Dysfunction of calcium-regulated exocytosis at a single-cell level causes catecholamine hypersecretion in patients with pheochromocytoma

Houy, Sébastien; Streit, Laura; Drissa, Inès; Rame, Marion; Decraene, Charles; Moog, Sophie; Brunaud, Laurent; Lanoix, Joël; Chelbi, Rabie; Bihain, Florence; Lacomme, Stéphanie; Lomazzi, Sandra; Campoli, Philippe; Vix, Michel; Mutter, Didier; Paramithiotis, Eustache; Dubessy, Christophe; Vitale, Nicolas; Ory, Stéphane; Gasman, Stéphane

doi:10.1016/j.canlet.2022.215765

Cited by 5 publications

(3 citation statements)

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“…A recent study in primary PHEO cells demonstrated an increase in many proteins involved in vesicular exocytosis or CATs synthesis as well as a higher number of exocytotic events in PHEOs compared with chromaffin cells at the single cell level for the same stimulation ( 42 ). This suggests in cells secreting high concentrations of CATs an increase in the number of NVs rather than an increase in the storage capacity of each NV.…”

Section: Discussionmentioning

confidence: 99%

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension

et al. 2022

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IntroductionNeuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO.MethodCatecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting.ResultsPlasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation.ConclusionThe low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB.

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Section: Discussionmentioning

confidence: 99%

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension

et al. 2022

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“…MIBG can enter chromaffin cells through active uptake via the cellular membrane norepinephrine transporter, become deposited in storage granules (chromaffin granules) via vesicular monoamine transporters (VMAT) type 1 and type 2, and be released via Ca 2+ -triggered exocytosis from adrenal chromaffin cells 13,25 . NPY and chromogranin B (CHGB) are stimulatory regulators of the exocytotic secretory machinery, 26–28 and proprotein convertase subtilisin/kexin type 1 (PCSK1) is involved in hormone processing 29 . In contrast, rabphilin 3A (RPH3A) and calmodulin (CALM) are inhibitory regulators of exocytotic catecholamine release 25,27 .…”

Section: Resultsmentioning

confidence: 99%

“…13,25 NPY and chromogranin B (CHGB) are stimulatory regulators of the exocytotic secretory machinery, [26][27][28] and proprotein convertase subtilisin/kexin type 1 (PCSK1) is involved in hormone processing. 29 In contrast, rabphilin 3A (RPH3A) and calmodulin (CALM) are inhibitory regulators of exocytotic catecholamine release. 25,27 We first compared expression of catecholamine biosynthesis-and secretion-associated genes between 6 MIBG-negative PCC tumors (PCC #1-6 in Table 1 and Fig.…”

Section: Comparison Of Molecular Features Between Mibg-negative and M...mentioning

confidence: 99%

Increasing Catecholamine Secretion Through NPY in Pheochromocytomas With False-Negative 123I-MIBG Scintigraphy

Ruike,

Suzuki,

Yokote

2024

Clin Nucl Med

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Introduction 123I-MIBG has been well established as a functional imaging tool, and 131I-MIBG therapy is being considered for catecholamine-secreting tumors. Tumors with the characteristics of a noradrenergic biochemical phenotype, small, malignant, metastatic, extra-adrenal, bilateral, and hereditary, especially SDHx-related tumors, are reported to correlate with reduced MIBG uptake. However, the potential molecular mechanisms influencing MIBG uptake have been poorly studied. Patients and Methods To identify critical genes that may enhance MIBG accumulation in pheochromocytomas (PCCs), we performed RNA-seq analyses for 16 operated patients with PCCs (6 MIBG-negative and 10 MIBG-positive) combined with RT-qPCR for 27 PCCs (5 MIBG-negative and 22 MIBG-positive) and examined primary cultures of the surgical tissues. Results In the present study, 6 adrenal nodules of 66 nodules surgically removed from 63 patients with PCCs (9%) were MIBG negative. MIBG, a guanethidine analog of norepinephrine, can enter chromaffin cells through active uptake via the cellular membrane, be deposited in chromaffin granules, and be released via Ca2+-triggered exocytosis from adrenal chromaffin cells. When we compared expression of several catecholamine biosynthesis and secretion-associated genes between MIBG-negative and MIBG-positive tumors using transcriptome analyses, we found that neuropeptide Y, which is contained in chromaffin granules, was significantly increased in MIBG-negative tumors. NPY stimulated norepinephrine secretion dose-dependently in primary cell culture derived from MIBG-positive PCC. In our study, MIBG-negative PCCs were all norepinephrine-hypersecreting tumors. Conclusions These data indicate that NPY upregulation in PCCs may stimulate chromaffin granule catecholamine secretion, which is associated with false-negative 123I-MIBG scintigraphy.

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Phospholipase D and cancer metastasis: A focus on exosomes

Wolf

Tanguy²,

Wang³

et al. 2023

Advances in Biological Regulation

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Dysfunction of calcium-regulated exocytosis at a single-cell level causes catecholamine hypersecretion in patients with pheochromocytoma

Cited by 5 publications

References 46 publications

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension

Increasing Catecholamine Secretion Through NPY in Pheochromocytomas With False-Negative 123I-MIBG Scintigraphy

Phospholipase D and cancer metastasis: A focus on exosomes

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