of the PPGL tumours carry a germ line mutation in one of a number of susceptibility genes of which those that are found in succinate dehydrogenase (SDH) or in von Hippel-Lindau (VHL) genes manifest a strong pseudohypoxic phenotype. Mutations in SDH are oncogenic, forming tumours in a select subset of tissues, but the cause for this remains elusive. Although elevated succinate levels lead to increase in hypoxia-like signalling, there are other phenotypes that are being increasingly recognised in SDH-mutated PPGL, such as DNA hypermethylation. Further, recently unveiled changes in metabolic re-wiring of SDH-deficient cells might help to decipher cancer related roles of SDH in the future. In this review, we will discuss the various implications that the malfunctioning SDH can have and its impact on cancer development.

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…In addition to the stabilization of HIFα, SDHx ‐mutation‐induced increases in ROS have been shown to cause genomic instability that may contribute to tumorigenesis . Nevertheless, experimental evidence for ROS in various models of SDH dysfunction is not consistent, as some suggests that ROS are increased or normal, a finding which is extensively reviewed by Kluckova and coworkers …”

“…Recognition of these pathophysiological characteristics provides unique opportunities for diagnostic and therapeutic strategies. Over the past years, several excellent reviews, such as those by Kucklova et al, Morin et al and Vicha et al, have discussed the pathophysiology of SDHx ‐related tumors . In the current review, we first present a short summary of the SDH protein and the clinical features of SDHx ‐mutation carriers.…”

“…Over the past years, several excellent reviews, such as those by Kucklova of SDHx-related tumors. [8][9][10] In the current review, we first present a short summary of the SDH protein and the clinical features of SDHxmutation carriers. We then focus on the oncometabolite succinate and its pivotal role in tumorigenesis in SDHx-related tumors, as well as on the implications for clinical practice, especially diagnostics and therapeutic options related to metastatic disease.…”

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

“…As many phenomena in hypoxia could be explained by HIF1A, hypoxia‐independent activation of HIF1A signaling could mimic many hypoxia‐mediated phenomena, even in the normoxia condition. Thus, these mechanisms underlying oxygen‐independent activation of HIF1A signaling are now termed pseudohypoxia . From this perspective, we describe an overview of pseudohypoxia in cancer and recent findings.…”

“…Thus, these mechanisms underlying oxygen-independent activation of HIF1A signaling are now termed pseudohypoxia. [10][11][12][13] From this perspective, we describe an overview of pseudohypoxia in cancer and recent findings.…”