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 increasingly use microvascular networks whose permeability, architecture and diameters are more similar to in vivo microvascular beds.
“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]
The Results section reports that the authors grew robust three-dimensional microvascular networks, supporting this paper as an example of a study using such networks. Our copy does not establish that their vessels’ permeability, architecture, or diameters are more similar to in vivo microvascular beds, nor does it document an increasing trend in their use. No page number is available in the indexed passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDormancy can be induced by endothelial-derived factors.
“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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“Endothelial cell sprouting abolishes inhibitory growth signals in dormant tumor cells to allow metastasis of breast cancer cells in different organs (Ghajar et al. 2013).”
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“These organotypic 3D models recapitulated what was observed in vivo in mice and zebra fish, where the stable trunk of the microvasculature allowed breast cancer cell lines to become dormant but where the vessels were sprouting, the tumor cells ‘woke’ up and grew, revealing that a stable microvasculature induces sustai…”
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Self-citationEndothelial Notch1 Activity Facilitates Metastasis
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BackgroundTGF-β in developmental and fibrogenic EMTs
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BackgroundVascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α
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“mechanisms enabling tumor cells to emerge from dormancy are poorly understood, but there is increasing evidence that tumor-stromal interactions, and the osteoblast 2, 3 , perivascular 4 and perisinusoidal 5 niche are critical mediators of tumor cell dormancy and bone colonization.”
The bone microenvironment invigorates metastatic seeds for further dissemination
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Self-citationThe Multifaceted Role of Perivascular Macrophages in Tumors
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STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma
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“…can be physically segregated along the abluminal surface of blood vessels, as mature endothelial cells produce thrombospondin, which induces dormancy, whereas angiogenic endothelial cells produce periostin, tenascin C, versican and TGF-, which promote metastatic outgrowth (Ghajar et al., 2013).”
Targeting cancer stem cells to suppress acquired chemotherapy resistance
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Interstitial fluid flow in cancer: implications for disease progression and treatment
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Targeting Breast Cancer Metastasis
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“Interestingly, bone marrow appears to be an important site for vessel co-option in both primary and secondary bone malignancies which, in turn, might explain the development of tumour dormancy in bones and the higher rate of chemoresistance [55,56].”
BackgroundThe current paradigm and challenges ahead for the dormancy of disseminated tumor cells
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“For example, endothelial cells (ECs) mixed with stromal cells in a 3D hydrogel provided insights on how vascular sprouts mediate breast cancer growth (6).”
BackgroundResultMechanisms of Cancer Cell Dormancy—Another Hallmark of Cancer?
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“In a recent study using engineered microvascular niches derived from primary human umbilical endothelial cells, the authors examined the behavior of disseminated tumor cells and demonstrated that microvasculature niches that tend to promote cellular quiescence express increased thrombospondin-1, a glycoprotein known t…”
BackgroundMicrofluidics: A New Tool for Modeling Cancer–Immune Interactions
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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].”
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Circulating and disseminated tumor cells: harbingers or initiators of metastasis?
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“But one component common to every PVN is microvascular endothelium, and in the case of breast cancer, growth-arrested DTCs are intimately associated with brain, lung, and bone marrow vasculature (Ghajar et al., 2013).”
BackgroundInfluentialSelf-citationParadoxical effects of chemotherapy on tumor relapse and metastasis promotion
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Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment
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Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer
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“TGF-β promotes breast cancer cell outgrowth from dormancy in metastatic sites, and our PDX models implicate TGF-β signaling activation in metastasisinitiating cells [20, 66], suggesting that combination therapy of doxorubicin and PFD may have additional inhibitory effects on metastasis-initiating cells.”
BackgroundSlow growth determines nonheritable antibiotic resistance in Salmonella enterica
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- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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