Phenylethanolamine N-methyltransferase downregulation is associated with malignant pheochromocytoma/paraganglioma.
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ABSTRACT:
SUBMITTER: Lee SE
PROVIDER: S-EPMC5029690 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
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Phenylethanolamine N-methyltransferase downregulation is associated with malignant pheochromocytoma/paraganglioma.
Lee Seung Eun SE Oh Ensel E Lee Boram B Kim Yu Jin YJ Oh Doo-Yi DY Jung Kyungsoo K Choi Jong-Sun JS Kim Junghan J Kim Sung Joo SJ Yang Jung Wook JW An Jungsuk J Oh Young Lyun YL Choi Yoon La YL
Oncotarget 20160401 17
Malignant pheochromocytoma/paraganglioma (PCC/PGL) is defined by the presence of metastases at non-chromaffin sites, which makes it difficult to prospectively diagnose malignancy. Here, we performed array CGH (aCGH) and paired gene expression profiling of fresh, frozen PCC/PGL samples (n = 12), including three malignant tumors, to identify genes that distinguish benign from malignant tumors. Most PCC/PGL cases showed few copy number aberrations, regardless of malignancy status, but mRNA analysis ...[more]
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Project description:AIMS:In recent years, aberrant DNA methylation of specific CpG sites has been detected in many types of malignant tumors, and the epigenetic regulation of promoter CpG sites is considered an important mechanism underlying carcinogenesis. This study aimed to establish the epigenetics of the malignant transformation of malignant pheochromocytoma (PCC) and paraganglioma (PGL) by performing a methylation analysis. MATERIALS AND METHODS:Based on the results of the Infinium HumanMethylation450 BeadChip array using DNA samples of PCC/PGL patients, candidate CpG sites that were hyper/hypo-methylated in metastatic tumors relative to those in the primary tumors of 2 patients with malignant PCC/PGL were selected. The methylation levels of the chosen candidate CpG sites were evaluated quantitatively. RESULTS:Twelve CpG sites were selected as hypermethylated candidates, and 16 CpG sites were selected as hypomethylated candidates. Using two quantitative methylation analysis methods, one hypermethylated site (cg02119938) and one hypomethylated site (cg26870725) remained as candidates. These sites were related to ACSBG1 (acyl-CoA synthetase bubblegum family member 1) and MAST1 (microtubule-associated serine-threonine kinase 1), respectively. Immunohistochemical studies of ACSBG1 and MAST1 revealed that epigenetic changes in the malignant transformation of PCC/PGL might be associated with ACSBG1 silencing or MAST1 overexpression. CONCLUSIONS:Here, we report two noteworthy genes, ACSBG1 and MAST1; the aberrant promoter methylation/demethylation of these genes might be involved in their silencing/expression in malignant PCC/PGL. Further investigations are necessary to determine the role of ACSBG1 and/or MAST1 expression in malignant transformation and to establish pathological markers that can evaluate the malignant potential of PCC/PGL.
| S-EPMC5651299 | biostudies-literature
Project description:ObjectiveMetyrosine (alpha-methyl-para-tyrosine) effectively reduces catecholamine levels in patients with pheochromocytoma/paraganglioma. However, improvements in physiological and metabolic parameters and changes in endocrine function associated with metyrosine administration should be validated in comparison to surgery. This study was performed to confirm the effects of metyrosine on the physiological, metabolic, and endocrinological functions of patients with pheochromocytoma/paraganglioma in the perioperative period.DesignThis retrospective cohort study was performed at a single university hospital.MethodsWe included ten patients with pheochromocytoma/paraganglioma who received oral metyrosine after α-blocker therapy and consecutive surgeries. Urinary catecholamine metabolite levels and other clinical parameters were evaluated before and after metyrosine administration, and 1 week after surgery.ResultsThe mean age was 53.1 ± 16.1 years. Of the ten participants (four men and six women), nine had pheochromocytoma and one had paraganglioma. The median maximum metyrosine dose was 750 mg/day. Urinary catecholamine metabolite levels significantly decreased in a dose-dependent manner after metyrosine administration. Both systolic and diastolic blood pressure significantly decreased after metyrosine and surgical treatment. Metyrosine administration significantly improved insulin sensitivity, although surgery improved the the basal insulin secretion. Additionally, serum prolactin and thyroid-stimulatory hormone levels were significantly increased by metyrosine treatment, whereas plasma renin activity was decreased.ConclusionsMetyrosine significantly reduced catecholamines in patients with pheochromocytoma/paraganglioma and ensured the safety of the surgery. Adjustment of metyrosine administration may make surgical pretreatment more effective in achieving stabilized blood pressure and improving glucose metabolism. Endocrine parameters may manifest as the systemic effects of metyrosine administration.
| S-EPMC10563611 | biostudies-literature
Project description:Prediction of malignant behavior of pheochromocytoma (PC) or paraganglioma (PG) is of limited value. The Cancer Genome Atlas (TCGA) and the French 'Cortico et Médullosurrénale: les Tumeurs Endocrines' (COMETE) network in Paris (France) facilitate accurate differentiation of malignant PC/PG based on genetic information. Therefore, the objective of this transcriptome analysis is to identify the prognostic genes underlying the differentiation of malignant PC/PG in the TCGA and COMETE databases. TCGA carries data pertaining to multigenomic analysis of 173 PC/PG surgical resection samples while the COMETE cohort contains data involving 188 PC/PG surgical resection samples. Clinical information and mRNA expression datasets were downloaded from TCGA and COMETE databases. Based on eligibility criteria, 58 of 173 PC/PG samples in TCGA and 171 of 188 PC/PG samples collected by the COMETE network were selected. Using Ingenuity Pathway Analysis, the mRNA expression of malignant and benign PC/PG was compared. The 58 samples in TCGA included 11 malignant and 47 benign cases. Among the 171 samples obtained from the COMETE cohort, 19 were malignant and 152 were benign. A comparative analysis of the mRNA expression data of the two databases revealed that 11 up/downregulated pathways involved in malignant PC/PG were related to cancer signaling, metabolic alteration, and prominent mitosis, whereas 6 upregulated genes and 1 downregulated gene were significantly enriched in the functional annotation pathways. The TCGA and COMETE databases showed differences in mRNA expression associated with malignant and benign PC/PG. Improved recognition of prognostic genes facilitates the diagnosis and treatment of PC/PG.
| S-EPMC6530119 | biostudies-literature
Project description:Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
| S-EPMC10107524 | biostudies-literature
Project description:Fibroblast growth factor 21 (FGF21) is a hepatokine with beneficial effects on metabolism. Our aim was to evaluate the relationship between the serum FGF21, and energy and glucose metabolism in 40 patients with pheochromocytoma/functional paraganglioma (PPGL), in comparison with 21 obese patients and 26 lean healthy controls. 27 patients with PPGL were examined one year after tumor removal. Basic anthropometric and biochemical measurements were done. Energy metabolism was measured by indirect calorimetry (Vmax-Encore 29N). FGF21 was measured by ELISA. FGF21 was higher in PPGL than in controls (174.2 (283) pg/mL vs. 107.9 (116) pg/mL; p < 0.001) and comparable with obese (174.2 (283) pg/mL vs. 160.4 (180); p = NS). After tumor removal, FGF21 decreased (176.4 (284) pg/mL vs. 131.3 (225) pg/mL; p < 0.001). Higher levels of FGF21 were expressed, particularly in patients with diabetes. FGF21 positively correlated in PPGL with age (p = 0.005), BMI (p = 0.028), glycemia (p = 0.002), and glycated hemoglobin (p = 0.014). In conclusion, long-term catecholamine overproduction in PPGL leads to the elevation in serum FGF21, especially in patients with secondary diabetes. FGF21 levels were comparable between obese and PPGL patients, despite different anthropometric indices. We did not find a relationship between FGF21 and hypermetabolism in PPGL. Tumor removal led to the normalization of FGF21 and the other metabolic abnormalities.
| S-EPMC6520899 | biostudies-literature
Project description:Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
| S-EPMC8905338 | biostudies-literature
Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.
| S-EPMC7482423 | biostudies-literature
Project description:Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat. This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines, and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized. Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (hypoxia-inducible factor 2 alpha [HIF2α] inhibitors, tumor vaccination together with checkpoint inhibitors, antiangiogenic therapies, kinase signaling inhibitors) are under evaluation in clinical trials. The HIF2α inhibitor belzutifan may prove to be particularly interesting for cluster 1B-/VHL/EPAS1-related PPGLs, whereas antiangiogenic therapies seem to be primarily effective in cluster 1A-/SDHx-related PPGLs. Some combination therapies currently being evaluated in clinical trials, such as temozolomide/olaparib, temozolomide/talazoparib, or cabozantinib/atezolizumab, will provide data for novel therapy for metastatic PPGLs. It is likely that advances in such molecular targeted therapies will play an essential role in the future treatment of these tumors, with more personalized therapy options paving the way towards improved therapeutic outcomes.
| S-EPMC9923802 | biostudies-literature
Project description:Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10-15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.
| S-EPMC10073672 | biostudies-literature
Project description:Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated with high cardiovascular morbidity and variable risk of malignancy. The current therapy of choice is surgical resection. Nevertheless, PCCs/PGLs are associated with a lifelong risk of tumor persistence or recurrence. A high rate of germline or somatic mutations in numerous genes has been found in these tumors. For some, the tumorigenic processes are initiated during embryogenesis. Such tumors carry gene mutations leading to pseudohypoxic phenotypes and show more immature characteristics than other chromaffin cell tumors; they are also often multifocal or metastatic and occur at an early age, often during childhood. Cancer stem cells (CSCs) are cells with an inherent ability of self-renewal, de-differentiation, and capacity to initiate and maintain malignant tumor growth. Targeting CSCs to inhibit cancer progression has become an attractive anti-cancer therapeutic strategy. Despite progress for this strategy for solid tumors such as neuroblastoma, brain, breast, and colon cancers, no substantial advance has been made employing similar strategies in PCCs/PGLs. In the current review, we discuss findings related to the identification of normal chromaffin stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs in PCCs/PGLs. Additionally, we examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating especially recurrent and metastatic tumors.
| S-EPMC7051940 | biostudies-literature