{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:05:22Z","timestamp":1789574722138,"version":"build-2803163510"},"reference-count":165,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T00:00:00Z","timestamp":1696809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","doi-asserted-by":"publisher","award":["JP 22K09208"],"award-info":[{"award-number":["JP 22K09208"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>High invasiveness is a characteristic of glioblastoma (GBM), making radical resection almost impossible, and thus, resulting in a tumor with inevitable recurrence. GBM recurrence may be caused by glioma stem-like cells (GSCs) that survive many kinds of therapy. GSCs with high expression levels of CD44 are highly invasive and resistant to radio-chemotherapy. CD44 is a multifunctional molecule that promotes the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways reciprocally activate invasion and proliferation under different hypoxic conditions. Severe hypoxia (0.5\u20132.5% O2) upregulates hypoxia-inducible factor (HIF)-1\u03b1, which then activates target genes, including CD44, TGF-\u03b2, and cMET, all of which are related to tumor migration and invasion. In contrast, moderate hypoxia (2.5\u20135% O2) upregulates HIF-2\u03b1, which activates target genes, such as vascular endothelial growth factor (VEGF)\/VEGFR2, cMYC, and cyclin D1. All these genes are related to tumor proliferation. Oxygen environments around GBM can change before and after tumor resection. Before resection, the oxygen concentration at the tumor periphery is severely hypoxic. In the reparative stage after resection, the resection cavity shows moderate hypoxia. These observations suggest that upregulated CD44 under severe hypoxia may promote the migration and invasion of tumor cells. Conversely, when tumor resection leads to moderate hypoxia, upregulated HIF-2\u03b1 activates HIF-2\u03b1 target genes. The phenotypic transition regulated by CD44, leading to a dichotomy between invasion and proliferation according to hypoxic conditions, may play a crucial role in GBM recurrence.<\/jats:p>","DOI":"10.3390\/cancers15194898","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T10:48:33Z","timestamp":1696848513000},"page":"4898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["A Narrative Review on CD44\u2019s Role in Glioblastoma Invasion, Proliferation, and Tumor Recurrence"],"prefix":"10.3390","volume":"15","author":[{"given":"Akihiro","family":"Inoue","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Ohnishi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"},{"name":"Department of Neurosurgery, Advanced Brain Disease Center, Washoukai Sadamoto Hospital, 1-6-1 Takehara, Matsuyama 790-0052, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Ohtsuka","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-7838","authenticated-orcid":false,"given":"Kosuke","family":"Kusakabe","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1615-7526","authenticated-orcid":false,"given":"Hajime","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicene, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1056-5948","authenticated-orcid":false,"given":"Junya","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicene, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeharu","family":"Kunieda","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nature11287","article-title":"A restricted cell population propagates glioblastoma growth after chemotherapy","volume":"488","author":"Chen","year":"2012","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lathia, J.D., Gallagher, J., Myers, J.T., Li, M., Vasanji, A., McLendon, R.E., Hjelmeland, A.B., Huang, A.Y., and Rich, J.N. 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