Gastric cancer: adding glycosylation to the equation

•Glycosylation changes are a hallmark of cancer cells. •Glycosylation plays a key role in fundamental pathophysiological steps of GC. •Deciphering GC cell “glycans code” contributes to its molecular understanding. •Glycan biomarkers hold an opportunity for improving early cancer diagnosis and therapy. Gastric cancer has a high incidence and mortality, so there is a pressing need to understand the underlying molecular mechanisms in order to discover novel biomarkers. Glycosylation alterations are frequent during gastric carcinogenesis and cancer progression. This review describes the role of glycans from the initial steps of the carcinogenesis process, in which Helicobacter pylori adheres to host mucosa glycans and modulates the glycophenotype, as well as how glycans interfere with epithelial cell adhesion by modulating epithelial cadherin functionality in gastric cancer progression. Other mechanisms regulating gastric cancer malignant behavior are discussed, such as increased sialylation interfering with key signaling pathways and integrin glycosylation leading to an invasive phenotype. Applications of these glycosylation alterations in the clinical management of gastric cancer patients are discussed. Gastric cancer has a high incidence and mortality, so there is a pressing need to understand the underlying molecular mechanisms in order to discover novel biomarkers. Glycosylation alterations are frequent during gastric carcinogenesis and cancer progression. This review describes the role of glycans from the initial steps of the carcinogenesis process, in which Helicobacter pylori adheres to host mucosa glycans and modulates the glycophenotype, as well as how glycans interfere with epithelial cell adhesion by modulating epithelial cadherin functionality in gastric cancer progression. Other mechanisms regulating gastric cancer malignant behavior are discussed, such as increased sialylation interfering with key signaling pathways and integrin glycosylation leading to an invasive phenotype. Applications of these glycosylation alterations in the clinical management of gastric cancer patients are discussed. is a protein degradation pathway in the endoplasmic reticulum that has a central clearance function in the cell. Is a cellular pathway that targets misfolded proteins and mutant proteins for ubiquitination and subsequent degradation by a protein-degrading complex called the proteosome. an intestinal-type gastric cancer syndrome with familial aggregation. The criteria of the International Gastric Cancer Linkage Consortium for FIGC vary accordingly with countries with high incidence of FIGC or low incidence of FIGC. The germline genetic defect underlying the disease remains unknown. a post- and co-translational modification process in which carbohydrates (glycans, saccharides, or sugars) are covalently attached to proteins, lipids, or other organic molecules. It is a tightly regulated process that occurs in the endoplasmic reticulum and Golgi compartment of all eukaryotic cells. This process depends on the availability of nucleotide sugar donors and on the coordinated action of a large number of enzymes (glycosyltransferases and glycosidases). The majority of mammalian proteins synthesized in the endoplasmic reticulum undergo glycosylation. There are two main classes of protein glycosylation: N- and O-glycosylation. an inherited form of diffuse-type gastric cancer that represents a rare but incurable autosomal-dominant gastric cancer syndrome with high penetrance. It is a highly invasive type of tumor with early onset gastric cancer (diagnosed before 45 years of age). Approximately 45% of families with HDGC have germline alterations in the E-cadherin (CDH1) gene. This early gastric cancer is located beneath an intact mucosal surface, and therefore early detection is extremely difficult. Prophylactic total gastrectomy is usually advised after the age of 20 and before the age of 40. In 1999, the International Gastric Cancer Linkage Consortium (IGCLC) proposed specific criteria to define HDGC. Families with aggregation of gastric cancer and an index case with diffuse IGCLC, but not fulfilling the IGCLC criteria for HDGC, are termed familial diffuse gastric cancer (FDGC). a family of glycoproteins with a high content of serine, threonine, and proline residues, and numerous O-linked glycans. Mucins can be membrane-bound or secreted onto mucosal surfaces. Mucins are high-molecular-weight and heavily glycosylated proteins constituting an important interface between many epithelial surfaces of the body and the exterior environment. The main characteristic of mucins is their ability to form gels. this is characterized by the addition of the glycan chains to an aspargine residue of the nascent protein in a consensus sequence Asn-X-Ser/Thr, where X can be any amino acid with the exception of proline. The resulting N-glycan structures are generally classified into three principal categories: high mannose, complex, and hybrid types (see Figure 3 in main text). a stepwise process characterized by the covalent linkage of glycan chains to the hydroxyl group of a serine or threonine. The initial step of O-glycosylation is controlled by a family of GalNAc transferases that transfer an initial N-acetylgalactosamine (GalNAc) residue. No consensus sequence defines an O-linked glycosylation site. The initial GalNAc can be extended, branched and elongated by several glycosyltransferases.