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.
Highlights
A molecular mechanism of pulmonary metastasis through chondroitin sulfate remains unclear
Identification of chondroitin sulfate (CS)-E-binding Protein—To isolate the CS-Ebinding protein involved in the tumor metastasis, a CS-E-immobilized gel was prepared and mixed with a tissue extract prepared from adult mouse lungs
In this study one of the receptors for E-disaccharide-containing CS and heparan sulfate (HS) chains expressed at the surface of tumor cells with high metastatic potential was identified as Receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily of cell surface receptors that is predominantly expressed in the lung
Summary
A molecular mechanism of pulmonary metastasis through chondroitin sulfate remains unclear. 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. Glycosaminoglycan Binding to RAGE in Lung Metastasis display antibody was increased in ovarian and pancreatic cancers, resulting in alterations in tumor growth and tumor cell motility through regulation of the signaling of the vascular endothelial growth factor and the cleavage of CD44, respectively (14, 15). The molecular mechanism underlying the inhibition of the metastatic process remains obscure In view of these observations, it was hypothesized that some specific receptor(s) that interacts with CS chains with E units expressed at the surface of tumor cells exists in the vascular endothelial cells of mouse lung. RAGE strongly bound to CS-E and to HS in vitro and to cell surface CS chains containing E units and HS with presumably unique structural motifs expressed by LLC cells, suggesting that GAGs at the cell surface play crucial roles in the lung metastasis of LLC cells and that at least one of the potential receptors for such metastasis-mediating GAG chains is RAGE
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