Angiogenin promotes glioblastoma invasive growth through FOSL2-mediated upregulation of CD24 and MMP9.
Glioblastoma (GBM) is the most aggressive brain tumor and patients suffer from
neurological debilitation and die from rapid disease progression due to the lack of
effective therapeutics. The current treatment includes surgery, radiation, and
chemotherapy. More recently, anti-angiogenic therapy with bevacizumab, a humanized
anti-VEGF antibody, has been added and shown to improve ... read moreneurological conditions.
However, bevacizumab fails to extend overall patient survival, and results in a more
invasive recurrent disease characterized by a robust perivascular invasion phenotype.
Angiogenin (ANG) is significantly upregulated in higher-grade gliomas, and is one of the
two most upregulated genes in bevacizumab-resistant GBM. ANG expression is inversely
correlated with GBM patient survival, particularly in the proneural subtype. However,
the mechanism by which ANG contributes to GBM progression is unknown. I therefore
established a PDGF-induced proneural GBM model under the ANG null background and
investigated the function and mechanism of ANG in GBM tumorigenesis and progression. I
showed that ANG deficiency is not sufficient to prevent PDGFB-induced mouse proneural
GBM in the Ink4a/Arf null background. However, lack of ANG expression significantly
extends animal survival as a result of decreased cancer cell proliferation, reduced
extracellular matrix remodeling, and less perivascular tumor invasion. I found that ANG
activates MMP-9 expression and consequently increases extracellular matrix remodeling
and GBM invasion, which likely contributes to perivascular invasion in vivo. I also
showed that ANG upregulates CD24 that mediates the interaction of GBM cells with
endothelial cells thereby promoting perivascular invasion.Mechanistically, I found that
ANG induces MMP-9 and CD24 expression through upregulation of FOSL2, a member of the Fos
family proteins and a transcription factor for both CD24 and MMP-9. I found that ANG
activates FOSL2 both transcriptionally through binding to its promoter region and
post-translationally by stimulating its nuclear localization via the ERK pathway.
Moreover, I found that expressions of FOSL2, MMP- 9, and CD24 are significantly
correlated with ANG expression in GBM patients. Lastly, I showed that neomycin, an ANG
inhibitor, significantly increased survival of GBM mice, accompanied with reduced
expression of Mmp-9 and Fosl2, decreased extracellular matrix remodeling, and diminished
perivascular invasion, resembling the phenotype observed in ANG knockout tumors. In
summary, I present two key findings: 1) ANG promotes perivascular invasion of GBM
through the FOSL2-CD24/MMP-9 pathway; 2) ANG inhibition effectively reduces perivascular
invasion and extends survival of mice in a proneural GBM model. This thesis has revealed
an unexpected role of ANG, an angiogenic protein, in regulating perivascular invasion of
GBM. More importantly, these findings suggest a novel strategy for GBM therapy based on
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Guo-fu Hu.
Committee: Brent Cochran, Philip Hinds, Philip Tsichlis, Gary Sahagian, and Paul Anderson.
Keywords: Biology, Molecular biology, and Oncology.read less