Tumor induction of VEGF promoter activity in stromal cells.
We have established a line of transgenic mice expressing the A. victoria green fluorescent protein (GFP) under the control of the promoter for vascular endothelial growth factor (VEGF). Mice bearing the transgene show green cellular fluorescence around the healing margins and throughout the granulation tissue of superficial ulcerative wounds. Implantation of solid tumors in the transgenic mice leads to an accumulation of green fluorescence resulting from tumor induction of host VEGF promoter activity. With time, the fluorescent cells invade the tumor and can be seen throughout the tumor mass. Spontaneous mammary tumors induced by oncogene expression in the VEGF-GFP mouse show strong stromal, but not tumor, expression of GFP. In both wound and tumor models the predominant GFP-positive cells are fibroblasts. The finding that the VEGF promoter of nontransformed cells is strongly activated by the tumor microenvironment points to a need to analyze and understand stromal cell collaboration in tumor angiogenesis.
Fukumura
D
D
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston 02114, USA.
Xavier
R
R
Sugiura
T
T
Chen
Y
Y
Park
E C
EC
Lu
N
N
Selig
M
M
Nielsen
G
G
Taksir
T
T
Jain
R K
RK
Seed
B
B
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D007202:Indicators and Reagents; D008164:Luminescent Proteins / Q000235:genetics; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012867:Skin / Q000293:injuries; D017154:Stromal Cells / Q000502:physiology* / Q000648:ultrastructure; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000235:genetics
D016228:Endothelial Growth Factors; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D049452:Green Fluorescent Proteins