Abstract 4907: Knockdown of MMP-9 inhibits radiation-induced invasive phenotype, angiogenesis and tumor growth in glioma cancer stem cells.

Abstract

Abstract Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs). It is thought that tumor regrowth or recurrence originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. GSCs are also resistant to conventional chemotherapy and radiation therapy, and a low dose of ionizing radiation can induce stem cell-like properties in heterogeneous cancer cells. In the present study, an isolated glioma stem cell population exhibited a significant differential expression of MMP-9 and a low dose of irradiation enhanced MMP-9 expression levels. Transfection of GSCs with pMMP-9-Si inhibited radiation-induced MMP-9 activity and protein levels as well as cell proliferation. The sphere de-differentiating and invasive ability of GSCs were also reduced in MMP-9 knockdown cells when compared with mock and pSV controls. MMP-9 knockdown led to the induction of apoptotic cell death as determined by FACS and TUNEL analyses, and caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage. pMMP-9-Si transfection also inhibited radiation-induced angiogenesis in vitro and in vivo in GSCs. Further, pMMP-9-Si treatment inhibited pre-established glioma tumor growth in an intracranial model. In addition, GSC xenograft tissue sections from mice that were treated with MMP-9 siRNA showed reduced expression of VEGF and the angiogenic marker, CD31. Indeed, TUNEL analysis of tumor sections collected from the combination group of pMMP-9-Si and irradiation revealed more apoptotic cells. These results validate the usefulness of targeting MMP-9 and provide a novel perspective in the treatment of the cancer stem cell population with its higher resistance to radiotherapy. Citation Format: Chandramu Chetty, Shivani Ponnala, Meena Gujrati, Jasti S. Rao. Knockdown of MMP-9 inhibits radiation-induced invasive phenotype, angiogenesis and tumor growth in glioma cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4907. doi:10.1158/1538-7445.AM2013-4907