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.