Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.
Angiogenesis is a significant prognostic factor in breast cancer, but the factors that control angiogenesis in vivo are not well defined. Multiple angiogenic polypeptides are known, and we have determined the expression of seven of these in primary human breast cancers; the relationship of expression to estrogen receptor and vascular density was also examined. Vascular endothelial growth factor (VEGF) and its four isoforms (121, 165, 189, and 206 amino acids), transforming growth factor (TGF)-beta1, pleiotrophin, acidic and basic fibroblast growth factor (FGF), placental growth factor, and thymidine phosphorylase (platelet-derived endothelial cell growth factor) were quantitated by RNase protection analysis. beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermal growth factor receptor, and vascular density were analyzed in 64 primary breast cancers. All tumors expressed at least six different vascular growth factors. VEGF was most abundant, and the transcript for the 121-amino acid form predominated. Other angiogenic factors expressed at high levels were thymidine phosphorylase and TGF-beta1. Expression of most of the angiogenic factors did not correlate with that of ER or vascular density. However, thymidine phosphorylase did, with a correlation coefficient of 0.3 (P = 0.03). There were significant associations of pleiotrophin with acidic FGF expression (P = 0.001) and TGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001). Thus, angiogenesis may involve a coordinate regulation of some vascular growth factors. High VEGF expression correlated with poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptor expression. Basic FGF was also assessed by ELISA and was more highly expressed in tumors than normal breast tissues (median, 346 microg/ml cytosol; range, 54-1323 versus median, 149; range, 32-509; P = 0.01). Implications for therapy are that broad spectrum agents that block features common to these factors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenic factors are expressed. Inhibiting endothelial migration or agents directly toxic to endothelium would be of value in a combined approach to therapy.
Relf
M
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Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, England.
LeJeune
S
S
Scott
P A
PA
Fox
S
S
Smith
K
K
Leek
R
R
Moghaddam
A
A
Whitehouse
R
R
Bicknell
R
R
Harris
A L
AL
D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D018572:Disease-Free Survival; D016228:Endothelial Growth Factors / Q000502:physiology*; D016220:Fibroblast Growth Factor 1 / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008222:Lymphokines / Q000502:physiology; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002352:Carrier Proteins; D016207:Cytokines; D016228:Endothelial Growth Factors; D008222:Lymphokines; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C066845:pleiotrophin; D000072483:Placenta Growth Factor; D013939:Thymidine Phosphorylase