The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo.
We report that hypoxia regulates and influences the level of the angiogenic enzyme platelet-derived endothelial cell growth factor (PD-ECGF), also called thymidine phosphorylase, in vitro and in vivo. Levels of PD-ECGF protein increased 6-fold in the breast cancer cell line MDA 231 after 16 h of growth in 0.3% oxygen. A simultaneous increase in enzyme activity was observed. Immunohistochemical staining of MDA 231 tumors grown in nu/nu mice showed increased expression of PD-ECGF in those parts of the tumor that are proximal to the areas of necrosis. In addition, increased and widespread staining for PD-ECGF protein was obtained when the tumor vascular supply was occluded for 2 h by clamping. Lowering the media pH to 6.3-6.7 in vitro also resulted in an increase in PD-ECGF protein levels. This study demonstrates that tumor microenvironmental factors can result in the specific up-regulation of an angiogenic enzyme that can also activate 5-fluorouracil prodrugs and hence is exploitable therapeutically.
Griffiths
L
L
Experimental Oncology, Medical Research Council Harwell, Chilton, United Kingdom.
Dachs
G U
GU
Bicknell
R
R
Harris
A L
AL
Stratford
I J
IJ
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013939:Thymidine Phosphorylase