期刊
ONCOGENE
卷 29, 期 30, 页码 4276-4286出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.176
关键词
angiogenesis; DNA vaccination; breast cancer; Delta-like ligand 4; endothelial tip cell
资金
- Swedish Cancer Society
- Swedish Research Council
- Karolinska Institutet Cancer network
- Ake Wiberg's foundation
- Jeansson's foundation
- Swedish National Board of Health and Welfare
- Alex and Eva Wallstrom foundation
- Magn. Bergvall foundation
- Karolinska Institute Research foundations
The Notch ligand delta-like ligand 4 (DLL4) is an essential component expressed by endothelial tip cells during angiogenic sprouting. We have described a conceptually novel therapeutic strategy for targeting tumor angiogenesis and endothelial tip cells based on DNA vaccination against DLL4. Immunization with DLL4-encoding plasmid DNA by in vivo electroporation severely retarded the growth of orthotopically implanted mammary carcinomas in mice by induction of a nonproductive angiogenic response. Mechanistically, vaccination brought about a break in tolerance against the self-antigen, DLL4, as evidenced by the production of inhibitory and inherently therapeutic antibodies against mouse DLL4. Importantly, no evidence for a delayed wound healing response, or for toxicity associated with pharmacological blockade of DLL4 signaling, was noted in mice immunized with the DLL4 vaccine. We have thus developed a well-tolerated DNA vaccination strategy targeting the endothelial tip cells and the antigen DLL4 with proven therapeutic efficacy in mouse models of mammary carcinoma; a disease that has been reported to dramatically induce the expression of DLL4. Conceivably, induction of immunity toward principal mediators of pathological angiogenesis could provide protection against recurrent malignant disease in the adjuvant setting. Oncogene (2010) 29, 4276-4286; doi: 10.1038/onc.2010.176; published online 24 May 2010
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