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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

1
Department 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.
2
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
3
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
4
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
5
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
7
Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
8
Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
9
Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10
Department 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.

PMID:
24856586
PMCID:
PMC4180632
DOI:
10.1016/j.ccr.2014.04.005
[Indexed for MEDLINE]
Free PMC Article
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