VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Rosandra N. Kaplan, Rebecca D. Riba, Stergios Zacharoulis, Anna H. Bramley, Loïc Vincent, Carla Costa, Daniel D. MacDonald, David K. Jin, Koji Shido, Scott A. Kerns, Zhenping Zhu, Daniel Hicklin, Yan Wu, Jeffrey L. Port, Nasser Altorki, Elisa R. Port, Davide Ruggero, Sergey V. Shmelkov, Kristian K. Jensen, Shahin Rafii () and David Lyden ()
Additional contact information
Rosandra N. Kaplan: Department of Pediatrics and the Children's Blood Foundation Laboratories
Rebecca D. Riba: Department of Pediatrics and the Children's Blood Foundation Laboratories
Stergios Zacharoulis: Department of Pediatrics and the Children's Blood Foundation Laboratories
Anna H. Bramley: Department of Pediatrics and the Children's Blood Foundation Laboratories
Loïc Vincent: Genetic Medicine
Daniel D. MacDonald: Department of Pediatrics and the Children's Blood Foundation Laboratories
David K. Jin: Genetic Medicine
Koji Shido: Genetic Medicine
Scott A. Kerns: Department of Pediatrics and the Children's Blood Foundation Laboratories
Zhenping Zhu: Imclone Systems Incorporated
Daniel Hicklin: Imclone Systems Incorporated
Yan Wu: Imclone Systems Incorporated
Jeffrey L. Port: Surgery, Weill Cornell Medical College of Cornell University
Nasser Altorki: Surgery, Weill Cornell Medical College of Cornell University
Elisa R. Port: Surgery, Memorial Sloan-Kettering Cancer Center
Davide Ruggero: Fox Chase Cancer Center
Sergey V. Shmelkov: Department of Pediatrics and the Children's Blood Foundation Laboratories
Kristian K. Jensen: Department of Pediatrics and the Children's Blood Foundation Laboratories
Shahin Rafii: Howard Hughes Medical Institute
David Lyden: Department of Pediatrics and the Children's Blood Foundation Laboratories

Nature, 2005, vol. 438, issue 7069, 820-827

Abstract: 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 α4β1), 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.

Date: 2005
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DOI: 10.1038/nature04186

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