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From the Laboratory of Virology,*
Istituto Superiore di
Sanità, Rome, the Cancer Institute,
University of Bologna, Bologna, and the Human Pathology
Institute,
D'Annunzio University,
Chieti, Italy
Our group had previously shown that transfer of the mouse
interferon (IFN)-
1 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-
was
strongly impaired, whereas IFN-
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-ß gene. We have also compared the tumorigenicity of these clones
with that of TS/A cells expressing IFN-
1. BALB/c mice
were inoculated subcutaneously with parental TS/A cells,
transduction control TS/A cells, or TS/A cells producing
IFN-
or IFN-ß. 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-
, IFN-ß, or IFN-
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-ß, but not with clones
expressing low levels of the cytokine, as observed for cells
expressing IFN-
. IFN-
secretion by TS/A cells at the site of
tumor growth induced a stronger inflammatory response as compared with
IFN-ß, which appeared to be more active in the inhibition of
tumor-induced angiogenesis. Notably, the metastatic ability of
IFN-ß-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-
proved to be poorly metastatic. These findings represent the first
comparison of the effectiveness of IFN-
versus
IFN-ß 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.
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