Glycosylation effects on cancer development

Changes in glycosylation associated with oncogenic transformation were first demonstrated with glycosphingolipids over four decades ago. Certain gangliosides, GM3, GD1a and GD1b, which are highly expressed on non-transformed cells, were found to be greatly reduced upon oncogenic transformation [1, 2]. A subsequent study using a temperaturesensitive mutant of avian sarcoma virus showed close correlation between reduction of GM3 expression and appearance of transformed cell phenotypes. Further study by transfecting GM3-synthase gene into v-Jun transformed mouse and chicken fibroblast cells introduced an important concept that the oncogenic phenotype of cancer cells can be reverted to normal-like phenotype by manipulating the expression level of certain glycosphingolipids [3]. Many studies along similar lines have since been developed with various types of cells. Numerous studies have demonstrated the close association of various types of N-glycans and O-glycans with cancer development. These findings could potentially be applied to interfere with cancer progression or reversion to normal cell phenotypes. Elevated expression of Nacetylglucosaminyltransferases, such as GnT-III and GnT-V, which are involved in branching modifications of N-glycans, has been observed upon cellular transformation [4]. In addition, the truncated O-glycans known as Tn and its sialylated version Sialyl Tn antigen, are often found to be expressed by many different cancers in immunohistochemical studies, and can arise from altered expression of the enzymes involved in O-glycosylation of proteins [5]. Finally, elevated expression of Lewis-related glycans, such as Sialyl Lewis A on mucin-type glycoproteins of tumor cells has been observed, and is the basis of serum biomarker test for cancer, such as the CA-19-9 antigen [6, 7]. In this specialized volume, entitled “Glycosylation Effects on Cancer Development”, we present some of the recent progress and the development of new concepts in this important and growing area. T. Miyagi and her colleagues describe altered expression of four types of sialidases in cancer cells and focus on Neu3, which has enhanced expression in various cancer cells. Neu3 is known to specifically hydrolyze gangliosides including GM3, but not sialyl groups of other glycans, and is indicated to stimulate cell growth through interacting with growth factor receptors. In addition, the authors discuss their result that the knockdown of Neu3 expression by siRNA causes apoptosis in cancer cells, and suggest Neu3 could be a useful target for inhibition of cancer progression. K. Furukawa’s group summarizes their studies on GD3 and GD2, which are highly expressed in melanomas and small cell lung cancer cells. They found that the gangliosides enhance cell motility and invasiveness by stimulating focal adhesion kinase and Lyn kinase, which phosphorylate paxillin and p130Cas. Further studies using the reconstructed membrane system indicated GD3 and GD2 function in glycosphingolipidenriched microdomains/rafts. This line of study may eventually lead to a novel approach to block cancer metastasis. S. Sonnino and his colleagues report, for the first time, the effect of ionizing radiations on plasma membraneS.-i. Hakomori (*) Division of Biomembrane Research, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA e-mail: hakomori@u.washington.edu