Interferon (IFN)-beta gene transfer into TS/A adenocarcinoma cells and comparison with IFN-alpha: differential effects on tumorigenicity and host response.
Our group had previously shown that transfer of the mouse interferon (IFN)-alpha1 gene into the metastasizing TS/A mammary adenocarcinoma resulted in T-cell-mediated tumor rejection and development of antitumor immunity. Moreover, we had shown that the metastatic ability of TS/A tumor cells producing IFN-alpha was strongly impaired, whereas IFN-gamma expression did not influence or augmented metastasis formation by TS/A cells. In this study, we have analyzed the in vitro and in vivo behavior of various TS/A tumor cell clones isolated after the transduction with a recombinant retroviral vector carrying the mouse IFN-beta gene. We have also compared the tumorigenicity of these clones with that of TS/A cells expressing IFN-alpha1. BALB/c mice were inoculated subcutaneously with parental TS/A cells, transduction control TS/A cells, or TS/A cells producing IFN-alpha or IFN-beta. Tumor growth was evaluated by the measurement of tumor masses and analysis of survival. The features of tumor growth and rejection were examined by histological and immunohistochemical analyses. The metastatic ability of parental TS/A cells, transduction control TS/A cells, or TS/A cells producing IFN-alpha, IFN-beta, or IFN-gamma was evaluated after intravenous injection of the tumor cells into BALB/c mice by counting of the lung metastatic nodules and analysis of survival. A strong inhibition of tumorigenicity and development of tumor immunity were observed upon subcutaneous injection of syngeneic mice with TS/A tumor cells producing high amounts of IFN-beta, but not with clones expressing low levels of the cytokine, as observed for cells expressing IFN-alpha. IFN-alpha secretion by TS/A cells at the site of tumor growth induced a stronger inflammatory response as compared with IFN-beta, which appeared to be more active in the inhibition of tumor-induced angiogenesis. Notably, the metastatic ability of IFN-beta-producing TS/A cells after intravenous injection was either not affected or only slightly impaired as compared with parental TS/A tumor cells. In contrast, even cells producing low levels of IFN-alpha proved to be poorly metastatic. These findings represent the first comparison of the effectiveness of IFN-alpha versus IFN-beta produced by genetically modified cells on their tumorigenic behavior and suggest the existence of some notable differences in the capabilities of these two cytokines to induce a host antitumor reactivity in mice.
Rozera
C
C
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Carlei
D
D
Lollini
P L
PL
De Giovanni
C
C
Musiani
P
P
Di Carlo
E
E
Belardelli
F
F
Ferrantini
M
M
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D000818:Animals; D015197:Carcinogenicity Tests; D002469:Cell Separation; D002999:Clone Cells; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000401:mortality; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D016899:Interferon-beta