IFN-γ withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin αvβ3 signaling
Wei Gong
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorGui-Mei Zhang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorYi Liu
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorZhang Lei
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorDong Li
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorYe Yuan
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorCorresponding Author
Bo Huang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of ChinaSearch for more papers by this authorCorresponding Author
Zuo-Hua Feng
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Fax: +86-27-83650754
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of ChinaSearch for more papers by this authorWei Gong
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorGui-Mei Zhang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorYi Liu
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorZhang Lei
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorDong Li
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorYe Yuan
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Search for more papers by this authorCorresponding Author
Bo Huang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of ChinaSearch for more papers by this authorCorresponding Author
Zuo-Hua Feng
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Fax: +86-27-83650754
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of ChinaSearch for more papers by this authorAbstract
Immunotherapy can effectively suppress tumor, yet complete tumor eradication occurs infrequently. The metastatic potential of remnant tumor cells after immunotherapy and the underlying mechanisms have not been fully elucidated. Here, we report that the termination of immunotherapy strikingly increases the metastatic potential of remnant melanoma. This is mainly due to the withdrawal of IFN-γ after immunotherapy. The relief of IFN-γ stress led to the increase of αvβ3 integrin expression in B16 cells, which increased the adhesion of B16 cells to fibrinogen, fibronectin and laminin. Through αvβ3 signaling, the activation of FAK, upregulation of cdc2, production of active MMP-2 and MMP-9 and actin polymerization were intensified in B16 cells stimulated with ECM molecules 24 h after the withdrawal of IFN-γ. The i.v. injection of such tumor cells into mice resulted in more metastatic tumor nodes in lung and shortened the survival of mice. The pitfall of immunotherapy termination can be remedied by the administration of recombinant CBD-HepII polypeptide of fibronectin, which effectively inhibits αvβ3 signaling. These findings suggest that the risk of tumor metastasis can be increased after the termination of immunotherapy, due to the withdrawal of IFN-γ and that targeting αvβ3 signaling pathway can improve the therapeutic effect of immunotherapeutic approaches by reducing such metastatic risk. © 2008 Wiley-Liss, Inc.
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