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Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling

GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synt...

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Autores principales: Ungefroren, Hendrik, Künstner, Axel, Busch, Hauke, Franzenburg, Sören, Luley, Kim, Viol, Fabrice, Schrader, Jörg, Konukiewitz, Björn, Wellner, Ulrich F., Meyhöfer, Sebastian M., Keck, Tobias, Marquardt, Jens-Uwe, Lehnert, Hendrik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781720/
https://www.ncbi.nlm.nih.gov/pubmed/36555512
http://dx.doi.org/10.3390/ijms232415868
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author Ungefroren, Hendrik
Künstner, Axel
Busch, Hauke
Franzenburg, Sören
Luley, Kim
Viol, Fabrice
Schrader, Jörg
Konukiewitz, Björn
Wellner, Ulrich F.
Meyhöfer, Sebastian M.
Keck, Tobias
Marquardt, Jens-Uwe
Lehnert, Hendrik
author_facet Ungefroren, Hendrik
Künstner, Axel
Busch, Hauke
Franzenburg, Sören
Luley, Kim
Viol, Fabrice
Schrader, Jörg
Konukiewitz, Björn
Wellner, Ulrich F.
Meyhöfer, Sebastian M.
Keck, Tobias
Marquardt, Jens-Uwe
Lehnert, Hendrik
author_sort Ungefroren, Hendrik
collection PubMed
description GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-β. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-β1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-β1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-β1 with upregulation of the established TGF-β target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-β1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-β treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-β signaling is not confined to BON cells but is a general feature of panNETs.
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spelling pubmed-97817202022-12-24 Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling Ungefroren, Hendrik Künstner, Axel Busch, Hauke Franzenburg, Sören Luley, Kim Viol, Fabrice Schrader, Jörg Konukiewitz, Björn Wellner, Ulrich F. Meyhöfer, Sebastian M. Keck, Tobias Marquardt, Jens-Uwe Lehnert, Hendrik Int J Mol Sci Article GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-β. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-β1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-β1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-β1 with upregulation of the established TGF-β target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-β1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-β treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-β signaling is not confined to BON cells but is a general feature of panNETs. MDPI 2022-12-14 /pmc/articles/PMC9781720/ /pubmed/36555512 http://dx.doi.org/10.3390/ijms232415868 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ungefroren, Hendrik
Künstner, Axel
Busch, Hauke
Franzenburg, Sören
Luley, Kim
Viol, Fabrice
Schrader, Jörg
Konukiewitz, Björn
Wellner, Ulrich F.
Meyhöfer, Sebastian M.
Keck, Tobias
Marquardt, Jens-Uwe
Lehnert, Hendrik
Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling
title Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling
title_full Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling
title_fullStr Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling
title_full_unstemmed Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling
title_short Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling
title_sort differential effects of somatostatin, octreotide, and lanreotide on neuroendocrine differentiation and proliferation in established and primary net cell lines: possible crosstalk with tgf-β signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781720/
https://www.ncbi.nlm.nih.gov/pubmed/36555512
http://dx.doi.org/10.3390/ijms232415868
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