1. Department of Pediatrics and the Children's Blood Foundation Laboratories,
2. Cell and Developmental Biology,
3. Howard Hughes Medical Institute,
4. Genetic Medicine and
5. Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue and
6. Department of Pediatrics and
7. Surgery, Memorial Sloan-Kettering Cancer Center, 1233 York Avenue, New York, New York 10021, USA
8. Imclone Systems Incorporated, New York, New York 10014, USA
9. Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
10. *These authors contributed equally to this work

Correspondence to: Shahin Rafii^3,4David Lyden^1,2,6 Correspondence and requests for materials should be addressed to D.L. (Email: dcl2001@med.cornell.edu) or S.R. (Email: srafii@med.cornell.edu).

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 ₄₁), 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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.