Suppression of tumorigenicity and metastasis in murine UV-2237 fibrosarcoma cells by infection with a retroviral vector harboring the interferon-beta gene.
In this study, we endeavored to determine the effectiveness of interferon beta (IFNbeta) gene therapy against highly metastatic murine UV-2237m fibrosarcoma cells. UV-2237m cells were engineered to produce murine IFNbeta constitutively following infection by a retroviral vector harboring the murine IFNbeta gene. Parental (UV-2237m-P), control-vector-transduced (UV-2237m-Neo), and IFNbeta-transduced (UV-2237m-IFNbeta) cells were injected subcutaneously (s.c.) or intravenously (i.v.) into syngeneic mice. Parental and control-transduced cells produced rapidly growing tumors, whereas IFNbeta-transduced cells did not. The tumorigenicity of IFNbeta-sensitive or -resistant parental cells was significantly suppressed when they were injected s.c. together with IFNbeta-transduced cells. The IFNbeta-transduced cells did not inhibit growth of parental cells injected s.c. at a distant site. UV-2237m-IFNbeta cells produced s.c. tumors in nude, SCID/Beige, and natural killer(NK)-cell-compromised syngeneic mice. The IFNbeta-transduced cells were more sensitive to in vitro splenic cell-mediated lysis than were the parental or control-transduced cells. Pretreatment of C3H/HeN mice with the NK-cell-selective antiserum (anti-asialoGM1) partially abrogated the cytotoxic activity of the cells. Cytotoxic activity was not observed in mixed culture of UV-2237m-IFNbeta cells and splenic cells from SCID/Beige mice. Significant cytotoxicity against UV-2237m-IFNbeta cells was mediated by macrophages activated by either IFNgamma, lipopolysaccharide, or a combination of both. Our data led us to conclude that the constitutive expression of IFNbeta can suppress tumorigenicity and metastasis of UV-2237m cells, which is due, in part, to activation of host effector cells.
Dong
Z
Z
Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. zdong@notes.mdacc.tmc.edu
Juang
S H
SH
Kumar
R
R
Eue
I
I
Xie
K
K
Bielenberg
D
D
Lu
W
W
Bucana
C
C
Yang
X
X
Fidler
I J
IJ
D000818:Animals; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000494:pharmacology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000473:pathology; D012190:Retroviridae / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D016899:Interferon-beta