Epithelial ovarian cancer cell adhesion to extracellular matrix proteins and the effect on adhesion of peptide inhibitors of adhesion receptors

Epithelian ovarian cancer is the fourth commonest cause of cancer death in women. Affecting patients in their prime, its aetiology is obscure. Current therapy cures only the minority of patients. New methods of treatment are required and alternative approaches such as intraperitoneal therapy are suggested by the natural history of the disease, in particular its propensity for spread through the abdominal cavity, attaching to and proliferating on the peritoneum. Considering this feature of local spread and attachment, this study was designed to examine the characteristics of ovarian cancer cell adhesion to matrix proteins and investigate the effect on adhesion, of peptides described as inhibitors of cell adhesion in tumour systems. The laboratory investigation was set against a review of the experience, with ovarian cancer of the CRC Wessex Medical Oncology Unit Southampton, which confirmed the reported clinical features, natural history and response to treatment in these patients. Areas where improvement in patients management might be achieved are discussed. Immunofluorescence microscopy on samples of peritoneum was performed and confirmed published reports of the protein constituents of the sub mesothelial matrix. The same antibodies and staining technique were applied to 7 ovarian cancer cell lines, to determine patterns of auto production of matrix proteins. Adhesion of these cell lines to laminin, fibronectin and collagen was measured and comparisons made between them. With adhesion profiles determined, attempts to inhibit adhesion with peptide fragments of laminin (YIGSR) and fibronectin (GRGDS) were made. Results of these experiments showed a marked variation between cells examined in terms of protein adhesion and the effect of peptides. Inhibition of cell adhesion was seen with several cell lines, in particular, adhesion to fibronectin with the peptide (GRGDS). From this work it appears that ovarian cancer cells express a range of adhesion receptors for the extracellular matrix including a fibronectin receptor and at least 1 polyspecific receptor. This thesis has provided information regarding the adhesion of ovarian cancer cells to matrix and the receptors responsible for this adhesion. A method of adhesion inhibition has been demonstrated and further experiments to assess the possible therapeutic application of this process are suggested.