Endothelial Subniches Differentially Modulate Tumor Dormancy

Following dissemination to distant organs, tumor cells often enter a quiescent state and persist for long periods prior to induction of metastatic outgrowth. However, the mechanisms that promote disseminated tumor cell (DTC) quiescence and the factors that trigger escape from this dormant state are unclear. Ghajar and colleagues hypothesized that endothelial cells and components of the microvascular basement membrane in metastatic sites such as the lung, bone marrow, liver, and brain may regulate the establishment of a dormant niche in breast cancer. Consistent with this idea, quiescent DTCs resided on the microvascular endothelium of the lung, bone marrow, and brain in mouse models of human breast cancer metastasis. In addition, the presence of endothelial cells in 3-dimensional, organotypic microvascular niches decreased breast cancer cell growth and induced sustained tumor cell quiescence. This tumor-suppressive phenotype was dependent on local secretion of thrombospondin 1 (TSP1) from endothelial cells into the basement membrane surrounding mature microvessels, which were associated with slowly dividing tumor cells, suggesting that established vasculature maintains DTC dormancy. In contrast, TSP1 expression was not detected at sprouting neovascular tips, which were associated with more rapidly proliferating tumor cells. Reduction in endothelial tips impaired breast cancer cell growth, whereas enhanced tip formation accelerated tumor cell growth both in vitro and in a zebrafish model, suggesting that neovascular sprouting stimulates metastatic outgrowth. The ability of neovascular tip cells to promote breast cancer cell growth was mediated by increased expression of protumorigenic factors, including periostin (POSTN) and active TGF-β1; treatment of microvascular niche cultures with POSTN and TGF-β1 was sufficient to overcome growth suppression and increase tumor cell outgrowth. These results identify endothelial subniches that differentially regulate tumor cell quiescence and metastatic outgrowth and suggest that suppression of neovascular formation may limit breast cancer relapse.

Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 2013 Jun 2 [Epub ahead of print].

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