© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 18, 1375-1384,
September 19, 2001
© 2001 Oxford University Press
Epidermal Growth Factor Receptor Signaling and the Invasive Phenotype of Ovarian Carcinoma Cells
Affiliations of authors: Ö. Alper, Department of Oncology, Georgetown University, Washington, DC; E. S. Bergmann-Leitner (Laboratory of Tumor Immunology and Biology), T. A. Bennett, W. G. Stetler-Stevenson (Extracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research), National Cancer Institute, Bethesda, MD; N. F. Hacker, Gynaecological Cancer Center, Royal Hospital for Women, Randwick, Australia; K. Stromberg, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, National Institutes of Health, Bethesda.
Correspondence to: William G. Stetler-Stevenson, M.D., Ph.D., National Institutes of Health, Bldg. 10, Rm. 2A33, MSC 1500, Bethesda, MD 20892–1500 (e-mail: sstevenw{at}mail.nih.gov).
Dedicated to ovarian cancer victim Georgina Emslie Stevenson (December 3, 1925–April 22, 1982) by W. G. Stetler-Stevenson.
Background: Most (70%–100%) ovarian carcinomas express high levels of the epidermal growth factor receptor (EGFR). To examine the relationship between EGFR and the invasive phenotype, we assessed integrin expression, adhesion, matrix metalloproteinase (MMP) activity, and migration in ovarian cancer cells in which EGFR expression was modified. Methods: NIH:OVCAR-8 human ovarian carcinoma cells were transfected with an expression vector containing the human EGFR complementary DNA in an antisense orientation (EGFR-antisense cells) or the vector alone (vector control cells). We compared vector control and EGFR-antisense cells for cell morphology and adhesion by light microscopy, expression of 
6- and 3-integrin subunits by flow cytometry, MMP and tissue inhibitor of MMP (TIMP) activity by zymography, and migration by a wound migration assay. In some experiments, EGFR kinase activity in parental cells was inhibited by treatment with PD153035. All statistical tests were two-sided. Results: EGFR-antisense cells were morphologically distinct from vector control cells and had a selective decrease in adhesion to laminin-1 that was not observed with vector control cells (P = .008) or on other extracellular matrix substrates. Compared with vector control cells, cell surface 6-integrin expression decreased by approximately 80% (difference = 78.7%; 95% confidence interval [CI] = 77.8% to 79.6), MMP-9 activity decreased by approximately 50%, and TIMP activity increased by approximately 50% in EGFR-antisense cells. Vector control cells were highly motile (5.51 arbitrary distance unit; 95% CI = 4.98 to 6.04), whereas the EGFR-antisense cells were not (0.99 arbitrary distance units; 95% CI = 0.38 to 1.60). The morphology and integrin profile of NIH:OVCAR-8 parental cells treated with PD153035 were similar to those of the EGFR-antisense cells. Conclusions: Reduced EGFR expression in ovarian carcinoma cells decreased their adhesion to laminin-1, expression of the 6-integrin subunit (a well-characterized laminin-1 receptor), and MMP-9 activity. These data support the hypothesis that EGFR overexpression in ovarian cancer cells results in multiple phenotypic changes that enhance the invasive phenotype.
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