Extracellular matrix interacts with interferon alpha protein: retention and display of cytotoxicity.
We have been investigating the efficacy of an intratumoral interferon (IFN)-alpha gene transfer against solid cancers, and found that when the gene is transduced into the subcutaneous tumors, IFN-alpha concentration is markedly increased in the injected tumor but not in the serum. To explain this effective confinement of IFN-alpha to target tissues, we hypothesized that the extracellular matrix in the tumors interacts with IFN-alpha. In this study, a solid-phase-binding assay and immunoprecipitation demonstrated that the IFN-alpha binds directly to matrix proteins. Immunohistochemical staining showed a co-localization of IFN-alpha with pericellular fibronectin. In addition, matrix-bound IFN-alpha protein transduced intracellular signaling and potentiated its cytotoxic activity, suggesting that the retention of IFN-alpha protein on extracellular matrix is likely to play a role in its in vivo biological activity. The data suggest a therapeutic advantage of the intratumoral IFN-alpha gene transfer over the conventional parenteral therapy both in the safety and efficacy.
Yoshida
Kimiko
K
Section for Studies on Host-Immune Response, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Kondoh
Atsushi
A
Narumi
Kenta
K
Yoshida
Teruhiko
T
Aoki
Kazunori
K
D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D014161:Transduction, Genetic
D005353:Fibronectins; D016898:Interferon-alpha