Mesenchymal mode of migration participates in pulmonary metastasis of mouse osteosarcoma LM8
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RESEARCH PAPER
Mesenchymal mode of migration participates in pulmonary metastasis of mouse osteosarcoma LM8 Yoshihiro Yui • Kazuyuki Itoh • Kiyoko Yoshioka • Norifumi Naka • Motonobu Watanabe • Yoshimi Hiraumi • Hiroshi Matsubara • Ken-ichiro Watanabe Kazumi Sano • Tatsutoshi Nakahata • Souichi Adachi
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Received: 24 December 2009 / Accepted: 16 September 2010 / Published online: 26 September 2010 Ó Springer Science+Business Media B.V. 2010
Abstract The outcomes of osteosarcoma patients still remain poor because of intractable pulmonary metastasis. We previously established a highly metastatic osteosarcoma cell line, LM8 from Dunn mouse osteosarcoma by in vivo selection. We herein aimed to clarify the characteristic biological features related with high metastatic potential and new target molecules to suppress pulmonary metastasis of osteosarcoma, using this syngeneic spontaneous metastatic model. LM8 cells acquired fibroblastic morphology with striking filopodia on the cell surface. Immunostaining showed faint stress fiber formation and peripherally localized integrin b1, and biochemical analyses showed the activated Cdc42 and autophosphorylation of focal adhesion kinase (FAK) in LM8 cells when compared to Dunn cells.
Electronic supplementary material The online version of this article (doi:10.1007/s10585-010-9352-x) contains supplementary material, which is available to authorized users. Y. Yui M. Watanabe Y. Hiraumi H. Matsubara K. Watanabe T. Nakahata S. Adachi Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shougoin, Sakyo-ku, Kyoto, Japan Y. Yui (&) K. Itoh K. Yoshioka Department of Biology, Osaka Medical Center of Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan e-mail: [email protected]
LM8 cells had activated motility in single cell migration mode. LM8 migration was increased by a Rho-associated kinase (ROCK) inhibitor, Y-27632, while decreased by Cdc42 silencing using RNA interference system. We found that a clinically approved camptothecin analog, irinotecan suppressed the migration, Cdc42 activity, and autophosphorylation of FAK, and attenuated integrin b1 distribution selectively in LM8 cells. Daily oral administration of irinotecan significantly reduced the rate and size of pulmonary metastasis in syngeneic C3H mice. The fibroblastic morphology and activated cell migration with the dependency on Cdc42 but not Rho-ROCK signaling pathway argued that LM8 moved in mesenchymal mode of cell migration. This activated mesenchymal migration was a key component of the pulmonary metastasis of LM8 cells. The inhibition of mesenchymal migration by irinotecan, in addition to its cytotoxic effects, might be effective in preventing pulmonary metastasis of osteosarcoma. Keywords Osteosarcoma Metastasis Mesenchymal migration Cdc42 Irinotecan Abbreviations ECM Extracellular matrix 3D Three dimensions FAK Focal adhesion kinase MMP Matrix metalloproteinase ROCK Rho-associated kinase
N. Naka Muscloskeletal O
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