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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-12, Vol.102 (50), p.18111-18116
Main Authors: Spring, Herbert, Thomas Schüler, Arnold, Bernd, Hämmerling, Günter J., Ganss, Ruth
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Blood vessels
Bone marrow
Bone marrow cells
Bone Marrow Cells - cytology
Bone Marrow Cells - metabolism
Bones
CC chemokines
Cell Movement - physiology
Chemokines
Chemokines - metabolism
Endothelial cells
Endothelial Cells - cytology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Liver
Medical research
Mice
Mice, Transgenic
Microscopy, Confocal
Neovascularization, Pathologic - metabolism
Progenitor cells
Receptors
Receptors, CCR2
Receptors, CCR5 - metabolism
Receptors, Chemokine - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Stem Cells - cytology
Stem Cells - metabolism
Tumors
Vascular Endothelial Growth Factor A - metabolism
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0507158102