title: Receptor for advanced glycation end products (RAGE) functions as receptor for specific sulfated glycosaminoglycans, and anti-RAGE antibody or sulfated glycosaminoglycans delivered in vivo inhibit pulmonary metastasis of tumor cells.
abstract: Altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) at the surfaces of tumor cells plays a key role in malignant transformation and tumor metastasis. Previously we demonstrated that a Lewis lung carcinoma (LLC)-derived tumor cell line with high metastatic potential had a higher proportion of E-disaccharide units, GlcUA-GalNAc(4,6-O-disulfate), in CS chains than low metastatic LLC cells and that such CS chains are involved in the metastatic process. The metastasis was markedly inhibited by the pre-administration of CS-E from squid cartilage rich in E units or by preincubation with a phage display antibody specific for CS-E. However, the molecular mechanism of the inhibition remains to be investigated. In this study the receptor molecule for CS chains containing E-disaccharides expressed on LLC cells was revealed to be receptor for advanced glycation end products (RAGE), which is a member of the immunoglobulin superfamily predominantly expressed in the lung. Interestingly, RAGE bound strongly to not only E-disaccharide, but also HS-expressing LLC cells. Furthermore, the colonization of the lungs by LLC cells was effectively inhibited by the blocking of CS or HS chains at the tumor cell surface with an anti-RAGE antibody through intravenous injections in a dose-dependent manner. These results provide the clear evidence that RAGE is at least one of the critical receptors for CS and HS chains expressed at the tumor cell surface and involved in experimental lung metastasis and that CS/HS and RAGE are potential molecular targets in the treatment of pulmonary metastasis.
authors.affiliation: Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049832:Decapodiformes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006025:Glycosaminoglycans / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D006025:Glycosaminoglycans; D009363:Neoplasm Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic