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Cancer Cell. 2014 Jun 16;25(6):719-34. doi: 10.1016/j.ccr.2014.04.005. Epub 2014 May 22.

Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.

Author information

  • 1Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
  • 2Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 3Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 4Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 5Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 6Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 7Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
  • 8Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 9Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 10Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: rkalluri@mdanderson.org.

Erratum in

  • Cancer Cell. 2015 Dec 14;28(6):831-3.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24856586
[PubMed - indexed for MEDLINE]
PMCID:
PMC4180632
Free PMC Article
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