VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche Journal Article
| Authors: | Kaplan, R. N.; Riba, R. D.; Zacharoulis, S.; Bramley, A. H.; Vincent, L.; Costa, C.; MacDonald, D. D.; Jin, D. K.; Shido, K.; Kerns, S. A.; Zhu, Z.; Hicklin, D.; Wu, Y.; Port, J. L.; Altorki, N.; Port, E. R.; Ruggero, D.; Shmelkov, S. V.; Jensen, K. K.; Rafii, S.; Lyden, D. |
| Article Title: | VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche |
| 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 α 4β 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. © 2005 Nature Publishing Group. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; nonhuman; protein function; neoplasms; cell proliferation; animal cell; mouse; animals; mice; animal tissue; metastasis; biology; animal model; protein; wild type; animalia; mice, transgenic; regulatory mechanism; cell culture; tumors; substrate specificity; tumor cell; bone; neoplasm metastasis; organ specificity; hematopoietic stem cells; fibroblast; cell movement; upregulation; hematopoietic stem cell; antibodies; up-regulation; vascular endothelial growth factor receptor-1; growth factor; cell adhesion; antibody; vasculotropin receptor 1; knockout mouse; matrix metalloproteinases; fibronectin; inhibitor of differentiation 3; inhibitor of differentiation proteins; culture media, conditioned; matrix metalloproteinase 9; very late activation antigen 4; fibronectins; integrin alpha4beta1; tumour cells |
| Journal Title: | Nature |
| Volume: | 438 |
| Issue: | 7069 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-12-08 |
| Start Page: | 820 |
| End Page: | 827 |
| Language: | English |
| DOI: | 10.1038/nature04186 |
| PUBMED: | 16341007 |
| PROVIDER: | scopus |
| PMCID: | PMC2945882 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 828" - "Export Date: 24 October 2012" - "CODEN: NATUA" - "Source: Scopus" |
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