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Endogenous Expression of Transforming Growth Factor ß1 Inhibits Growth and Tumorigenicity and Enhances Fas-mediated Apoptosis in a Murine High-Grade Glioma Model¹

Preuss Laboratory for Brain Tumor Research [D. M. A., D. D. B.], Laboratory of Molecular Immunopathology [D. M. A., L. P. H.], and Department of Radiation Oncology [F. M. K.], Duke University Medical Center, Durham, North Carolina 27710

It has been hypothesized that transforming growth factor ß (TGF-ß) may prevent immune-mediated glioma cell elimination; however, previous work has also indicated that increased TGF-ß may lead to reduced proliferation, induction of apoptosis, and enhancement of Fas-induced apoptosis. We have investigated the role of TGF-ß in the progression of malignant glioma using an immunocompetent murine model. SMA 560 malignant glioma cells were stably transfected with constructs that resulted in over- or underproduction of active TGF-ß1. Using these cell lines, we have shown that (a) TGF-ß1 inhibits induction of antitumor cytotoxicity when the tumor cells are given s.c. but not when they are given intracranially; (b) Fas/APO-1 is expressed on SMA 560 cells in vitro and in vivo, SMA 560 cells are susceptible to TGF-ß1- and Fas-induced apoptosis in vitro, and TGF-ß1 and Fas act synergistically to induce glioma cell death; (c) increased levels of endogenous TGF-ß1 production by SMA 560 cells lead to increased sensitivity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-ß1 reduces the rate of s.c. SMA 560 tumor growth and also reduces the tumorigenicity of tumors located in the central nervous system, with opposite effects observed with underproduction of TGF-ß1 using antisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-ß1-overproducing cells. Taken together, these results indicate that, despite decreased induction of CTL responses, the dominant net effect of TGF-ß1 on the growth of the SMA 560 murine high-grade glioma in vivo is growth inhibition. This contrasts with results seen with non-central nervous system malignant tumors in immunocompetent animals, in which TGF-ß1 production provides a major growth advantage.

¹ This work was supported by NIH Grants CA61227 (to L. P. H.) and CA11898 and NS 20023 (both to D. D. B.), the Pediatric Brain Tumor Foundation (to D. D. B.), and a Children's Miracle Network grant (to D. M. A.). D. M. A. is the recipient of an Australian National Health & Medical Research Council Neil Hamilton Fairley Fellowship.

² To whom requests for reprints should be addressed. Phone: (919) 684-5018; Fax: (919) 684-5231.

Received 5/ 5/97. Accepted 11/12/97.

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