Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma

Transl Oncol. 2021 May 27;14(8):101137. doi: 10.1016/j.tranon.2021.101137. Online ahead of print.ABSTRACTThe poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence, GSCs with highly invasive and highly migratory activities must assume a less-motile state and proliferate to regenerate tumor mass. Elucidating the molecular mechanism underlying this transition from a highly invasive phenotype to a less-invasive, proliferative tumor could facilitate the identification of effective molecular targets for treating GBM. Here, we demonstrate that severe hypoxia (1% O2) upregulates CD44 expression via activation of hypoxia-inducible factor (HIF-1α), inducing GSCs to assume a highly invasive tumor. In contrast, moderate hypoxia (5% O2) upregulates osteopontin expression via activation of HIF-2α. The upregulated osteopontin inhibits CD44-promoted GSC migration and invasion and stimulates GSC proliferation, inducing GSCs to assume a less-invasive, highly proliferative tumor. These data indicate that the GSC phenotype is determined by interaction between CD44 and osteopontin. The expression of both CD44 and osteopontin is regulated by differential hypoxia levels. We found that CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo. Mouse brain tumors generated from CD44-knockdown GSCs exhibited diminished invasiveness, and the mice survived significantly longer t...

Source: Translational Oncology - May 30, 2021 Category: Cancer & Oncology Authors: Masahiro Nishikawa Akihiro Inoue Takanori Ohnishi Hajime Yano Saya Ozaki Yonehiro Kanemura Satoshi Suehiro Yoshihiro Ohtsuka Shohei Kohno Shiro Ohue Seiji Shigekawa Hideaki Watanabe Riko Kitazawa Junya Tanaka Takeharu Kunieda Source Type: research