The perivascular niche regulates breast tumor dormancy

By Cyrus M. Ghajar, H. Peinado, H. Mori, Irina R Matei, Kimberley J. Evason, H. Brazier, D. Almeida, A. Koller, K. Hajjar, D. Stainier and 3 more. Nature Cell Biology, 2013

1,049 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/875bd18a33506074e53ac41d837035f4a008306f

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Citations in the corpus

EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “For example, the apparent dormancy-inducing actions of the perivascular niche noted above seem to be reversed during neo-vascularization as sprouting endothelial tip cells secrete TGF-β1 and periostin (POSTN), which can break dormancy and promote tumor cell proliferation (Ghajar et al., 2013).”
Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance (2019, background): “Intriguingly, the signals that induce dormancy and reactivation appear to be physically segregated along blood vessels: even if fully competent for metastatic reactivation, TNBC cells receive either inhibitory (TSP1, which inhibits TGF-β) or stimulatory (TGF-β and TGF-β-induced matrix proteins— such”
In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform (2016, background): “Tumor cells embedded within the surrounding ECM on the periphery of self-assembled vessel networks can be both activated or arrested in a dormant state due to interactions with the vessel endothelium (Ghajar et al., 2013).”
Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice (2018, background): “In contrast, increased extracellular matrix (ECM) deposition and sprouting angiogenesis have been shown to trigger awakening and metastasis in experimental models (6, 7).”
Characteristics and Significance of the Pre-metastatic Niche. (2016, background): “Some important ECM components are fibronectin, MMPs, versican, periostin, and tenascin-C (Ghajar et al., 2013; Kim et al., 2009).”
Systems Biology of Cancer Metastasis (2019, background): “…state of the dormant cancer cell, such as their epigenetic state, while others provide evidence for elements of the microenvironment, such as the resident quiescent vascular cells, for maintaining adjacent disseminated tumor cells in a dormant, growth arrested state 53,54 ,(Ghajar et al., 2013).”