The perivascular niche regulates breast tumour dormancy.

Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ
Nat Cell Biol. 2013 15 (7): 807-17

PMID: 23728425 · PMCID: PMC3826912 · DOI:10.1038/ncb2767

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.

MeSH Terms (20)

Animals Bone Marrow Neoplasms Brain Neoplasms Breast Neoplasms Cell Adhesion Molecules Endothelium, Vascular Female Fluorescent Antibody Technique Humans Lung Neoplasms Mice Neoplasm, Residual Neovascularization, Pathologic Pericytes Stem Cell Niche Thrombospondin 1 Transforming Growth Factor beta Tumor Cells, Cultured Tumor Microenvironment Zebrafish

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