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Whole transcriptome analysis of canine pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. G...

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Autores principales: van den Berg, Marit F., Kooistra, Hans S., Grinwis, Guy C. M., Nicoli, Stefano, Golinelli, Stefania, Stammeleer, Lisa, van Wolferen, Monique E., Timmermans-Sprang, Elpetra P. M., Zandvliet, Maurice M. J. M., van Steenbeek, Frank G., Galac, Sara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10484483/
https://www.ncbi.nlm.nih.gov/pubmed/37691636
http://dx.doi.org/10.3389/fvets.2023.1155804
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author van den Berg, Marit F.
Kooistra, Hans S.
Grinwis, Guy C. M.
Nicoli, Stefano
Golinelli, Stefania
Stammeleer, Lisa
van Wolferen, Monique E.
Timmermans-Sprang, Elpetra P. M.
Zandvliet, Maurice M. J. M.
van Steenbeek, Frank G.
Galac, Sara
author_facet van den Berg, Marit F.
Kooistra, Hans S.
Grinwis, Guy C. M.
Nicoli, Stefano
Golinelli, Stefania
Stammeleer, Lisa
van Wolferen, Monique E.
Timmermans-Sprang, Elpetra P. M.
Zandvliet, Maurice M. J. M.
van Steenbeek, Frank G.
Galac, Sara
author_sort van den Berg, Marit F.
collection PubMed
description Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. Given the current lack of effective medical treatment, there is a need for novel therapeutic strategies. To identify druggable pathways driving PPGL development, we performed RNA sequencing on PPGLs (n = 19) and normal adrenal medullas (NAMs; n = 10) of dogs. Principal component analysis (PCA) revealed that PPGLs clearly clustered apart from NAMs. In total, 4,218 genes were differentially expressed between PPGLs and NAMs. Of these, 232 had a log(2) fold change of >3 or < −3, of which 149 were upregulated in PPGLs, and 83 were downregulated. Compared with NAMs, PPGLs had increased expression of genes related to the cell cycle, tumor development, progression and metastasis, hypoxia and angiogenesis, and the Wnt signaling pathway, and decreased expression of genes related to adrenal steroidogenesis. Our data revealed several overexpressed genes that could provide targets for novel therapeutics, such as Ret Proto-Oncogene (RET), Dopamine Receptor D2 (DRD2), and Secreted Frizzled Related Protein 2 (SFRP2). Based on the PCA, PPGLs were classified into 2 groups, of which group 1 had significantly higher Ki67 scores (p = 0.035) and shorter survival times (p = 0.04) than group 2. Increased expression of 1 of the differentially expressed genes between group 1 and 2, pleiotrophin (PTN), appeared to correlate with a more aggressive tumor phenotype. This study has shed light on the transcriptomic profile of canine PPGL, yielding new insights into the pathogenesis of these tumors in dogs, and revealed potential novel targets for therapy. In addition, we identified 2 transcriptionally distinct groups of PPGLs that had significantly different survival times.
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spelling pubmed-104844832023-09-08 Whole transcriptome analysis of canine pheochromocytoma and paraganglioma van den Berg, Marit F. Kooistra, Hans S. Grinwis, Guy C. M. Nicoli, Stefano Golinelli, Stefania Stammeleer, Lisa van Wolferen, Monique E. Timmermans-Sprang, Elpetra P. M. Zandvliet, Maurice M. J. M. van Steenbeek, Frank G. Galac, Sara Front Vet Sci Veterinary Science Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. Given the current lack of effective medical treatment, there is a need for novel therapeutic strategies. To identify druggable pathways driving PPGL development, we performed RNA sequencing on PPGLs (n = 19) and normal adrenal medullas (NAMs; n = 10) of dogs. Principal component analysis (PCA) revealed that PPGLs clearly clustered apart from NAMs. In total, 4,218 genes were differentially expressed between PPGLs and NAMs. Of these, 232 had a log(2) fold change of >3 or < −3, of which 149 were upregulated in PPGLs, and 83 were downregulated. Compared with NAMs, PPGLs had increased expression of genes related to the cell cycle, tumor development, progression and metastasis, hypoxia and angiogenesis, and the Wnt signaling pathway, and decreased expression of genes related to adrenal steroidogenesis. Our data revealed several overexpressed genes that could provide targets for novel therapeutics, such as Ret Proto-Oncogene (RET), Dopamine Receptor D2 (DRD2), and Secreted Frizzled Related Protein 2 (SFRP2). Based on the PCA, PPGLs were classified into 2 groups, of which group 1 had significantly higher Ki67 scores (p = 0.035) and shorter survival times (p = 0.04) than group 2. Increased expression of 1 of the differentially expressed genes between group 1 and 2, pleiotrophin (PTN), appeared to correlate with a more aggressive tumor phenotype. This study has shed light on the transcriptomic profile of canine PPGL, yielding new insights into the pathogenesis of these tumors in dogs, and revealed potential novel targets for therapy. In addition, we identified 2 transcriptionally distinct groups of PPGLs that had significantly different survival times. Frontiers Media S.A. 2023-08-24 /pmc/articles/PMC10484483/ /pubmed/37691636 http://dx.doi.org/10.3389/fvets.2023.1155804 Text en Copyright © 2023 van den Berg, Kooistra, Grinwis, Nicoli, Golinelli, Stammeleer, van Wolferen, Timmermans-Sprang, Zandvliet, van Steenbeek and Galac. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Veterinary Science
van den Berg, Marit F.
Kooistra, Hans S.
Grinwis, Guy C. M.
Nicoli, Stefano
Golinelli, Stefania
Stammeleer, Lisa
van Wolferen, Monique E.
Timmermans-Sprang, Elpetra P. M.
Zandvliet, Maurice M. J. M.
van Steenbeek, Frank G.
Galac, Sara
Whole transcriptome analysis of canine pheochromocytoma and paraganglioma
title Whole transcriptome analysis of canine pheochromocytoma and paraganglioma
title_full Whole transcriptome analysis of canine pheochromocytoma and paraganglioma
title_fullStr Whole transcriptome analysis of canine pheochromocytoma and paraganglioma
title_full_unstemmed Whole transcriptome analysis of canine pheochromocytoma and paraganglioma
title_short Whole transcriptome analysis of canine pheochromocytoma and paraganglioma
title_sort whole transcriptome analysis of canine pheochromocytoma and paraganglioma
topic Veterinary Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10484483/
https://www.ncbi.nlm.nih.gov/pubmed/37691636
http://dx.doi.org/10.3389/fvets.2023.1155804
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