Journal Article

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

Ruggero, Davide, Lyden, David, Costa, Carla, Shido, Koji, Riba, Rebecca D., Port, Elisa R., MacDonald, Daniel D., Rafii, Shahin, Hicklin, Daniel, Vincent, Loïc, Kerns, Scott A., Jensen, Kristian K., Altorki, Nasser, Wu, Yan, Zhu, Zhenping, Kaplan, Rosandra N., Port, Jeffrey L., Bramley, Anna H., Shmelkov, Sergey V., Jin, David K., Zacharoulis, Stergios

2005

Overview

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 α 4 β 1 ), 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. The ‘pre-metastatic’ niche Many tumours have a tendency towards metastasis to specific organs. The mechanisms that guide tumour cells to a specific tissue are largely unknown, but current thinking is that it may involve molecular differences inherent in the tumour cells themselves, modulated by the effects of immune cells and other tissues. New research suggests another possibility: haematopoietic precursor cells in the bone marrow expressing VEGFR1 appear to home in on specific sites before the tumour cells get there, paving the way for wandering metastatic cells by forming niches where they can locate and multiply. The concept of a pre-metastatic niche, in which non-cancer cells promote future metastasis, is a novel one that raises the possibility that targeting VEGFR1 and related molecules could have therapeutic value.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Antigens / Biological and medical sciences / Bone marrow / Cell Adhesion / Cell Movement - drug effects / Cell Proliferation / Culture Media, Conditioned - pharmacology / Dissemination / Fibronectins - metabolism / Gene expression / Growth factors / Hematology / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - metabolism / Humanities and Social Sciences / Humans / Inhibitor of Differentiation Proteins - metabolism / Integrin alpha4beta1 - metabolism / Matrix Metalloproteinase 9 / Matrix Metalloproteinases - metabolism / Medical sciences / Mice / Mice, Transgenic / multidisciplinary / Neoplasm Metastasis - pathology / Neoplasm Metastasis - physiopathology / Neoplasms - metabolism / Neoplasms - pathology / Organ Specificity / Rodents / Science / Science (multidisciplinary) / Substrate Specificity / Tumor cell / Tumors / Up-Regulation / Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors / Vascular Endothelial Growth Factor Receptor-1 - metabolism