Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension
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, u...
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.1027856/full |
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| author | Annick Mühlethaler-Mottet Silvia Uccella Silvia Uccella Deborah Marchiori Stefano La Rosa Stefano La Rosa Jean Daraspe Katia Balmas Bourloud Maja Beck Popovic Philippe J. Eugster Eric Grouzmann Karim Abid |
| author_facet | Annick Mühlethaler-Mottet Silvia Uccella Silvia Uccella Deborah Marchiori Stefano La Rosa Stefano La Rosa Jean Daraspe Katia Balmas Bourloud Maja Beck Popovic Philippe J. Eugster Eric Grouzmann Karim Abid |
| author_sort | Annick Mühlethaler-Mottet |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T05:26:29Z |
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| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-10T05:26:29Z |
| publishDate | 2022-12-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-0be2e91700d544bdaa49dfb928866c442023-03-07T16:33:11ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-12-011310.3389/fendo.2022.10278561027856Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertensionAnnick Mühlethaler-Mottet0Silvia Uccella1Silvia Uccella2Deborah Marchiori3Stefano La Rosa4Stefano La Rosa5Jean Daraspe6Katia Balmas Bourloud7Maja Beck Popovic8Philippe J. Eugster9Eric Grouzmann10Karim Abid11Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandDepartment of Biomedical Sciences, Humanitas University, Milan, ItalyPathology Service, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, ItalyUnit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, ItalyUnit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, ItalyInstitute of Pathology, Department of Laboratory Medicine and Pathology, University of Lausanne, Lausanne, SwitzerlandElectron Microscopy Facility (EMF), University of Lausanne, Lausanne, SwitzerlandPediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandPediatric Hematology Oncology Unit, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandService of Clinical Pharmacology and Toxicology, Lausanne University Hospital, Lausanne, SwitzerlandService of Clinical Pharmacology and Toxicology, Lausanne University Hospital, Lausanne, SwitzerlandService of Clinical Pharmacology and Toxicology, Lausanne University Hospital, Lausanne, SwitzerlandIntroductionNeuroblastoma (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.https://www.frontiersin.org/articles/10.3389/fendo.2022.1027856/fullneuroblastomapheochromocytomacatecholaminemetanephrinebiomarkersneurosecretory vesicles |
| spellingShingle | Annick Mühlethaler-Mottet Silvia Uccella Silvia Uccella Deborah Marchiori Stefano La Rosa Stefano La Rosa Jean Daraspe Katia Balmas Bourloud Maja Beck Popovic Philippe J. Eugster Eric Grouzmann Karim Abid Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension Frontiers in Endocrinology neuroblastoma pheochromocytoma catecholamine metanephrine biomarkers neurosecretory vesicles |
| title | Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension |
| title_full | Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension |
| title_fullStr | Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension |
| title_full_unstemmed | Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension |
| title_short | Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension |
| title_sort | low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension |
| topic | neuroblastoma pheochromocytoma catecholamine metanephrine biomarkers neurosecretory vesicles |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.1027856/full |
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