VEGFR1-positive Haematopoietic Bone Marrow Progenitors Initiate the Pre-Metastatic Niche

Nature. 2005 Dec 8;438(7069):820-7. doi: 10.1038/nature04186.

Abstract

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Movement* / drug effects
  • Cell Proliferation
  • Culture Media, Conditioned / pharmacology
  • Fibronectins / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Inhibitor of Differentiation Proteins / metabolism
  • Integrin alpha4beta1 / metabolism
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Transgenic
  • Neoplasm Metastasis / pathology*
  • Neoplasm Metastasis / physiopathology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Organ Specificity
  • Substrate Specificity
  • Up-Regulation
  • Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism*

Substances

  • Culture Media, Conditioned
  • Fibronectins
  • Inhibitor of Differentiation Proteins
  • Integrin alpha4beta1
  • Idb3 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-1
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse