Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis.
Recent studies have revealed significant efficacy of the marine sponge glycolipid, alpha-galactosylceramide (alpha-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of alpha-GalCer to prevent tumor development had never, to our knowledge, been evaluated in mouse models of chemical- and oncogene-dependent carcinogenesis. In this study, we demonstrate that long-term administration of soluble alpha-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2/neu transgenic mice, and spontaneous sarcomas in p53-/- mice. Weekly treatment of mice with alpha-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-gamma and IL-4 concentrations. Consistent with the antimetastatic activity of alpha-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-gammaand tumor necrosis factor-related apoptosis-inducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1+alphabetaTCR+ cell-based immune therapy can inhibit primary tumorigenesis.
Hayakawa
Yoshihiro
Y
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne 8006, Australia.
Rovero
Stefania
S
Forni
Guido
G
Smyth
Mark J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005354:Fibrosarcoma / Q000378:metabolism; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000494:pharmacology*; D016158:Genes, p53; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008024:Ligands; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000970:Antineoplastic Agents; D005699:Galactosylceramides; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D008024:Ligands; D008748:Methylcholanthrene; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C103873:KRN 7000