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Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival
Open accessAbstract
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.
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In the citing paper
“subsequent preclinical studies that suppressed in the long term the CAF subset known to be Hedgehog responsive also demonstrated more rapid PDAC progression35,36.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [36]
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“preclinical studies suggesting that the non-specific targeting or deletion of stromal fibroblasts may not enhance tumour control35,36.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [36]
In the citing paper
“depletion of stromal fibroblasts through hedgehog inhibition, epithelial sonic hedgehog deletion, stromal ablation, or inhibition of lysyl oxidase like-2 increases tumor access to the blood supply and facilitates metastasis, having deleterious consequences on natural history of the disease159–162”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [159]
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“Subsequently, attempts to inactivate CAFs through sonic hedgehog inhibition proved ineffective in patients289, and preclinical studies that were conducted after the fact pinpointed reasons for this failure159,290.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [159]
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“However, inactivation of TGF-β signaling in stromal fibroblasts potentiates neoplasia in adjacent epithelia245.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [245]
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Metadata
- Authors
- Özdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., De Jesus-Acosta, A., Sharma, P., Heidari, P., Mahmood, U., Chin, L., Moses, H. L., Weaver, V. M., Maitra, A., Allison, J. P., LeBleu, V. S., & Kalluri, R.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, San Francisco (US)
- Vanderbilt University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Kalluri, Raghu
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 25
- Issue
- 6
- Pages
- 719-734
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4180632
- OpenAlex
- W2088110734
- Cited by
- 2,681
- References
- 59
- Citations by year
- 2026: 248 · 2025: 215 · 2024: 232 · 2023: 245 · 2022: 309 · 2021: 280 · 2020: 256 · 2019: 185 · 2018: 187 · 2017: 170 · 2016: 168 · 2015: 143 · 2014: 43
- FWCI
- 84.54
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-12-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (144809)
- Oncosuisse
- National Institutes of Health
- National Cancer Institute (U01CA151925, P50CA127003, CA163191, R01CA113669, R01CA155370, CA 155370, UO1 CA151925, U54CA163191, R01CA125550, P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK81976, R01DK081576, DK-55001, R01DK055001)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- pancreatic ductal adenocarcinoma, cancer-associated fibroblasts, myofibroblasts, tumor stroma, fibrosis, alpha-smooth muscle actin, pancreatic intraepithelial neoplasia, tumor hypoxia, epithelial-mesenchymal transition, cancer stem cells, regulatory T cells, immunosuppression, gemcitabine resistance, tumor progression, patient survival
- MeSH terms
- Animals, Disease Models, Animal, Fibroblasts, Fibrosis, Humans, Immune Tolerance, Mice, Transgenic, Pancreatic Neoplasms, Survival Analysis, Carcinoma, Pancreatic Ductal, Mice
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