STEM-18. HYPOXIA-REGULATED EXPRESSION OF CD44 AND OSTEOPONTIN CAN CHANGE THE PHENOTYPE OF GLIOMA STEM-LIKE CELLS FROM HIGHLY INVASIVE TO LESS INVASIVE/PROLIFERATIVE TUMORS IN GLIOBLASTOMA

Abstract

Abstract BACKGROUND The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive and highly migratory glioma stem-like cells(GSCs) in tumors. Upon GBM recurrence or progression, the highly invasive phenotype of GSCs changes to a less-motile, proliferative phenotype, thus generating tumor mass. Elucidating the molecular mechanism underlying this phenotypic transition could lead to the identification of effective molecular targets for treating GBM. METHODS We examined the effects of hypoxia (1% O2: severe or 5% O2: moderate) on the expression and functions of hypoxia-inducible factor(HIF), CD44 and osteopontin (OPN) to clarify the role of these molecules in GBM tumor invasion and proliferation. We also investigated the anti-tumor effects of CD44 knockdown in vitro and in vivo using a GSC-transplantation mouse model. RESULTS Severe Hypoxia upregulates CD44 expression via activation of HIF-1α, inducing GSCs to assume a highly invasive phenotype. In contrast, moderate hypoxia upregulates OPN expression via activation of HIF-2α. OPN inhibits CD44-promoted GSC migration and invasion and stimulates GSC proliferation, resulting in GSCs assuming a less-invasive, highly proliferative phenotype. CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo, and the mice survived significantly longer than control mice. CONCLUSION The highly invasive phenotype of GSCs can be reversed by switching from severe to moderate hypoxia, leading to less-invasive and proliferative tumors. CD44 and OPN play a central role in regulating GSC invasion and proliferation by inducing a phenotypic transition, suggesting that these molecules could be effective targets for treating GBM.