Advances in uterine protein research: reproduction and cancer.
Uterine protein research has advanced from the measurements of specific compounds to detailed analysis of the genes that regulate protein synthesis and build up the complex carbohydrate structures that play important functional roles. Some 80% of all human proteins are glycoproteins. Functional glycomics highlights the importance of glycosylation in glycoprotein function. Glycodelin is a representative example of functional glycomics because its various glycoforms have different functions. In the uterus, synthesis of glycodelin-A is temporally regulated by progesterone. During the estrogen-dominated fertile window, absence of glycodelin synthesis is significant because uterine glycodelin-A potently and dose-dependently inhibits sperm-egg binding, the initial step in fertilization. The anti-fertilization propensity of glycodelin-A during the luteal phase of the cycle is highly glycosylation-dependent, and there is an intricate functional interplay between spermatozoa, zona pellucida and the various glycodelin isoforms present in the uterine fluid, seminal plasma and follicular fluid, respectively. Endometrial glycodelin synthesis can be induced during the fertile window by administration of progestagens, such as in levonorgestrel hormone-releasing IUD and contraceptive implants. Glycodelin can be chemically modified in such a fashion that it blocks the binding site on CD4 for the HIV surface glycoprotein, synthesis of viral gp 120, and infection of peripheral blood mononuclear cells by the primary HIV isolate THA/93/051, thus potentially inhibiting HIV transmission. Now that a cell line producing the contraceptive isoform has been identified by recombinant technology, these findings may have application for locally applied antiviral contraception. Glycodelin also has immunosuppressive properties, suggesting that the recognition mechanisms in immune and reproductive systems may have converged. Given its inhibitory activity on natural killer cells, abundant at the fetomaternal interphase, the high glycodelin concentration at the same site suggests a role in fetomaternal defense mechanisms. This may be relevant in women with recurrent miscarriage, in whom both the serum and uterine fluid glycodelin concentrations are decreased. Experiments on cancer cell lines have demonstrated increased epithelial differentiation by glycodelin cDNA transfection, and also by co-culture of cancer cells with normal stromal cells in the presence of basement membrane components. Both approaches result in glycodelin expression concomitant with decreased cell proliferation and reversion of the malignant phenotype. These results suggest an active role of normal stromal cells, basement membrane components and glycodelin in epithelial differentiation and glandular morphogenesis. This disposition of glycodelin is significant in patients with certain carcinomas, in which glycodelin-expressing tumors carry better prognosis than glycodelin-negative tumors of the same clinical stage and histological grade. Research on functional glycomics continues to produce significant information on fundamental aspects of fertilization, implantation, pregnancy and cancer.