Nature Reviews Drug Discovery 4, 477-488 (2005); doi:10.1038/nrd1751
GLYCANS IN CANCER AND INFLAMMATION — POTENTIAL FOR THERAPEUTICS AND DIAGNOSTICS
Danielle H. Dube & Carolyn R. Bertozzi about the authors
Abstract
Changes in glycosylation are often a hallmark of disease states. For example, cancer cells frequently display glycans at different levels or with fundamentally different structures than those observed on normal cells. This phenomenon was first described in the early 1970s, but the molecular details underlying such transformations were poorly understood. In the past decade advances in genomics, proteomics and mass spectrometry have enabled the association of specific glycan structures with disease states. In some cases, the functional significance of disease-associated changes in glycosylation has been revealed. This review highlights changes in glycosylation associated with cancer and chronic inflammation and new therapeutic and diagnostic strategies that are based on the underlying glycobiology.
Summary:
Glycans, which decorate all eukaryotic cell surfaces, undergo changes in structure with the onset of diseases such as cancer and inflammation. This article highlights some examples of disease-associated glycans and the possibility of exploiting these glycans for therapeutic or diagnostic strategies.
Cancer-associated changes in glycosylation include both the under- and overexpression of naturally-occurring glycans as well as neoexpression of glycans normally restricted to embryonic tissues. These structures most often arise from changes in the expression levels of glycosylating enzymes (glycosyltransferases and glycosidases) in cancerous versus healthy cells.
To dissect the roles of glycans in metastasis and tumour formation, cellular glycans have been structurally perturbed in a number of ways. The general conclusion of these studies is that certain glycans seem to play a role in cancer progression.
Given the functional link between aberrant glycosylation and malignancy, therapeutics that block the formation of cancer-associated glycans might have an effect on tumour progression. The immune system can be recruited to target cancer cells on the basis of their altered glycosylation.
Several glycan-based vaccines are presently undergoing clinical evaluation with some encouraging preliminary results.
Existing diagnostic methods used to monitor tumour-specific glycosylation require surgical biopsy followed by histological analysis with lectins or monoclonal antibodies. An interesting future direction in the field is to target aberrant glycosylation with probes for non-invasive imaging.
Specific carbohydrate epitopes, such as 6-sulpho sialyl Lewis x, initiate leukocyte homing to sites of chronic inflammation by enabling leukocyte-endothelial cell adhesion via the leukocyte receptor L-selectin and are specifically expressed at disease sites.
Drugs that block the selectins or the biosynthesis of their glycan ligands are under investigation in the pharmaceutical industry. In addition, there is an opportunity for the development of noninvasive diagnostics that might identify sites of chronic inflammation prior to the presentation of disease symptoms.