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The perivascular niche regulates breast tumour dormancy
Open accessAbstract
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.
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“Recent studies are increasingly employing microvascular networks (µVNs)[21, 23, 24], where the permeability, architecture and diameters of vessels are more similar to those found in in vivo microvascular beds (Figure 2A) [21].”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [24]
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“Studies have shown that dormancy can be induced by endothelial derived factors[24], thus demonstrating the need for microfluidic models that recapitulate interactions between ECs and tumor cells, using for example µVNs.”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [24]
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“[13] that dormant cancer cells are located close to stable vasculature, whereas vascular remodeling was associated with proliferating tumour cells.”
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“In addition, thrombospondin-1, produced by endothelial cells, can promote the transition of DTCs to a dormant state[34].”
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Metadata
- Authors
- Ghajar, C. M., Peinado, H., Mori, H., Matei, I. R., Evason, K. J., Brazier, H., Almeida, D., Koller, A., Hajjar, K. A., Stainier, D. Y. R., Chen, E. I., Lyden, D., & Bissell, M. J.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Weill Cornell Medicine (US)
- University of California, San Francisco (US)
- Stony Brook University (US)
- Champalimaud Foundation (PT)
- Corresponding author
- Ghajar, Cyrus M.
- Bissell, Mina J.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2013-06-02
- Volume
- 15
- Issue
- 7
- Pages
- 807-817
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3826912
- OpenAlex
- W2155542819
- Cited by
- 1,148
- References
- 65
- Citations by year
- 2026: 62 · 2025: 68 · 2024: 70 · 2023: 86 · 2022: 89 · 2021: 122 · 2020: 125 · 2019: 97 · 2018: 98 · 2017: 69 · 2016: 89 · 2015: 64 · 2014: 78 · 2013: 29
- FWCI
- 46.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL042493, R01HL054737, R01HL090895, HL54737)
- National Cancer Institute (U54CA126552, U54CA143836, U01CA169538, R37CA064786)
- National Center for Research Resources (1 S10 RR023680-1, S10RR023680)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- breast cancer, tumor dormancy, disseminated tumor cells, perivascular niche, endothelial cells, thrombospondin-1, TGF-β1, periostin, organotypic culture, micrometastases, microcirculation
- MeSH terms
- Animals, Brain Neoplasms, Breast Neoplasms, Endothelium, Vascular, Female, Fluorescent Antibody Technique, Humans, Lung Neoplasms, Neovascularization, Pathologic, Tumor Cells, Cultured, Zebrafish, Cell Adhesion Molecules, Transforming Growth Factor beta, Neoplasm, Residual, Bone Marrow Neoplasms, Thrombospondin 1, Pericytes, Mice, Stem Cell Niche, Tumor Microenvironment
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