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Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211975/ https://www.ncbi.nlm.nih.gov/pubmed/32371554 http://dx.doi.org/10.26508/lsa.201900573 |
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author | Parajuli, Parash Nguyen, Thien Ly Prunier, Céline Razzaque, Mohammed S Xu, Keli Atfi, Azeddine |
author_facet | Parajuli, Parash Nguyen, Thien Ly Prunier, Céline Razzaque, Mohammed S Xu, Keli Atfi, Azeddine |
author_sort | Parajuli, Parash |
collection | PubMed |
description | Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfolding. Using a mouse model of Kras(G12D)-driven PDAC, which faithfully recapitulates the progression of the human disease, we observed a massive and selective depletion of β-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-β) signaling during PDAC progression caused erosion of β-cell mass through apoptosis. Suppressing TGF-β signaling, either pharmacologically through TGF-β immunoneutralization or genetically through deletion of Smad4 or TGF-β type II receptor (TβRII), afforded substantial protection against PDAC-driven β-cell depletion. From a translational perspective, both activation of TGF-β signaling and depletion of β-cells frequently occur in human PDAC, providing a mechanistic explanation for the pathogenesis of diabetes in PDAC patients, and further implicating new-onset diabetes as a potential early prognostic marker for PDAC. |
format | Online Article Text |
id | pubmed-7211975 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-72119752020-05-15 Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells Parajuli, Parash Nguyen, Thien Ly Prunier, Céline Razzaque, Mohammed S Xu, Keli Atfi, Azeddine Life Sci Alliance Research Articles Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfolding. Using a mouse model of Kras(G12D)-driven PDAC, which faithfully recapitulates the progression of the human disease, we observed a massive and selective depletion of β-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-β) signaling during PDAC progression caused erosion of β-cell mass through apoptosis. Suppressing TGF-β signaling, either pharmacologically through TGF-β immunoneutralization or genetically through deletion of Smad4 or TGF-β type II receptor (TβRII), afforded substantial protection against PDAC-driven β-cell depletion. From a translational perspective, both activation of TGF-β signaling and depletion of β-cells frequently occur in human PDAC, providing a mechanistic explanation for the pathogenesis of diabetes in PDAC patients, and further implicating new-onset diabetes as a potential early prognostic marker for PDAC. Life Science Alliance LLC 2020-05-05 /pmc/articles/PMC7211975/ /pubmed/32371554 http://dx.doi.org/10.26508/lsa.201900573 Text en © 2020 Parajuli et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Parajuli, Parash Nguyen, Thien Ly Prunier, Céline Razzaque, Mohammed S Xu, Keli Atfi, Azeddine Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells |
title | Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells |
title_full | Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells |
title_fullStr | Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells |
title_full_unstemmed | Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells |
title_short | Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells |
title_sort | pancreatic cancer triggers diabetes through tgf-β–mediated selective depletion of islet β-cells |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211975/ https://www.ncbi.nlm.nih.gov/pubmed/32371554 http://dx.doi.org/10.26508/lsa.201900573 |
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