ENDOGENOUS EXPRESSION OF TRANSFORMING-GROWTH-FACTOR BETA-1 INHIBITS GROWTH AND TUMORIGENICITY AND ENHANCES FAS-MEDIATED APOPTOSIS IN A MURINE HIGH-GRADE GLIOMA MODEL

It has been hypothesized that transforming growth factor beta (TGF-bet a) may prevent immune-mediated glioma cell elimination; however, previ ous work has also indicated that increased TGF-beta may lead to reduce d proliferation, induction of apoptosis, and enhancement of Fas-induce d apoptosis, We have investigated the role of TGF-beta in the progress ion of malignant glioma using an immunocompetent murine model. SMA 560 malignant glioma cells were stably transfected with constructs that r esulted in over- or underproduction of active TGF-beta 1, Using these cell lines, we have shown that (a) TGF-beta 1 inhibits induction of an titumor 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 c ells in vitro and in vivo, SMA 560 cells are susceptible to TGF-beta 1 - and Fas-induced apoptosis in vitro, and TGF-beta 1 and Fas act syner gistically to induce glioma cell death; (c) increased levels of endoge nous TGF-beta 1 production by SMA 560 cells lead to increased sensitiv ity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-be ta 1 reduces the rate of s.c. SMA 560 tumor growth and also reduces th e tumorigenicity of tumors located in the central nervous system, with opposite effects observed with underproduction of TGF-beta 1 using an tisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-beta 1-overproducing cells. Taken together, these results indicate that, de spite decreased induction of CTL responses, the dominant net effect of TGF-beta 1 on the growth of the SMA 560 murine high-grade glioma in v ivo is growth inhibition, This contrasts with results seen with non-ce ntral nervous system malignant tumors in immunocompetent animals, in w hich TGF-beta 1 production provides a major growth advantage.