Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells.
Cell surface heparan sulfate plays a critical role in regulating the metastatic behavior of tumor cells, whereas the role of chondroitin sulfate/dermatan sulfate (CS/DS) has been little understood in this context. Here, we characterized CS/DS chains from the murine osteosarcoma cell line LM8G7, which forms tumor nodules in liver. Structural analysis of the CS/DS chains showed a higher proportion of GlcUA beta 1-3GalNAc(4,6-O-disulfate) (E-units) in LM8G7 (12%) than in its parental cell line LM8 (6%), which rarely forms tumors in the liver. Immunostaining with GD3G7, an antibody specific to E-units, confirmed the higher expression of the epitope in LM8G7 than LM8 cells. The tumor focal formation of LM8G7 cells in the liver in mice was effectively inhibited by the preadministration of CS-E (rich in E-unit) or the preincubation of the antibody GD3G7 with the tumor cells. CS-E or GD3G7 inhibited the adhesion of LM8G7 cells to a laminin-coated plate in vitro. In addition, the invasive ability of LM8G7 cells in vitro was also reduced by the addition of CS-E or the antibody. Further, CS-E or the antibody inhibited the proliferation of LM8G7 cells dose dependently. The binding of LM8G7 cells to VEGF in vitro was also significantly reduced by CS-E and GD3G7. Thus, the present study reveals the significance of highly sulfated CS/DS structures in the liver colonization of osteosarcoma cells and also provides a framework for the development of GAG-based anticancer molecules.
Basappa
Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
Murugan
Sengottuvelan
S
Sugahara
Kazuki N
KN
Lee
Chun Man
CM
ten Dam
Gerdy B
GB
van Kuppevelt
Toin H
TH
Miyasaka
Masayuki
M
Yamada
Shuhei
S
Sugahara
Kazuyuki
K
D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D000078792:Midkine; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000912:Antibodies, Neoplasm; D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; C524376:antibody GD3G7, human; D016222:Fibroblast Growth Factor 2; D000078792:Midkine; D017228:Hepatocyte Growth Factor; D002809:Chondroitin Sulfates