Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma
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Abstract
There is growing evidence that antiangiogenic therapy stimulates cancer cell invasion and metastasis. However, the underlying molecular mechanisms responsible for these changes have not been fully defined. Here, we report that anti-VEGF therapy promotes local invasion and metastasis by inducing collagen signaling in cancer cells. We show that chronic VEGF inhibition in a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDA) induces hypoxia, a less differentiated mesenchymal-like tumor cell phenotype, TGF-β expression, and collagen deposition and signaling. In addition, we show that collagen signaling is critical for protumorigenic activity of TGF-β in vitro. To further model the impact of collagen signaling in tumors, we evaluated PDA in mice lacking Sparc, a protein that reduces collagen binding to cell surface receptors. Importantly, we show that loss of Sparc increases collagen signaling and tumor progression. Together, these findings suggest that collagen actively promotes PDA spread and that enhanced disease progression associated with anti-VEGF therapy can arise from elevated extracellular matrix–mediated signaling. Cancer Res; 74(4); 1032–44. ©2013 AACR.
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Collagen acts as a signaling molecule by activating discoidin domain receptor signaling in PDAC pathology.
“Collagen also acts as a signaling molecule, activating discoidin domain receptor signaling that shape multiple roles in PDAC pathology168–171”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [170]
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- Authors
- Aguilera, K. Y., Rivera, L. B., Hur, H., Carbon, J. G., Toombs, J. E., Goldstein, C. D., Dellinger, M. T., Castrillon, D. H., & Brekken, R. A.
- Affiliations
- University of California, San Francisco (US)
- Authors' Affiliations: 1Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research; Departments of 2Pathology and 3Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Neurological Surgery, University of California San Francisco, San Francisco, California; and 5Department of Surgery, Ajou University School of Medicine, Suwon, Korea
- Corresponding author
- Brekken, Rolf A.
- ORCID
- Venue
- Cancer Research
- Published
- 2014-02-15
- Volume
- 74
- Issue
- 4
- Pages
- 1032-1044
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3944405
- OpenAlex
- W2107932305
- Cited by
- 100
- References
- 56
- Citations by year
- 2025: 4 · 2024: 6 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 10 · 2016: 7 · 2015: 8 · 2014: 3
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Funders
- American Association for Cancer Research
- National Institutes of Health
- National Cancer Institute (F31CA168350, R01CA118240, R01CA137181, U01CA141576)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- collagen signaling, anti-VEGF therapy, pancreatic ductal adenocarcinoma, tumor progression, tumor invasion, metastasis, hypoxia, TGF-beta, SPARC, extracellular matrix, mesenchymal phenotype, anti-angiogenic therapy resistance
- MeSH terms
- Bevacizumab, Animals, Collagen, Disease Models, Animal, Mice, Transgenic, Neoplasm Invasiveness, Pancreatic Neoplasms, Signal Transduction, Treatment Failure, Disease Progression, Carcinoma, Pancreatic Ductal, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice, Antibodies, Monoclonal, Humanized
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