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Marked Prevention of Tumor Growth and Metastasis by a Novel Immunosuppressive Agent, FTY720, in Mouse Breast Cancer Models

Department of Urology Osaka Medical College, Takatsuki, Osaka, 569-8686 [H. A., Y. K.]; Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871 [S. T., N. I., J. D. W., N. N., A. O.]; Department of Anatomy and Biology [Y. I., Y. O.], Laboratory Animal Center [J. M.], and First Department of Internal Medicine and Central Research Laboratory [R. F., M. H., T. I.], Osaka Medical College, Takatsuki, Osaka, 569-8686; and Department of Experimental Surgery and Bioengineering, National Children’s Medical Research Center, Setagaya, Tokyo, 154-8509 [S. S.] Japan

FTY720 is a unique immunosuppressive agent that exerts its activity by inducing apoptosis in lymphocytes. We conducted the present study to investigate the effects of FTY720 on cancer growth and metastasis, as well as its mechanism of action. In vitro treatment with FTY720 induced dramatic cancer cell apoptosis in a mouse breast cancer cell line, JygMC(A). Electron microscopy revealed distinct changes on the cell surface with decreased filopodias and microvilli in cancer cells treated with FTY720 at 2 µM and clear evidence of apoptosis at 10 µM. Interestingly, the effect of FTY720 was significantly less in the normal fibroblasts than in the cancer cells, indicating greater susceptibility of cancer cells to the agent. We then tested the in vivo effect of FTY720 in a mouse breast cancer model created by inoculating JygMC(A) cells (s.c.) in the flank region of BALB/c-nu/nu mice at three different dosages (2, 5, and 10 mg/kg/day; n = 30/group). Tumor growth was markedly suppressed at a dosage of 5 mg/kg or more without notable side effects. In addition, tumor metastasis, which was dramatically evident in control mice, was significantly prevented even at a low dose (2 mg/kg/day), resulting in a significant prolongation of animal survival. These data led us to additionally investigate the mechanism of action, especially the prevention of metastasis at a low dose. FTY720 treatment at 2 µM caused a remarkable cytoskeletal change with deformed and decreased filopodias in cancer cells. In addition, it significantly decreased the ability of cancer cells to adhere and migrate to extracellular matrix components, and markedly reduced the expression of integrins on the cancer cell surface. These results indicate that FTY720 is a potent anticancer agent that induces cancer cell apoptosis and is markedly effective for prevention of metastasis. The changes of cellular structure with reduction of integrin expression may be one of its underlying mechanisms of action.

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