Hartman Institute for Therapeutic Organ Regeneration

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

TitleVEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.
Publication TypeJournal Article
Year of Publication2005
AuthorsKaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D
JournalNature
Volume438
Issue7069
Pagination820-7
Date Published2005 Dec 08
ISSN1476-4687
KeywordsAnimals, Cell Adhesion, Cell Movement, Cell Proliferation, Culture Media, Conditioned, Fibronectins, Hematopoietic Stem Cells, Humans, Inhibitor of Differentiation Proteins, Integrin alpha4beta1, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Mice, Mice, Transgenic, Neoplasm Metastasis, Neoplasms, Organ Specificity, Substrate Specificity, Up-Regulation, Vascular Endothelial Growth Factor Receptor-1
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 alpha4beta1), 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.

DOI10.1038/nature04186
Alternate JournalNature
PubMed ID16341007
PubMed Central IDPMC2945882
Grant ListP01 HL067839-020004 / HL / NHLBI NIH HHS / United States
R01 HL061849-04 / HL / NHLBI NIH HHS / United States
R01 HL058707-04 / HL / NHLBI NIH HHS / United States
P01 HL067839 / HL / NHLBI NIH HHS / United States
R01 HL058707-03 / HL / NHLBI NIH HHS / United States
R01 HL061849-03S1 / HL / NHLBI NIH HHS / United States
R01 HL061849-05 / HL / NHLBI NIH HHS / United States
P01 HL067839-010004 / HL / NHLBI NIH HHS / United States
R01 HL061849-02 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
P01 HL067839-040004 / HL / NHLBI NIH HHS / United States
R01 HL061849-03 / HL / NHLBI NIH HHS / United States
R01 HL061849 / HL / NHLBI NIH HHS / United States
P01 HL067839-050004 / HL / NHLBI NIH HHS / United States
P01 HL067839-030004 / HL / NHLBI NIH HHS / United States

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Hartman Institute for Therapeutic Organ Regeneration
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