Tumor-Associated Glycans and Their Functional Roles in the Multistep Process of Human Cancer Progression

Abstract

Cancer develops through a multistep process of carcinogenesis. This process accompanies incremental alterations of expression of biologically functional glycans on the surface of cancer cells. A variety of glycans are expressed in nonmalignant epithelial cells, including several normal glycans serving as ligands for siglecs, the immunosuppressive molecules carried by interstitial immune cells. These normal glycans decrease or disappear and are replaced by cancer-associated glycans at the early stages of carcinogenesis. This glycan transition facilitates production by mucosal immune cells of inflammatory mediators that are known to promote cancer progression. Expression of glycans that regulate growth factor receptor functions is also affected at the early stages of cancers. The major mechanism involved in glycan alteration at the early stages is epigenetic silencing through DNA methylation and/or histone deacetylation/methylation of genes responsible for synthesis of normal glycans, leading to their incomplete synthesis. In the locally advanced stages, multiple glycan-related genes are induced transcriptionally and posttranscriptionally by tumor hypoxia and epithelio-mesenchymal transition, thus further culminating in abnormal expression of cancer-associated glycans. Some such glycans serve as specific ligands for selectins, the cell adhesion molecules carried by vascular endothelial cells, and facilitate tumor vascularization and ultimately hematogenous metastasis. Advanced cancer cells which have undergone epithelio-mesenchymal transition share biological characteristics with so-called cancer stem cells, and glycans associated with such cells are currently known to be frequently expressed in human embryonic stem cells as well.