Abstract 1385: TGF beta regulates tumor resistance to antiangiogenic therapy through POSTN in glioma stem cell models

Abstract

Abstract Periostin (osteoblast-specific factor 2, POSTN) is a 90-kDa ECM (extracellular matrix) protein containing an amino-terminal EMI, tandem repeat of four fascilin-domains and carboxyl-terminal domain including a heparin-binding site. Stromal POSTN plays a key role in regulating cancer stem cell (CSC) maintenance and expansion during metastatic colonization. Recently, it has been reported that POSTN functions as a progression associated and prognostic biomarker in glioma via inducing an invasive and proliferative phenotype. POSTN mRNA expression was significantly higher in grade IV gliomas than in grade II and grade III tumors. POSTN interacts with several integrin receptors such as αvβ1 and αvβ3 to regulate cellular response including cell proliferation, EMT (epithelial-mesenchymal transition) and cell migration. We demonstrated in previous studies that bevacizumab (Bevacizumab, Roche/Genentech) increased glioblastoma invasion in vivo. In the present study, we investigated the role of POSTN and its receptor in tumor invasion and resistance to antiangiogenic therapy. POSTN expression after treatment with avastin in vivo was increased as measured by Western blot and immunofluorescence. Stable knockdown of POSTN expression using specific shRNA abrogated expression of EMT (CAMK2N1, COL1A2, KRT14, COL3A1 and MMP-9) and angiogenesis-related (ANGPTL4, VEGFA, CXCL5, HPSE and EFNA3) genes compared to controls. VEGF expression was decreased in POSTN shRNA, and POSTN shRNA infected cells decreased invasion in both GSC11 and GSC272 glioma stem cell lines. TGF beta1 increased secretion of POSTN and phosphorylation of smad3 through a decrease in POSTN binding to smad3. Moreover, recombinant POSTN increased glioma cell invasion in an intergrin β1 receptor-dependent fashion. In animal experiments, median survival of animals implanted with GSC272-control cells was 63 days, while GSC272-bevacizumab was 84.5 days and knock down of POSTN was 84 days (p<0.05). Treatment with bevacizumab increased survival of POSTN shPOSTN tumors to 114.5 days compare to control (p<0.01). Tumor volume was decreased in the bevacizumab treatment (1.35 mm3) and POSTN shRNA (0.05 mm3) groups compared to controls (7.04 mm3). However, no tumor was observed in mice treated with both POSTN shRNA and bevacizumab. Bevacizumab increased TGF beta expression in GSC272 tumor tissue whereas tumors from POSTN shRNA mice treated with bevacizumab did not show evidence of TGF beta expression. Collectively, our data suggests that TGF beta increases POSTN secretion which appears to play an important role in glioma invasion and resistance to antiangiogenic therapy. Citation Format: Soon Young Park, Yuji Piao, Ningyi Tiao, Verlene Henry, Jianwen Dong, John Frederick de Groot. TGF beta regulates tumor resistance to antiangiogenic therapy through POSTN in glioma stem cell models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1385. doi:10.1158/1538-7445.AM2015-1385