From transcriptional profiling to tumor biology in pheochromocytoma and paraganglioma.
ABSTRACT This review summarizes the way in which inherited mutations define global gene expression in pheochromocytoma (PCC) and paraganglioma (PGL), and how the use of gene expression analysis has advanced our understanding of these diseases. The biology of PCC and PGL tumors is diverse and it has become clear that there is no apparent single biology that defines these tumors. However, over the last 20 years, our understanding of the biology of PGL and PCC has been considerably advanced by the discovery of inherited mutations that predispose individuals to developing the disease. More recently, the use of transcriptomics to stratify tumors based on their gene expression profiles has, in particular, played a vital role in delineating novel mutations involved in the pathogenesis of these tumors. In this review, we describe our current understanding of the biology of cluster 1 (pseudohypoxic) tumors and how mutations that result in the pseudohypoxic phenotype that leads to changes in global gene expression. We also review the advances in our understanding of cluster 2 tumors, and in particular, focus on the newly described MAX tumors.
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- "One of them is the factor inhibiting HIF (FIH), which normally hydroxylates HIF-1α on the asparagine 803 residue. This blocks its interaction with the coactivators histone acetyltransferase p300 (p300) and cAMP-response element-binding protein (CBP) under normoxic conditions (Lando, et al. 2002; Mahon, et al. 2001) and thus inhibits the transactivation of HIF target genes (Cascon and Tennant 2012; Khan, et al. 2011). Also, SDHx mutations inhibit activity of the jumonji-domain (JmjC) histone demethylases (Cervera, et al. 2009; Xiao, et al. 2012). "
ABSTRACT: Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma/paraganglioma. Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species (ROS), and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor (HIF)) including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic pheochromocytomas/paragangliomas, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.Endocrine Related Cancer 02/2014; DOI:10.1530/ERC-13-0398 · 4.91 Impact Factor
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- "Molecular profiling studies have identified ten germline mutations that cause hereditary pheochromocytoma and paragangliomas , . It has been suggested that these mutations can be divided into distinct molecular pathways causing errors in the HIF hypoxia-driven pathway (VHL, SDHB and SDHD) and errors in RNA synthesis and metabolism (RET, NF1, MAX, and TMEM127), while KIF1BBeta is thought to impact both pathways , . "
ABSTRACT: Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma.PLoS ONE 02/2013; 8(2):e56083. DOI:10.1371/journal.pone.0056083 · 3.23 Impact Factor
- Hormone and Metabolic Research 05/2012; 44(5):325-7. DOI:10.1055/s-0031-1299759 · 2.04 Impact Factor