Aberrent glycosylation in malignant and pre-malignant statesLink informatics for "Aberrent glycosylation in malignant and pre-malignant states"C O N T E N T SSee Also
DescriptionAltered glycosylation is a universal feature of cancer cells, and certain types of glycan structures are well-known markers for tumor progression. (1) Aberrant glycosylation occurs in essentially all types of experimental and human cancers, as has been observed for over 35 years, and many glycosyl epitopes constitute tumor-associated antigens. A long-standing debate is whether aberrant glycosylation is a result or a cause of cancer. Many recent studies indicate that some, if not all, aberrant glycosylation is a result of initial oncogenic transformation, as well as a key event in induction of invasion and metastasis. Glycosylation promoting or inhibiting tumor cell invasion and metastasis is of crucial importance in current cancer research. Nevertheless, this area of study has received little attention from most cell biologists involved in cancer research, mainly because structural and functional concepts of glycosylation in cancer are more difficult to understand than the functional role of certain proteins and their genes in defining cancer cell phenotypes. Glycosylation appears to be considered "in the shade" of more popular topics such as oncogenes and antioncogenes, apoptosis, angiogenesis, growth factor receptors, integrins and cadherins function, etc., despite the fact that aberrant glycosylation profoundly affects all of these processes. (2). DiscussionThe earliest evidence came from observing the enhanced binding of plant lectins to animal tumor cells. Next, it was found that in vitro transformation of cells was frequently accompanied by a general increase in the size of metabolically labeled glycopeptides. With the advent of monoclonal antibody technology in the late 1970s, investigators in search of a “magic bullet” against cancer cells found that many of their “tumor-specific” antibodies were directed against carbohydrate epitopes, especially against those borne on glycosphingolipids. In most cases, further studies showed that these epitopes were “onco-fetal antigens,” i.e., they were also expressed in embryonic tissues, in tumor cells, and in a few cell types in the normal adult. Significant correlations between certain types of altered glycosylation and the actual prognosis of tumor-bearing animals or patients increased interest in these changes. Pathological roles of mucins with altered glycosylationMucins are large glycoproteins with a “rod-like” conformation caused by the presence of many clustered glycosylated serines and threonines in tandem repeat regions. Most epithelial mucin polypeptides belong to the MUC family. In the normal polarized epithelium, mucins are expressed exclusively on the apical domain, toward the lumen of the organ. Likewise, soluble mucins are secreted exclusively into the lumen. However, the loss of correct topology in malignant epithelial cells allows mucins to be expressed on all aspects of the cells, and soluble mucins can then enter the extracellular space and body fluids such as the blood plasma. The simultaneous expression of both membrane-bound and secreted forms of mucins by many carcinoma cells confounds any consistent discussion of their pathophysiological roles, since the two forms of mucins could actually have opposing effects. Regardless of this issue, the secreted mucins often appear in the bloodstream of patients with cancer and can be detected by monoclonal antibodies. In many instances, mucins appear to be the major carriers of altered glycosylation in carcinomas. The rod-like structures of the mucins and their negative charge are thought to repel intercellular interactions and sterically prevent other adhesion molecules such as cadherins and integrins from carrying out their functions. Thus, in some instances, mucins may act as “anti-adhesins” that can also promote displacement of a cell from the primary tumor during the initiation of metastates. Some evidence suggests that they might also block adhesion between blood-borne carcinoma cells and the host cytolytic cells such as natural killer cells. In addition, mucins may mask expression of antigenic peptides by MHC molecules. Another abnormal feature of carcinoma mucins is incomplete glycosylation. One common consequence is the expression of Tn and T antigens. Since such structures occur infrequently under normal circumstances, it is thought that they may provoke an immune response in the patient. Indeed, there is a correlation between the expression of the T and Tn antigens, the spontaneous expression of antibodies directed against them, and the prognosis of patients with carcinomas. The most extreme form of underglycosylation results in the expression of “naked” mucin polypeptides. Clinical trials are under way to deliberately provoke or enhance these immune responses by injecting patients with synthetic peptide antigens, sometimes bearing Tn or sialyl-Tn structures. It is of note that the best immune responses to the glycosylated antigens are seen when they are presented in arrays, exactly as seen on the mucins. This is presumably because of multivalent binding of the antigen to the surface immunoglobulin of B cells, giving maximum cellular activation.(1) Altered Expression of the ABH(O) Blood-Group-related StructuresThe loss of normal AB blood group expression (accompanied by increased expression of H and Ley structures) is associated with a poorer clinical prognosis of carcinomas in several studies. The reason for this correlation remains unknown. There are also rare instances in which a tumor may present an “illegal” blood group structure. The genetic basis for such a change remains unexplained, since the “B” transferase would theoretically require four independent amino acid changes to convert it into an A transferase. Regardless of the underlying mechanism, tumor regression has been noted in a few such cases, presumably mediated by the naturally occurring endogenous antibodies directed against the illegal structure.(3) LinksC O N T E N T SGlycosylation alterations of cells in late phase apoptosis from colon carcinomasGlycobiology. 1999 Dec;9(12):1337-45. Rapoport E, Pendu JL.
References1. Varki A, Cummings, E. et al Editors, Essentials of Glycobiology, Cold Spring Harbor Laboratory Press Cold Spring Harbor, New York 2. Senitiroh Hakomori. Glycosylation defining cancer malignancy: New wine in an old bottle. PNAS, August 6, 2002, vol. 99, no. 16 10231-10233 3. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.section.2684 |
