Fucosylated oligosaccharides have been implicated in multiple cell-cell interactions in inflammation and cell trafficking, differentiation and development, and malignancy. While descr iptive and functional data support the major hypothesis that alpha(1,2)fucosylated CD44 and other molecules mediate progression of metastatic adenocarcinoma from several epithelial cancers, definitive demonstration of the function of these cell surface epitopes in carcinogenesis is lacking. The long range goal of my research is to determine how alpha(1,2)fucosylated oligosaccharides are involved in cancer progression, with an intent of developing novel approaches to treat metastatic cancer with anti-adhesion therapies based on cell surface oligosaccharides. The approach I have chosen is to ablate in mice the transferase enzymes Fut1 and Fut2 required to generate alpha(1,2)fucosylated oligosaccharides. I am uniquely positioned to accomplish the proposed work as I have developed two knockout mouse lines and have enlisted the collaborators necessary for completion of this project. Because multiple glycosyltransferases are expressed in cancer cells, I have chosen to focus on the alpha(1,2)fucosyltransferase enzymes to either support their importance in neoplasia, or eliminate them from further consideration in the development of potential therapeutic targets. I propose the following Specific Aims: 1) To classify in non-neoplastic tissues the a l p ha(1,2)fucosyltransferase (Fut1 or Fut2) that synthesizes alpha(1,2)fucosylated H, Lewis B, and Lewis Y oncofetal antigens in order to assign a specific transferase gene to the expression of a specific set of cell surface oligosaccharides over-expressed in tumors. 2) To correlate expression of Fut1 and Fut2 with histologic progression of spontaneous colorectal tumors in mice carrying germline inactivating mutations in the transforming growth factor-beta signaling gene Smad3. 3) To test the importance of alpha(1,2)fucosylated oligosaccharides in colon cancer in vivo by determining the rate and extent of progression of colon tumors in Smad3 null mice. and in 1,2-dimethylhydrazine-induced tumors, in the presence and absence of cell surface alpha(1,2)fucose by crossing mice into the Fut1 and Fut2 null background.
| Domino, Steven E; Karnak, David M; Hurd, Elizabeth A (2007) Cell surface fucosylation does not affect development of colon tumors in mice with germline Smad3 mutation. Tumour Biol 28:77-83 |
| Hurd, Elizabeth A; Holmen, Jessica M; Hansson, Gunnar C et al. (2005) Gastrointestinal mucins of Fut2-null mice lack terminal fucosylation without affecting colonization by Candida albicans. Glycobiology 15:1002-7 |
| Iwamori, Masao; Domino, Steven E (2004) Tissue-specific loss of fucosylated glycolipids in mice with targeted deletion of alpha(1,2)fucosyltransferase genes. Biochem J 380:75-81 |
| Domino, Steven E; Hurd, Elizabeth A (2004) LacZ expression in Fut2-LacZ reporter mice reveals estrogen-regulated endocervical glandular expression during estrous cycle, hormone replacement, and pregnancy. Glycobiology 14:169-75 |
