Chemokines direct endothelial progenitors into tumor neovessels.
Tumor neovasculature substantially derives from sprouting of existing vessels, whereas the functional contribution of bone marrow-derived progenitors to neovessels remains controversial. We used transgenic mouse models of multistep carcinogenesis to monitor incorporation of bone marrow-derived cells into the neovasculature and to elucidate mechanisms of endothelial precursor cell (EPC) recruitment into the tumor microenvironment. We unequivocally demonstrate integration of bone marrow cells into the tumor vasculature as a late event in carcinogenesis that temporally correlates with VEGF release by the tumor and mobilization of circulating EPC in the periphery. Moreover, we demonstrate a chemokine-dependent mechanism of EPC homing into tumor, whereby neovessels of late-stage tumors release a battery of CC chemokines, which direct CCR2(+) and CCR5(+) progenitors into the vasculature. Thus, we show that tumor vessels promote their own growth and development in a self-amplifying fashion.
Spring
Herbert
H
Biomedical Structure Analysis Group, German Cancer Research Center, Heidelberg.
Schüler
Thomas
T
Arnold
Bernd
B
Hämmerling
Günter J
GJ
Ganss
Ruth
R
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C515335:Ccr2 protein, mouse; D018925:Chemokines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse