Abstract Date: 4/8/2014
Loyola Veronique Gressot, MD
Tiffany Doucette, PhD
Yuhui Yang, MS
Gregory Fuller, MD, PhD
Khatri Latha, PhD
Ganesh Rao, MD (Houston, TX)
STAT5b expression induces anti-apoptotic signaling pathways that mediate tumor cell proliferation and invasion in cancer. We hypothesized that overexpression of STAT5b contributes to the transition of gliomas from low- to high-grade; a progression that is poorly understood.
We analyzed the TCGA data set to determine expression patterns of STAT5b in glioma subtypes. We modeled STAT5b expression in vivo and assessed tumor latency, grade, and apoptotic and mitotic indices.
We found that STAT5b expression correlates with the Proneural(PN) relative to Mesenchymal and Neural subtypes of GBM(p<0.05). Therefore, we modeled STAT5b expression in a PDGFB-dependent PN model of glioma. In mice co-expressing PDGFB + STAT5b, 33/34(97%) formed tumors whereas 28/29(96%) tumor expressing PDGFB alone formed tumors. However, the cohort coexpressing STAT5b and PDGFB developed 8(24.2%) low-grade and 25(75.8%) high-grade tumors while the PDGFB alone cohort developed 21(75%) low grade and 7(25%) high-grade tumors(p=<0.0001; 95% CI: 2.91-30.17; OR: 9.38). Mice co-expressing STAT5b and PDGFB had a shorter survival time(p=0.0011;95% CI:1.66-4.57; HR:1.97). Tumors from the STAT5b+PDGFB injection set had a significantly lower rate of apoptosis (as quantified by CC3 staining) than tumors induced by PDGFB alone(p=0.0001). The mitotic index (based on pHH3) was similar between injection sets(p=0.2). Ectopic expression of STAT5b alone was insufficient to induce tumors.
We show that STAT5b expression is more prominent in the PN subtype. We also show that STAT5b promotes the malignant progression of gliomas from low- to high-grade tumors in vivo. For the PN subtype of GBM, STAT5b may be a relevant therapeutic target.
Article ID: AA-28625