Article

Nature 438, 820-827 (8 December 2005) | doi:10.1038/nature04186

VEGFR1-positive haematopoietic bone marrow progenitors = initiate the=20 pre-metastatic niche

Rosandra N. Kaplan^1,^2,^6,¹⁰,=20 Rebecca D. Riba^1,^2,¹⁰,=20 Stergios Zacharoulis^1,^2,^6,¹⁰,=20 Anna H. Bramley^1,²,=20 Lo=EFc Vincent⁴,=20 Carla Costa^1,²,=20 Daniel D. MacDonald^1,²,=20 David K. Jin⁴,=20 Koji Shido⁴,=20 Scott A. Kerns^1,²,=20 Zhenping Zhu⁸,=20 Daniel Hicklin⁸,=20 Yan Wu⁸,=20 Jeffrey L. Port⁵,=20 Nasser Altorki⁵,=20 Elisa R. Port⁷,=20 Davide Ruggero⁹,=20 Sergey V. Shmelkov^1,^2,⁴,=20 Kristian K. Jensen^1,²,=20 Shahin Rafii^3,⁴=20 and David Lyden^1,^2,⁶

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Abstract

The cellular and molecular mechanisms by which a tumour = cell=20 undergoes metastasis to a predetermined location are largely unknown. = Here we=20 demonstrate that bone marrow-derived haematopoietic progenitor cells = that=20 express vascular endothelial growth factor receptor 1 (VEGFR1; also = known as=20 Flt1) home to tumour-specific pre-metastatic sites and form cellular = clusters=20 before the arrival of tumour cells. Preventing VEGFR1 function using = antibodies=20 or by the removal of VEGFR1⁺ cells from the bone marrow of = wild-type=20 mice abrogates the formation of these pre-metastatic clusters and = prevents=20 tumour metastasis, whereas reconstitution with selected Id3 (inhibitor = of=20 differentiation 3)-competent VEGFR1⁺ cells establishes = cluster=20 formation and tumour metastasis in Id3 knockout mice. We also show that=20 VEGFR1⁺ cells express VLA-4 (also known as integrin 3Dalpha=20 ₄ 3Dbeta=20 ₁), and that tumour-specific growth factors = upregulate=20 fibronectin=97a VLA-4 ligand=97in resident fibroblasts, providing a = permissive niche=20 for incoming tumour cells. Conditioned media obtained from distinct = tumour types=20 with unique patterns of metastatic spread redirected fibronectin = expression and=20 cluster formation, thereby transforming the metastatic profile. These = findings=20 demonstrate a requirement for VEGFR1⁺ haematopoietic = progenitors in=20 the regulation of metastasis, and suggest that expression patterns of=20 fibronectin and VEGFR1⁺VLA-4⁺ clusters dictate=20 organ-specific tumour spread.

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Department of Pediatrics and the Children's Blood = Foundation=20 Laboratories,
Cell and Developmental Biology,
Howard Hughes Medical Institute,
Genetic Medicine and
Surgery, Weill Cornell Medical College of Cornell = University, 1300=20 York Avenue and
Department of Pediatrics and
Surgery, Memorial Sloan-Kettering Cancer Center, 1233 York = Avenue,=20 New York, New York 10021, USA=20
Imclone Systems Incorporated, New York, New York 10014, = USA=20
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, = USA=20
*These authors contributed equally to this work

Correspondence to: Shahin Rafii^3,⁴David=20 Lyden^1,^2,⁶=20 Correspondence and requests for materials should be addressed to D.L.=20 (Email: dcl2001@med.cornell.edu) or = S.R.=20 (Email: srafii@med.cornell.edu).

Received 13 May 2005; Accepted 19 August = 2005

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VEGFR1-positive haematopoietic bone marrow progenitors = initiate the=20 pre-metastatic niche

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