The Perivascular Niche Regulates Breast Tumour Dormancy

Nat Cell Biol. 2013 Jul;15(7):807-17. doi: 10.1038/ncb2767. Epub 2013 Jun 2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Neoplasms / blood supply
  • Bone Marrow Neoplasms / metabolism
  • Bone Marrow Neoplasms / secondary*
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Adhesion Molecules / metabolism
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • Neoplasm, Residual / blood supply
  • Neoplasm, Residual / metabolism
  • Neoplasm, Residual / pathology*
  • Neovascularization, Pathologic*
  • Pericytes / metabolism
  • Pericytes / pathology*
  • Stem Cell Niche / physiology
  • Thrombospondin 1 / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Zebrafish / growth & development
  • Zebrafish / metabolism

Substances

  • Cell Adhesion Molecules
  • Postn protein, mouse
  • Thrombospondin 1
  • Transforming Growth Factor beta