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VEGFR1-positive haematopoietic bone marrow
progenitors initiate the pre-metastatic niche
Kaplan
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
Department of Pediatrics and the Children's Blood Foundation
Laboratories, Weill Cornell Medical College of Cornell University, New
York, New York 10021, USA.
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.
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