Pheochromocytoma: The First Metabolic Endocrine Cancer

Abstract

Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics allowed us to take a closer look at the metabolic changes present in pheochromocytomas and paragangliomas (PHEOs/PGLs). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies.

Paraganglioma of the tongue with SDHB gene mutation in a patient with Graves’ disease

“…Metabolomics allowed to group PGLs into two clusters depending on pathogenesis and catecholamine phenotype (Table ). Cluster 1 PGLs have an “immature” biochemical phenotype while cluster 2 PGLs have a “differentiated” phenotype . This clustering provided new strategies for treatment of malignant and metastatic PGLs .…”

“…The loss of SDH activity leads to a massive accumulation of succinate and high levels of this metabolite cause it to act as an oncometabolite, activating the hypoxia-induced signaling pathway related to angiogenesis, cell metabolism, and other tumor growth factors. [20][21][22] In addition, succinate can also promote a particular CpG island methylation phenotype (CIMP) by impairment of histone demethylation. 21 Metabolomics allowed to group PGLs into two clusters depending on pathogenesis and catecholamine phenotype (Table 2).…”

New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma

“…The main, and so far the most accepted hypothesis, relies on the stabilization of HIF proteins despite a normal oxygen supply (referred to as the pseudohypoxia hypothesis) resulting in induction of glucose uptake and consumption due to increased glycolysis despite normal oxygen supply (Warburg effect) [29–32]. HIF-1α and HIF-2α form heterodimers with the β subunit.…”

Metabolic Imaging of Glutamine in Cancer

“…However, caution should be taken that the apparent differences between gliomas and breast cancers may, in part, be due to the impact of both specific and nonspecific transport across the blood-brain barrier in gliomas. Other metabolic cancers also show abnormal glutamine metabolism, including several Krebs cycle-related endocrine tumors (pheochromocytoma and renal cell carcinoma) (21,22). These cancers are related to SDHB and FH mutations that result in abnormal glycolysis and presumably glutaminolysis working in symbiosis in these cancers.…”