ABSTRACT
Multiple genetic changes combined with selection pressure of the surrounding tissue environment are the primary features of tumor formation and progression. Gene mutations that promote growth and survival are maintained as tumors expand and evolve (Cairns, 1981). Tumor evolution or progression produces phenotypic and molecular heterogeneity in the cell population, and this can complicate the analysis of the malignant phenotypes at the level of biochemistry and cell biology (Poste & Fidler, 1980). Cancer mutations result in either lossof-function in a gene product, designated “tumor suppressor proteins” (e.g. p53, APC, WT1), or missense mutations which is gain-of function or activate of “proto-oncogenes” (e.g. H-Ras). Cancer genes have also been described as “caretaker” and “gatekeeper” genes, the latter regulate aspects of cellular proliferation, and the former control genomic integrity (reviewed in Kinzler & Vogelstein, 1997). The retinoblastoma gene Rb-1 is a gatekeeper gene, where
l, 6GlcNAc-branched N-glycans are up-regulated in oncogene transformed cells, and in human carcinomas where expression correlates with disease stage and prognosis. Forced expression of 1, 6N-acetylglucosaminyltransferaseV (GlcNAc-TV) in cell lines induces transformation and tumor formation in mice. Mgat5 gene expression is induced through Ras signaling pathways, and the branched N-glycan products are required for oncogene-dependent tumor growth and metastasis in vivo. In this regard, breast cancer growth and metastasis induced by a polyomavirus middle T transgene in mice is markedly suppress in Mgat5−/−mice compared to their Mgat5+/+ littermates. The 1, 6GlcNAc-branched N-glycans destabilise integrin receptor clustering, thereby enhancing focal adhesion turnover, associated intracellular growth signals and cell motility.
