Differential expression of angiopoietin-1 and angiopoietin-2 may enhance recruitment of bone-marrow-derived endothelial precursor cells into brain tumors.
OBJECTIVE
Angiogenesis is necessary for sustained neoplastic development. The angiopoietins Ang-1 and Ang-2 have been implicated in the regulation of this process; recent reports have suggested that a net gain in Ang-2 activity may be an initiating factor for tumor angiogenesis. We examined the recruitment of bone marrow-derived endothelial precursor cells into developing tumor neovasculature, and the spatial relationship between these cells and angiopoietin (Ang-1 and Ang-2) expression.


METHODS
For this study T-cell depleted knockout mice (RAG-2/KO-5.2) were lethally irradiated and their bone marrow was reconstituted by bone marrow cells (BMCs) from transgenic mice (C57BL/Ka-Thy1.1) expressing green fluorescent protein (GFP). Rat glioma cells (RT-2/RAG) were then injected into the transplanted animals to form solid brain tumors. The animals were killed and their brains were analysed using immunohistochemistry and fluorescence-activated cell sorting.


RESULTS
We found that BMCs migrated preferentially into the tumor when compared to adjacent healthy brain parenchyma. Furthermore, GFP+/CD34+ cells represented up to 8% of endothelial-like cells within the walls of tumor blood vessels. In the tumor, significant colocalization of Ang-2 with GFP+/CD34+ cells was noted (>80%), but colocalization with Ang-1 never exceeded 20%. In normal tissue directly surrounding the tumor, GFP+/CD34+ cells colocalized strongly with both angiopoietins (>75% and >70% for Ang-1 and Ang-2, respectively).


CONCLUSIONS
The relative increase in angiopoietin-2 activity in brain tumors may result in the creation of a pro-angiogenic environment that enhances the recruitment of putative bone marrow-derived endothelial precursor cells into the tumor's developing vascular tree.
Udani
V
V
Department of Neurosurgery, Stanford University Medical Center, California, USA. vikudani@stanford.edu
Santarelli
J
J
Yung
Y
Y
Cheshier
S
S
Andrews
A
A
Kasad
Z
Z
Tse
V
V
D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D001932:Brain Neoplasms / Q000098:blood supply*; D045744:Cell Line, Tumor / Q000637:transplantation; D019070:Cell Lineage; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005910:Glioma / Q000098:blood supply*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D011828:Radiation Chimera; D051381:Rats; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C499308:Rag2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins