Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 49, Pages 34294-34304Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806015200
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT)
- New Energy and Industrial Technology Development Organization
- Core Research for Evolutional Science and Technology Program of the Japan Science and Technology Agency, Human Frontier Science Program [RGP62/2004, RGP18/2005]
- Dutch Cancer Society Grant [2008-4058]
- Scientific Research on Priority Areas [17046028]
- Grants-in-Aid for Scientific Research [17046028] Funding Source: KAKEN
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The altered expression of cell surface chondroitin sulfate ( CS) and dermatan sulfate (DS) in cancer cells has been demonstrated to play a key role in malignant transformation and tumor metastasis. However, the functional highly sulfated structures in CS/DS chains and their involvement in the process have not been well documented. In the present study, a structural analysis of CS/DS from two mouse Lewis lung carcinoma (3LL)-derived cell lines with different metastatic potentials revealed a higher proportion of Delta(4,5)HexUA-GalNAc(4,6-O-disulfate) generated from E-units (GlcUA-GalNAc(4,6-O-disulfate)) in highly metastatic LM66-H11 cells than in low metastatic P29 cells, although much less CS/DS is expressed by LM66-H11 than P29 cells. This key finding prompted us to study the role of CS-E-like structures in experimental lung metastasis. The metastasis of LM66-H11 cells to lungs was effectively inhibited by enzymatic removal of tumor cell surface CS or by preadministration of CS-E rich in E-units in a dose-dependent manner. In addition, immunocytochemical analysis showed that LM66-H11 rather than P29 cells expressed more strongly the CS-E epitope, which was specifically recognized by the phage display antibody GD3G7. More importantly, this antibody and a CS-E decasaccharide fraction, the minimal structure recognized by GD3G7, strongly inhibited the metastasis of LM66-H11 cells probably by modifying the proliferative and invading behavior of the metastatic tumor cells. These results suggest that the E-unit-containing epitopes are involved in the metastatic process and a potential target for the diagnosis and treatment of malignant tumors.
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