GDF-15 contributes to proliferation and immune escape of malignant gliomas.
OBJECTIVE
Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-beta family. GDF-15 is necessary for the maintenance of pregnancy but has also been linked to other physiologic and pathologic conditions.


METHODS
The expression of GDF-15 in glioma cell lines was assessed by quantitative reverse transcriptase-PCR and immunoblot. GDF-15 levels in situ and in the peripheral blood of glioma patients were examined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The effects of short hairpin RNA-mediated GDF-15 inhibition on proliferation and immunogenicity of SMA-560 glioma cells were investigated by [methyl-(3)H]thymidine incorporation and immune-mediated target cell lysis. The impact of GDF-15 on glioma growth in vivo was assessed in syngeneic mice.


RESULTS
GDF-15 is expressed by gliomas of different WHO grades as assessed by immunohistochemistry. The high expression of GDF-15 in tumor tissue translates into elevated GDF-15 serum levels in glioblastoma patients compared with healthy controls. GDF-15 mRNA and protein are also detectable in human and mouse glioma cells in vitro. Silencing of GDF-15 by RNA interference reduces the proliferation of malignant glioma cells. Immunologically, the depletion of glioma-derived GDF-15 enhances the susceptibility of mouse glioma cells towards syngeneic natural killer cells and splenocytes. This results in a reduced in vivo tumorigenicity and increased T-cell infiltration of GDF-15-deficient glioma cells in syngeneic mice.


CONCLUSIONS
Although previous studies focusing on ectopic overexpression of GDF-15 have proposed unclear or antitumorigenic effects of GDF-15 in glioma cells, we here show that GDF-15 at endogenous levels contributes to proliferation and immune escape of malignant gliomas in an immunocompetent host.
Roth
Patrick
P
Laboratory of Molecular Neurooncology, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, Zurich, Switzerland. patrick.roth@usz.ch
Junker
Markus
M
Tritschler
Isabel
I
Mittelbronn
Michel
M
Dombrowski
Yvonne
Y
Breit
Samuel N
SN
Tabatabai
Ghazaleh
G
Wick
Wolfgang
W
Weller
Michael
M
Wischhusen
Jörg
J
D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology
D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering