15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma

Mannelli, Massimo; Rapizzi, Elena; Fucci, Rossella; Canu, Letizia; Ercolino, Tonino; Luconi, Michaela; Young, William F.

doi:10.1530/erc-15-0215

Cited by 12 publications

(14 citation statements)

References 85 publications

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“…One of the important metabolic pathways in mitochondria is the tri-carboxylic acid cycle (TCA) that provides reducing agents for Oxphos and metabolites for various biosynthetic pathways. Evident in endocrine cancers are mutations of TCA cycle operational enzymes, which are linked to EMT (66). The neuroendocrine tumors, pheochromocytoma and paragangliomas are associated with mutation of succinate dehydrogenase (SDH) that converts succinate to fumarate (66).…”

Section: Mitochondrial Regulation Of Emtmentioning

confidence: 99%

Metabolic Regulation of Epithelial to Mesenchymal Transition: Implications for Endocrine Cancer

Bhattacharya

Scimè

2019

Front. Endocrinol.

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The last few decades have witnessed an outstanding advancement in our understanding of the hallmarks of endocrine cancers. This includes the epithelial to mesenchymal transition (EMT), a process that alters the morphology and functional characteristics of carcinoma cells. The mesenchymal stem cell like phenotype produced by EMT allows the dislocation of cancer cells from the primary tumor site with inheritance of motility, metastatic and invasive properties. A fundamental driver thought to initiate and propagate EMT is metabolic reprogramming that occur during these transitions. Though there remains a paucity of data regarding the alterations that occur during EMT in endocrine cancers, the contribution of deregulated metabolism is a prominent feature. This mini review focuses on metabolic reprogramming events that occur in cancer cells and in particular those of endocrine origin. It highlights the main metabolic reprogramming outcomes of EMT, encompassing glycolysis, mitochondria oxidative phosphorylation and function, glutamine and lipid metabolism. Comprehending the metabolic changes that occur during EMT will help formulate potential bioenergetic targets as therapies for endocrine cancer metastasis.

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Section: Mitochondrial Regulation Of Emtmentioning

confidence: 99%

Metabolic Regulation of Epithelial to Mesenchymal Transition: Implications for Endocrine Cancer

Bhattacharya

Scimè

2019

Front. Endocrinol.

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“…The mitochondrial electron transport chain is the major endogenous source of ROS, which can damage cells or various cellular components. SDHB mutations were reported to especially cause a significant increase in ROS production and mitochondrial DNA mutability (70, 71), although pseudohypoxia can be observed in SDH-suppressed cells even in the absence of oxidative stress (61, 72). …”

Section: Metabolic Alterations In Pheos/pglsmentioning

confidence: 99%

Pheochromocytoma: The First Metabolic Endocrine Cancer

Jochmanová

Pacák

2016

Clinical Cancer Research

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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.

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“…These include genes encoding the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH), which functions in mitochondrial electron transport as complex II and in tricarboxylic acid (TCA) cycle by catalyzing the oxidation of succinate to fumarate. Impairment of SDH activity causes accumulation of the oncometabolite, succinate, affecting a wide spectrum of pathways ranging from pseudo-hypoxia signaling to epigenetic reprogramming (Jochmanova and Pacak 2016;Mannelli et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Primary fibroblast co-culture stimulates growth and metabolism in Sdhb-impaired mouse pheochromocytoma MTT cells

et al. 2018

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Pheochromocytomas and paragangliomas (PGLs) due to mutations of succinate dehydrogenase (SDH) B, a subunit of the SDH complex with a role in the Krebs cycle and the respiratory chain, tend to be larger at diagnosis and more prone to metastatic disease than other tumors. This presentation contrasts with the behavior of some cell line models of SDHB impairment, which show reduced growth compared to wild type. We hypothesize that reduced growth of SDHB-impaired monolayer culture models might reflect lack of support from sources within the tumor microenvironment. The present study therefore investigates how the microenvironment, modeled here by fibroblast co-culture, modulates cell metabolism, growth and invasion in an Sdhb-impaired mouse pheochromocytoma cell line. We employed two different constructs of short hairpin RNA to knockdown Sdhb and compared growth in a monolayer with and without fibroblast co-culture. Sdhb-silenced cells showed functional impairment of SDH with elevated succinate to fumarate ratio and decreased oxidative capacity. Cell growth was delayed with an increase in doubling time of 2 h or 20 h. Clonogenic cell survival and viability, on the other hand, were either unchanged or increased compared to control. In standard monolayer culture, no differences in pro-metastatic features were present. Co-culture with primary mouse fibroblast reversed the difference of proliferation between control and Sdhb knockdown but was unable to significantly influence invasiveness under these culture conditions. Metabolic studies identified that lactate secreted by fibroblasts was taken up preferentially by Sdhb-silenced cells. In summary, the present study identified a potential role for the tumor microenvironment in influencing phenotypic features of SDHB-mutated PGLs, providing a basis for the use of therapies targeted towards the tumor microenvironment.

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15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma

Cited by 12 publications

References 85 publications

Metabolic Regulation of Epithelial to Mesenchymal Transition: Implications for Endocrine Cancer

Metabolic Regulation of Epithelial to Mesenchymal Transition: Implications for Endocrine Cancer

Pheochromocytoma: The First Metabolic Endocrine Cancer

Primary fibroblast co-culture stimulates growth and metabolism in Sdhb-impaired mouse pheochromocytoma MTT cells

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