All cells are coated with specific types of sugars that are attached to membrane protein receptors. One important function of these sugars is to regulate the activity of the attached proteins. It has been known for decades that tumor cells exhibit an altered profile of cell surface sugars. In fact, this was one of the earliest known characteristics of a cancer cell. Moreover, changes in sugar composition are not random during carcinogenesis; there are specific sugars that are elevated, suggesting that these sugars contribute in some manner to the tumor cell phenotype. One of the well-known tumor-associated carbohydrates is alpha2-6-linked sialic acid, a sugar added by the ST6Gal-I enzyme. An extensive literature has shown that ST6Gal-I, and its associated sugar, are upregulated in many types of cancers including ovarian cancer. However, there is very little understanding of the functional consequences of ST6Gal-I upregulation, due to a lack of information regarding the identity of the specific proteins that carry these sugars.

Our laboratory provided key insight into the role of ST6Gal-I in carcinogenesis by identifying the beta1 integrin adhesion receptor as a cell surface protein that acquires high levels of alpha2-6 sialic acid when a cell becomes tumorigenic. The beta1 integrin is known to be a major regulator of cell migration and also cell survival. Our published and preliminary studies have shown that integrin sialylation significantly enhances a tumor cell's ability to crawl through extracellular matrices, a process that facilitates metastasis. We also reported that integrin sialylation protects tumor cells from galectin-3, which is a secreted molecule that induces tumor cell death. These collective results suggest that integrin sialylation promotes tumor progression through multiple mechanisms.

More recently, we have determined that the ST6Gal-I enzyme adds beta2-6 sialic acid to two others receptors, named Fas and TNFR1, that cause cell death. Importantly, our preliminary data show that sialylation of these receptors prevents cell death, thus enhancing tumor cell survival. Because the activity of ST6Gal-I affects so many different molecular pathways that are crucial for promoting a metastatic tumor cell phenotype (e.g., invasiveness and resistance to cell death), we hypothesize that blocking ST6Gal-I function in tumor cells could prove to be a very effective treatment for metastatic ovarian cancer. To our knowledge, no other group is currently evaluating ST6Gal-I as a therapeutic target for ovarian cancer; therefore, the proposed studies will advance a completely new direction in ovarian cancer research. The identification of new molecular pathways underlying the development and progression of ovarian cancer treatments is vitally important for developing alternative treatments. There is a critical need for such treatments, given that survival rates for ovarian cancer have not increased significantly in the last 30 years despite the generation of new chemotherapeutic drugs.