Active immunogene therapy of cancer with vaccine on the basis of chicken homologous matrix metalloproteinase-2.
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.
Su
Jing-Mei
JM
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.
Wei
Yu-Quan
YQ
Tian
Ling
L
Zhao
Xia
X
Yang
Li
L
He
Qiu-Ming
QM
Wang
Yu
Y
Lu
You
Y
Wu
Yang
Y
Liu
Fen
F
Liu
Ji-Yan
JY
Yang
Jin-Liang
JL
Lou
Yan-Yan
YY
Hu
Bing
B
Niu
Ting
T
Wen
Yan-Jun
YJ
Xiao
Fei
F
Deng
Hong-Xin
HX
Li
Jiong
J
Kan
Bing
B
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
D001323:Autoantibodies; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D061965:Matrix Metalloproteinase Inhibitors; D019444:Vaccines, DNA; D004247:DNA; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2