title: Active immunogene therapy of cancer with vaccine on the basis of chicken homologous matrix metalloproteinase-2.
abstract: Matrix metalloproteinase (MMP) family, in particular MMP-2, may play a key role in angiogenesis and tumor growth. It is conceivable that the breaking of immune tolerance of MMP-2 should be a useful approach to cancer therapy by active immunity. To test this concept, we constructed a plasmid DNA encoding chicken homologous MMP-2 (c-MMP-2) and control vectors. We found that the vaccine based on chicken homologous MMP-2 as a model antigen could induce both protective and therapeutic antitumor immunity. Autoantibodies against MMP-2 in sera of mice immunized with c-MMP-2 could be found by Western blotting analysis and ELISA assay. There was the deposition of autoantibodies within the tumor. IgG1 and IgG2b were substantially increased in response to c-MMP-2 immunization. The elevation of MMP-2 in the sera of tumor-bearing mice was abrogated with the vaccination of c-MMP-2. Transmigration of human endothelial cells and tumor cells through gelatin-coated filters was inhibited with immunoglobulins isolated from mice immunized with c-MMP-2. The gelatinase activity of MMP-2, including both latent MMP-2 (M(r) 72,000) and active MMP-2 (M(r) 66,000) derived from tumor tissues, was apparently inhibited by the vaccination with c-MMP-2. The antitumor activity and the inhibition of angiogenesis were acquired by the adoptive transfer of the purified immunoglobulins. The antitumor activity and production of autoantibodies against MMP-2 could be abrogated by the depletion of CD4(+) T lymphocytes. Angiogenesis was apparently inhibited within tumor, and chick CAMs angiogenesis was also inhibited. Thus, our findings may provide a vaccine strategy for cancer therapy through the induction of an autoimmune response against MMP-2 in a cross-reaction by the immunization with the single xenogeneic homologous MMP-2 gene and may be of importance in the additional exploration of the application of other xenogeneic homologous genes identified in human and other animal genome projects in cancer therapy.
authors.affiliation: Key Laboratory of Biotherapy of Human Diseases, Ministry of Education, P. R. China and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, The People's Republic of China.
authors.forename: Jing-Mei
authors.initials: JM
authors.lastname: Su
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Qiu-Ming
authors.initials: QM
authors.lastname: He
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Fen
authors.initials: F
authors.lastname: Liu
authors.forename: Ji-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Jin-Liang
authors.initials: JL
authors.lastname: Yang
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Lou
authors.forename: Bing
authors.initials: B
authors.lastname: Hu
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Wen
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Hong-Xin
authors.initials: HX
authors.lastname: Deng
authors.forename: Jiong
authors.initials: J
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Kan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002642:Chick Embryo; D002645:Chickens; D004247:DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005354:Fibrosarcoma / Q000098:blood supply / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D016233:Immunotherapy, Active / Q000379:methods*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000628:therapy; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D001323:Autoantibodies; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D061965:Matrix Metalloproteinase Inhibitors; D019444:Vaccines, DNA; D004247:DNA; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2