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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 302-309 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 58 |
| Issue number | 2 |
| State | Published - Jan 15 1998 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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Endogenous expression of transforming growth factor β1 inhibits growth and tumorigenicity and enhances fas-mediated apoptosis in a murine high- grade glioma model. / Ashley, David M.; Kong, Feng M.; Bigner, Darell D.; Hale, Laura P.
In: Cancer Research, Vol. 58, No. 2, 15.01.1998, p. 302-309.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endogenous expression of transforming growth factor β1 inhibits growth and tumorigenicity and enhances fas-mediated apoptosis in a murine high- grade glioma model
AU - Ashley, David M.
AU - Kong, Feng M.
AU - Bigner, Darell D.
AU - Hale, Laura P.
PY - 1998/1/15
Y1 - 1998/1/15
N2 - 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.
AB - 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.
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M3 - Article
C2 - 9443409
AN - SCOPUS:0031964370
VL - 58
SP - 302
EP - 309
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 2
ER -