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PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction
Pancreatic cancer is characterized by a pronounced fibro-inflammatory reaction that has been shown to contribute to cancer progression. Previous reports have demonstrated that pigment epithelium-derived factor (PEDF) has potent tumor suppressive effects in pancreatic cancer, though little is known a...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053722/ https://www.ncbi.nlm.nih.gov/pubmed/27058416 http://dx.doi.org/10.18632/oncotarget.8587 |
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author | Principe, Daniel R. DeCant, Brian Diaz, Andrew M. Mangan, Riley J. Hwang, Rosa Lowy, Andrew Shetuni, Brandon B. Sreekumar, Bharath K. Chung, Chuhan Bentrem, David J. Munshi, Hidayatullah G. Jung, Barbara Grippo, Paul J. Bishehsari, Faraz |
author_facet | Principe, Daniel R. DeCant, Brian Diaz, Andrew M. Mangan, Riley J. Hwang, Rosa Lowy, Andrew Shetuni, Brandon B. Sreekumar, Bharath K. Chung, Chuhan Bentrem, David J. Munshi, Hidayatullah G. Jung, Barbara Grippo, Paul J. Bishehsari, Faraz |
author_sort | Principe, Daniel R. |
collection | PubMed |
description | Pancreatic cancer is characterized by a pronounced fibro-inflammatory reaction that has been shown to contribute to cancer progression. Previous reports have demonstrated that pigment epithelium-derived factor (PEDF) has potent tumor suppressive effects in pancreatic cancer, though little is known about the mechanisms by which PEDF limits pancreatic tumorigenesis. We therefore employed human specimens, as well as mouse and in vitro models, to explore the effects of PEDF upon the pancreatic microenvironment. We found that PEDF expression is decreased in human pancreatic cancer samples compared to non-malignant tissue. Furthermore, PEDF-deficient patients displayed increased intratumoral inflammation/fibrosis. In mice, genetic ablation of PEDF increased cerulein-induced inflammation and fibrosis, and similarly enhanced these events in the background of oncogenic KRAS. In vitro, recombinant PEDF neutralized macrophage migration as well as inhibited macrophage-induced proliferation of tumor cells. Additionally, recombinant PEDF suppressed the synthesis of pro-inflammatory/pro-fibrotic cytokines both in vivo and in vitro, and reduced collagen I deposition and TGFβ synthesis by pancreatic stellate cells, consistent with reduced fibrosis. Combined, our results demonstrate that PEDF limits pancreatic cancer progression by attenuating the fibro-inflammatory reaction, and makes restoration of PEDF signaling a potential therapeutic approach to study in pancreatic cancer. |
format | Online Article Text |
id | pubmed-5053722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50537222016-10-12 PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction Principe, Daniel R. DeCant, Brian Diaz, Andrew M. Mangan, Riley J. Hwang, Rosa Lowy, Andrew Shetuni, Brandon B. Sreekumar, Bharath K. Chung, Chuhan Bentrem, David J. Munshi, Hidayatullah G. Jung, Barbara Grippo, Paul J. Bishehsari, Faraz Oncotarget Research Paper Pancreatic cancer is characterized by a pronounced fibro-inflammatory reaction that has been shown to contribute to cancer progression. Previous reports have demonstrated that pigment epithelium-derived factor (PEDF) has potent tumor suppressive effects in pancreatic cancer, though little is known about the mechanisms by which PEDF limits pancreatic tumorigenesis. We therefore employed human specimens, as well as mouse and in vitro models, to explore the effects of PEDF upon the pancreatic microenvironment. We found that PEDF expression is decreased in human pancreatic cancer samples compared to non-malignant tissue. Furthermore, PEDF-deficient patients displayed increased intratumoral inflammation/fibrosis. In mice, genetic ablation of PEDF increased cerulein-induced inflammation and fibrosis, and similarly enhanced these events in the background of oncogenic KRAS. In vitro, recombinant PEDF neutralized macrophage migration as well as inhibited macrophage-induced proliferation of tumor cells. Additionally, recombinant PEDF suppressed the synthesis of pro-inflammatory/pro-fibrotic cytokines both in vivo and in vitro, and reduced collagen I deposition and TGFβ synthesis by pancreatic stellate cells, consistent with reduced fibrosis. Combined, our results demonstrate that PEDF limits pancreatic cancer progression by attenuating the fibro-inflammatory reaction, and makes restoration of PEDF signaling a potential therapeutic approach to study in pancreatic cancer. Impact Journals LLC 2016-04-05 /pmc/articles/PMC5053722/ /pubmed/27058416 http://dx.doi.org/10.18632/oncotarget.8587 Text en Copyright: © 2016 Principe et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Principe, Daniel R. DeCant, Brian Diaz, Andrew M. Mangan, Riley J. Hwang, Rosa Lowy, Andrew Shetuni, Brandon B. Sreekumar, Bharath K. Chung, Chuhan Bentrem, David J. Munshi, Hidayatullah G. Jung, Barbara Grippo, Paul J. Bishehsari, Faraz PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
title | PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
title_full | PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
title_fullStr | PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
title_full_unstemmed | PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
title_short | PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
title_sort | pedf inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053722/ https://www.ncbi.nlm.nih.gov/pubmed/27058416 http://dx.doi.org/10.18632/oncotarget.8587 |
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