Journal
FEBS JOURNAL
Volume 280, Issue 10, Pages 2462-2470Publisher
WILEY-BLACKWELL
DOI: 10.1111/febs.12156
Keywords
chondroitin sulfate; dermatan sulfate; GalNAc-4-sulfate-6-O-sulfotransferase; heparan sulfate; Lewis lung carcinoma; proteoglycan; receptor for advanced glycation end-products; tumor metastasis
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Funding
- Japan Society for the Promotion of Science, Japan (JSPS) [23390016, 23790066]
- Matching Program for Innovations in Future Drug Discovery and Medical Care from The Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)
- Akiyama Life Science Foundation
- Grants-in-Aid for Scientific Research [23390016, 25860037, 23790066, 25670018] Funding Source: KAKEN
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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 acidGalNAc(4,6-O-disulfate), in CS chains than LLC cells with low metastatic potential, suggesting that Eunits 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 Eunits. RAGE strongly interacted with not only CS-E but also heparan sulfate invitro. 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 Eunits 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.
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