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Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes

Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ∼12% of PDACs have an angiogenesis gene signature with increased expression...

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Autores principales: Craven, Kelly E., Gore, Jesse, Wilson, Julie L., Korc, Murray
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808001/
https://www.ncbi.nlm.nih.gov/pubmed/26586478
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author Craven, Kelly E.
Gore, Jesse
Wilson, Julie L.
Korc, Murray
author_facet Craven, Kelly E.
Gore, Jesse
Wilson, Julie L.
Korc, Murray
author_sort Craven, Kelly E.
collection PubMed
description Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ∼12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro-angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ∼35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs). These PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, and many members of JAK signaling pathways. Moreover, expression of SMAD4 and HDAC9 correlates with endothelial cell abundance in PDAC tissues. Concomitantly targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib suppresses JAK1 phosphorylation and blocks proliferative cross-talk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs), and these anti-proliferative effects were mimicked by JAK1 silencing in ECs. By contrast, either inhibitor alone does not suppress their enhanced proliferation in 3D co-cultures. These findings suggest that targeting both TGF-β and JAK1 signaling could be explored therapeutically in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature.
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spelling pubmed-48080012016-04-19 Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes Craven, Kelly E. Gore, Jesse Wilson, Julie L. Korc, Murray Oncotarget Research Paper Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ∼12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro-angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ∼35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs). These PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, and many members of JAK signaling pathways. Moreover, expression of SMAD4 and HDAC9 correlates with endothelial cell abundance in PDAC tissues. Concomitantly targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib suppresses JAK1 phosphorylation and blocks proliferative cross-talk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs), and these anti-proliferative effects were mimicked by JAK1 silencing in ECs. By contrast, either inhibitor alone does not suppress their enhanced proliferation in 3D co-cultures. These findings suggest that targeting both TGF-β and JAK1 signaling could be explored therapeutically in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature. Impact Journals LLC 2015-11-18 /pmc/articles/PMC4808001/ /pubmed/26586478 Text en Copyright: © 2016 Craven 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
Craven, Kelly E.
Gore, Jesse
Wilson, Julie L.
Korc, Murray
Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
title Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
title_full Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
title_fullStr Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
title_full_unstemmed Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
title_short Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
title_sort angiogenic gene signature in human pancreatic cancer correlates with tgf-beta and inflammatory transcriptomes
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808001/
https://www.ncbi.nlm.nih.gov/pubmed/26586478
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