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Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
- Source :
-
Cancer cell [Cancer Cell] 2014 Jun 16; Vol. 25 (6), pp. 719-34. Date of Electronic Publication: 2014 May 22. - Publication Year :
- 2014
-
Abstract
- Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Carcinoma, Pancreatic Ductal immunology
Disease Models, Animal
Fibroblasts immunology
Fibrosis immunology
Humans
Immune Tolerance
Mice
Mice, Transgenic
Pancreatic Neoplasms immunology
Survival Analysis
Carcinoma, Pancreatic Ductal pathology
Fibroblasts pathology
Fibrosis pathology
Pancreatic Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 25
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 24856586
- Full Text :
- https://doi.org/10.1016/j.ccr.2014.04.005