Glycosaminoglycans are functional ligands for receptor for advanced glycation end‐products in tumors

• Published in: The FEBS journal 2013-05, Vol.280 (10), p.2462-2470
• Main Authors: Mizumoto, Shuji, Sugahara, Kazuyuki
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - metabolism; Antineoplastic Agents - pharmacology; Biochemistry; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; chondroitin sulfate; Chondroitin Sulfates - metabolism; Chondroitin Sulfates - pharmacology; dermatan sulfate; Dermatan Sulfate - metabolism; GalNAc‐4‐sulfate‐6‐O‐sulfotransferase; Glucuronic Acid - metabolism; heparan sulfate; Humans; Lewis lung carcinoma; Ligands; Lung - metabolism; Lung - pathology; Lung cancer; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Metastasis; Mice; Neoplasm Metastasis - pathology; Neoplasm Metastasis - prevention & control; Pathogenesis; Protein Interaction Mapping; proteoglycan; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; tumor metastasis
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.12156

Glycosaminoglycans, including chondroitin sulfate (CS), dermatan sulfate, and heparan sulfate, attached to proteoglycans at the surface of tumor cells play key roles in malignant transformation and metastasis. A Lewis lung carcinoma (LLC)‐derived tumor cell line with high metastatic potential shows a higher proportion of E disaccharide units, d‐glucuronic acid–GalNAc(4,6‐O‐disulfate), in CS chains than LLC cells with low metastatic potential, suggesting that E units in the CS chains contribute to the metastatic potential. In fact, the metastasis of LLC to mouse lungs is drastically inhibited by preadministration of CS‐E or a phage display antibody specific for CS‐E. However, the molecular mechanism underlying the pulmonary metastasis involving CS chains remained to be elucidated. Recently, receptor for advanced glycation end‐products (RAGE), which is predominantly expressed in the lung, was identified as a functional receptor for CS chains containing E units. RAGE strongly interacted with not only CS‐E but also heparan sulfate in vitro. The interaction with CS‐E required a decasaccharide length and a cluster of basic amino acids. Intriguingly, antibody against RAGE robustly inhibited the pulmonary metastasis of not only LLC but also B16 melanoma cells, which also colonize mouse lungs after injection into a tail vein. Thus, CS chains containing E units are involved in the metastatic process, and RAGE is a critical receptor for glycosaminoglycan chains expressed at the tumor cell surface. Hence, RAGE and glycosaminoglycans are potential targets of drugs for pulmonary metastasis and a number of other pathological conditions involving RAGE in the pathogenetic mechanism. Glycosaminoglycans attached to proteoglycans at the surface of tumor cells play key roles in malignant transformation and metastasis. Receptor for advanced glycation end‐products (RAGE) expressed in lung was identified as a functional receptor for glycosaminoglycans expressed at the tumor cell surface. Hence, RAGE and glycosaminoglycans are potential targets of drug discovery for pulmonary metastasis.