Endogenous expression of transforming growth factor β1 inhibits growth and tumorigenicity and enhances fas-mediated apoptosis in a murine high- grade glioma model

Abstract

It has been hypothesized that transforming growth factor β (TGF-β) may prevent immune-mediated glioma cell elimination; however, previous work has also indicated that increased TGF-β may lead to reduced proliferation, induction of apoptosis, and enhancement of Fas-induced apoptosis. We have investigated the role of TGF-β 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-β1. Using these cell lines, we have shown that (a) TGF-β1 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- β1- and Fas-induced apoptosis in vitro, and TGF-β1 and Fas act synergistically to induce glioma cell death; (c) increased levels of endogenous TGF-β1 production by SMA 560 cells lead to increased sensitivity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-β1 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 under-production of TGF-β1 using antisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-β1-overproducing cells. Taken together, these results indicate that, despite decreased induction of CTL responses, the dominant net effect of TGF-β1 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-β1 production provides a major growth advantage.