Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion

Sampson, John H., Ashley, David M., Archer, Gary E., Fuchs, Herbert E., Dranoff, Glenn, Hale, Laura P. and Bigner, Darell D. 1997, Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion, Neurosurgery, vol. 41, no. 6, pp. 1365-1372, doi: 10.1097/00006123-199712000-00024.

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Title Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion
Author(s) Sampson, John H.
Ashley, David M.
Archer, Gary E.
Fuchs, Herbert E.
Dranoff, Glenn
Hale, Laura P.
Bigner, Darell D.
Journal name Neurosurgery
Volume number 41
Issue number 6
Start page 1365
End page 1372
Total pages 8
Publisher Oxford University Press
Place of publication Oxford, Eng.
Publication date 1997-12
ISSN 0148-396X
Keyword(s) Animals
Astrocytoma
Brain Neoplasms
Carcinogenicity Tests
Cytokines
Female
Genetic Vectors
Histocompatibility Antigens Class I
Immunohistochemistry
Mice
Mice, Inbred Strains
Retroviridae
Transfection
Transforming Growth Factor beta
Tumor Cells, Cultured
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Surgery
Neurosciences & Neurology
animal models
astrocytomas
central nervous system neoplasms
gliomas
VM/Dk mice
TRANSFORMING GROWTH-FACTOR
CENTRAL-NERVOUS-SYSTEM
FACTOR-BETA
BRAIN-TUMORS
MONOCLONAL-ANTIBODIES
GLIOBLASTOMA CELLS
MALIGNANT GLIOMAS
INTERFERON-GAMMA
GENE-THERAPY
EXPRESSION
Summary OBJECTIVE: The promise of immunotherapies developed against brain tumors in animal models has not been realized in human clinical trials. This may be because of the routine use of rodent tumors artificially induced by chemicals or viruses that do not accurately portray the intrinsic qualities of spontaneously arising human tumors and that often fail to incorporate the role of immunosuppressants, such as transforming growth factor-beta, that are secreted by human gliomas. From an astrocytoma that arose spontaneously in inbred VM/Dk mice, we have characterized a highly tumorigenic spontaneous murine astrocytoma cell line (SMA-560) that retains features of glial differentiation and naturally produces high levels of biologically active transforming growth factor-beta. We have used this model to determine whether cytokine production by tumor cells will inhibit intracerebral astrocytoma growth. METHODS: Packaging cell lines producing replication-incompetent retroviral vectors were used to transfect the SMA-560 cell line in vitro with the genes encoding the murine cytokines interleukin (IL)-2, IL-3, IL-4, IL-6, tumor necrosis factor-alpha, gamma-interferon, or granulocyte-macrophage colony-stimulating factor or the costimulatory molecule B7.1 (CD80). RESULTS: Mice challenged intracerebrally with 5000 untransfected SMA-560 cells all succumbed to tumor within 30 days, with a median survival of 25 days. In contrast, mice challenged with SMA-560 cells producing IL-2, IL-4, or tumor necrosis factor-alpha each had a more than 400% increase in median survival (P < 0.0001). In these groups, 78.3% (18 of 23 mice), 66.7% (10 of 15 mice), and 60% (6 of 10 mice) of the mice, respectively, remained alive without evidence of tumor for longer than 100 days after the initial tumor challenge. All other cytokines tested and the expression of B7.1 failed to result in an increase in median survival. CONCLUSION: Using a spontaneous astrocytoma model in an inbred mouse strain, we have shown that cytokine production by glial tumors can abrogate their tumorigenicity in vivo despite production of transforming growth factor-beta. These results predict that approaches directed at cytokine production within intracerebral astrocytomas may be efficacious in human trials and that the "immunological privilege" of the brain may not be absolute under such conditions.
Language eng
DOI 10.1097/00006123-199712000-00024
Field of Research 1103 Clinical Sciences
1109 Neurosciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©1997, Oxford University Press
Persistent URL http://hdl.handle.net/10536/DRO/DU:30070913

Document type: Journal Article
Collection: School of Medicine
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