© 1995 by Oxford University Press
Journal of the National Cancer Institute, Vol. 87, No. 3, 213-219,
February 1995
© 1995 Oxford University Press
Enhancement of Tumor Growth and Vascular Density by Transfection of Vascular Endothelial Cell Growth Factor Into MCF–7 Human Breast Carcinoma Cells
Affiliations of authors: Molecular Angiogenesis Group, Imperial Cancer Research Fund, Institute of Molecular Medicine. University of Oxford, John Radcliffe Hospital England
Nuffield Department of Pathology, University of Oxford, John Radcliffe Hospital
Department of Pharmacology, University of Firenze Italy
Department of Gene Expression, G. F. Biotechnologische Forschung, Braunschweig, Federal Republic of Germany
Correspondence to: Roy Bicknell, D.Phil., Molecular Angiogenesis Group, Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, England.
Background: Vascular endothelia growth factor (VEGF) is a secreted endothelial-specific growth factor that is angiogenic in vivo. it is commonly expressed in a range of carcinomas. Purpose: The study was designed to investigate the effect of constitutive expression of VEGF on tumor formation by estrogen-dependent human MCF–7 breast carcinoma cells. Methods: A full-length complementary DNA encoding the shortest isoform of VEGF (VEGF121was stably transfected into MCF–7 cells. transfected clones were screened for VEGF121messenger RNA (mRNA) expression by ribonuclease protection analysis and for secretion of VEGF121protein by Western blot analysis. secretion of biologically active VEGF121by transfectants was confirmed by 1) a competitive radioreceptor-binding assay, 2) stimulation of the growth of microvascular endothelial cells in vitro, and 3) potent angiogenic activity in the rabbit corneal assay. tumor models were then established by subcutaneously implanting wildtype of VEGF121-transfected MCF–7 cells, together with either mouse BALB/3T3 clone A31 fibroblasts or human MDA–435S breast carcinoma cells, into ovariectomized nude mice either with or without a separately implanted slow-release estrogen pellet. Tumor vascularity was quantitatively assessed by capillary vessel counting after staining with the pan-endothelia marker CD31. Results: Stable VEGF121-overexpressing MCF–7cells were isolated and designated V12 cells. when implanted into the rabbit cornea, V12 cells elicited a strong directional outgrowth of capillaries. The growth rate of V12 cells in vitro was indistinguishable from that of MCF–7 wild—type cells. V12 cells formed faster growting tumors than did wild-type cells (P
.01) and showed a heterogeneous distribution of vessels when compared with the homogeneous distribution seen in tumors formed form wild-type cells. VEGF121 overexpression had no effect on hormone dependence or tamoxifen sensitivity of tumor formation by MCF–7 cells in mice. No macroscopic evidence for metastasis from subcutaneous implants was obtained conclusions: VEGF121 expression by breast carcinoma cells confers a growth advantange in vivo but not in vitro. Tumors formed by V12 transfectants were more vascular than those formed by wild-type MCF–7 cells, and we surmise that the growth advantage arises from increased tumor vascularization induced by VEGF121. Implications: Tumor formation by V12 cells could provide a useful model for the assessment of anti-angiogenic drugs. [J Natl Cancer Inst 87: 213–219, 1995]
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