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[Cancer Research 59, 1273-1277, March 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 1273-1277, March 15, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

Tumorigenicity of Mouse Thymoma Is Suppressed by Soluble Type II Transforming Growth Factor ß Receptor Therapy1

Jonghwa Won, Hongtae Kim, Eun Jeong Park, Yeonchul Hong, Seong-Jin Kim and Yungdae Yun2

Mogam Biotechnology Research Institute, Kyonggi-Do, 449–910, Korea [J. W., H. K., E. J. P., Y. H., Y. Y.]; and Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892 [S.-J. K.]

ABSTRACT

Many types of tumor cells overexpress transforming growth factor ß (TGF-ß), which is believed to promote tumor progression. We hypothesized that overexpression of the extracellular region of the type II TGF-ß receptor (soluble TßRII) would compete for or block TGF-ß binding to TßRs on immune cells, preventing TGF-ß-mediated immunosuppression and consequently resulting in the eradication of tumor cells. We tested this in the mouse thymoma cell line EL4, which has been reported to suppress cellular immunity by secreting a large amount of TGF-ß. Transduction of EL4 with recombinant retrovirus encoding soluble TßRII resulted in the secretion of heterogeneously glycosylated, 25 to 35 kDa truncated TßRII. Inoculation of 1 x 104 to 5 x 104 soluble TßRII-modified EL4 cells (EL4/Ts, EL4 cells transduced with recombinant retrovirus encoding soluble TßRII and neomycin resistance gene) s.c. to mice showed reduced tumorigenicity, as indicated by lower overall tumor incidence (7%, 1 of 14; P < 0.001) compared with unmodified EL4 (100%, 9 of 9) or vector-modified EL4 cells (EL4/neo, EL4 cells transduced with recombinant retrovirus encoding neomycin resistance gene; 100%, 4 of 4). Administration of mitomycin C-treated EL4/Ts cells (1 x 106) after EL4 inoculation (1 x 104) reduced tumor incidence from 100% (5 of 5 in mice inoculated with mitomycin C-treated EL4/neo) to 40% (4 of 10, P < 0.05), indicating that supply of soluble TßRII could actually block TGF-ß-mediated tumorigenesis. In vitro tumor cytotoxicity assays revealed 3–5-fold higher cytotoxic activity with lymphocytes from EL4/Ts-bearing mice compared with those from EL4- or EL4/neo-bearing mice, indicating that the observed tumor rejection was mediated by restoration of the tumor-specific cellular immunity. These data suggest that expression of soluble TßRII is an effective strategy for treating highly progressive tumors secreting TGF-ß.




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Copyright © 1999 by the American Association for Cancer Research.