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Molecular signals that drive reactivation of dormant tumor cells



DOI:10.1038/bonekey.2013.184

Molecular signals that drive reactivation of dormant tumor cells

Understanding why disseminated tumor cells (DTCs) from breast cancers remain dormant in lung, bone and brain tissue in some patients, only to activate many years later, could help develop therapies to prevent metastatic relapse. Using mouse models of metastasis, Ghajar et al. investigated the role of endothelial cells in the microvascular basement membrane, the most probable ‘landing site’ for DTCs in target tissues.

Use of a bioluminescent marker system revealed dormant breast cancer cells on the microvascular endothelium of the bone marrow and the lung. In vitro studies in which endothelial cells from the human umbilical vein were transduced with the E4ORF1 gene (a human adenoviral gene) to allow them to survive in culture showed that these cells formed stable 3D microvascular networks when co-cultured with fibroblasts from the bone marrow and from the lung. This highlighted the role of endothelial cells as the main regulator for DTC dormancy in these tissues.

Further experiments showed that thrombospondin-1 (TSP-1) is the main endothelium-derived tumor suppressor responsible for maintaining dormancy. Reactivation of dormant cells was induced in culture and in vivo by sprouting neovascular tips that had lost TSP-1 expression and that were expressing active TGF-β1 and periostin.

Editor’s comment

The findings in this study establish a paradigm of differential regulation of breast tumor dormancy and outgrowth in neovascular sub-niches that produce the tumor suppressor TSP-1 or the tumor-promoting factors periostin and TGF-β1, respectively.


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