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Suppression of hyaluronan synthesis attenuates the tumorigenicity of low‐grade chondrosarcoma
Author(s) -
Hamada Shunsuke,
Nishida Yoshihiro,
Zhuo Lisheng,
Shinomura Tamayuki,
Ikuta Kunihiro,
Arai Eisuke,
Koike Hiroshi,
Kimata Koji,
Ushida Takahiro,
Ishiguro Naoki
Publication year - 2018
Publication title -
journal of orthopaedic research®
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.23794
Subject(s) - chondrosarcoma , extracellular matrix , in vivo , cancer research , chemistry , cell , malignancy , in vitro , cell growth , hyaluronic acid , glycosaminoglycan , pathology , medicine , biology , biochemistry , anatomy , microbiology and biotechnology
Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Chondrosarcoma, particularly when low‐grade, is characterized by the formation of an extracellular matrix (ECM) containing abundant HA, and its drug/radiation resistance has become a clinically relevant problem. This study aimed to evaluate the effects of an HA synthesis inhibitor, 4‐methylumbelliferone (MU), on ECM formation as well as antitumor effects in chondrosarcoma. We investigated the effects of MU on rat chondrosarcoma (RCS) cells with a grade I histological malignancy in vitro and in vivo grafted model. HA binding protein (HABP) stainability on and around the RCS cells was effectively reduced with treatment of MU. ECM formation was markedly suppressed by MU at a dose of 1.0 mM. Cell proliferation was significantly reduced by MU at 24 h. Cell motility and invasion were suppressed in a dose‐dependent manner by MU. No significant changes in mRNA expression of Has1−3 were observed. Furthermore, MU inhibited the growth of grafted tumors in vivo. Histologically, chondrosarcoma cells of control tumors showed a cell‐clustering structure. HABP stainability was markedly decreased in the MU‐treated group. These results suggest that MU exhibits antitumor effects on low‐grade chondrosarcoma, via inhibition of HA accumulation and ECM formation. MU, which is an approved drug in bile therapy, could be a new off‐label medication for chondrosarcomas. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1573–1580, 2018.