Intramammary application of non-methylated-CpG oligodeoxynucleotides (CpG) inhibits both local and systemic mammary carcinogenesis in female BALB/c Her-2/neu transgenic mice.
CpG are powerful drugs activating the innate immune system. In this study, the ability of their intramammary administration in impeding the devastating progression of carcinogenesis in all the mammary glands of female BALB/c mice transgenic for the rat neu transforming oncogene was assessed. Starting when in situ carcinomas were scattered over all their mammary glands (week 10), mice received CpG injections in the stroma of the fourth left gland. Local neoplastic progression was inhibited by six monthly administrations. CpG not only delayed the onset of carcinomas in the injected gland, but also hampered their progression. Extended latency was observed for tumors in glands both close to and far from the injection site. When the experiment ended (week 45), no tumors were palpable in 67% of the injected glands and a markedly impaired tumor growth was evident in the others. An impressive local infiltrate of CD11b(+) cells with the morphologic features of macrophages, plasma cells, B220(+) B cells, and CD4(+) and CD8(+) T cells was quickly recruited to the CpG-treated glands. High quantities of IFN-gamma producing cells were only present in the ipsilateral axillary draining lymph nodes of the treated glands. Enhanced natural killer (NK) lytic activity was also detected in the spleens. Inhibition of progression was weaker when only four injections were given, and abolished by in vivo depletion of NK cells. CpG monotherapy is thus effective in an aggressive model of autochthonous cancer. The results strongly support the administration of CpG as a local monotherapy of multiple invasive microscopic lesions.
Mastini
Cristina
C
Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Torino, 10126 Torino, Italy.
Becker
Pablo D
PD
Iezzi
Manuela
M
Curcio
Claudia
C
Musiani
Piero
P
Forni
Guido
G
Cavallo
Federica
F
Guzmán
Carlos A
CA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage / Q000494:pharmacology*; D018450:Disease Progression; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects*; D007267:Injections; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009838:Oligodeoxyribonucleotides; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases; D013997:Time Factors
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D004247:DNA; D006023:Glycoproteins; D007371:Interferon-gamma; D009838:Oligodeoxyribonucleotides; D018719:Erb-b2 Receptor Tyrosine Kinases; C423449:CpG ODN 1826; C483804:Erbb2 protein, rat