Local production of TGF beta1 inhibits cerebral edema, enhances TNF-alpha induced apoptosis and improves survival in a murine glioma model.
We have previously reported that local secretion of either TNF-alpha or TGF beta1 by intracerebral SMA-560 malignant glioma tumor cells can reduce or eliminate tumor growth in mice. However, the use of TNF-alpha, while improving the overall survival of tumor bearing animals, was associated with early toxic deaths due to cerebral edema. In the present study, we demonstrate that TNF-alpha induces apoptosis of the SMA 560 cell line, as does TGF beta1, and that these two cytokines act in an additive fashion to enhance apoptosis and thus, to inhibit SMA 560 cell growth in vitro. Next, we show that the production of TGF beta1 when added to TNF-alpha production by central nervous system tumors in vivo abrogates any early deaths seen due to TNF-alpha toxicity and leads to a larger percentage of animals surviving CNS tumor challenge. Finally, we demonstrate that the production of TGF beta1 by tumor cells is associated with the abolition of tumor-associated cerebral edema in both TNF-alpha and in non-TNF-alpha producing tumors. These results are important for the development of effective and less toxic therapies for brain tumors, as well as for examining the pathogenesis of tumor-related cerebral edema.
Ashley
D M
DM
Preuss Laboratory for Brain Tumor Research, Duke University Medical Center, Durham, NC 27710, USA.
Sampson
J H
JH
Archer
G E
GE
Hale
L P
LP
Bigner
D D
DD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001929:Brain Edema / Q000378:metabolism*; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005910:Glioma / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D007763:Lac Operon; D051379:Mice; D008815:Mice, Inbred Strains; D012190:Retroviridae / Q000235:genetics; D012192:Retroviridae Infections; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology
D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha