CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.

Gliomas are the most frequent and deadly form of human primary brain tumors. Among them, the most common and aggressive type is the high-grade glioblastoma multiforme (GBM), which rapidly grows and renders patients a very poor prognosis. Meanwhile, cancer stem cells (CSCs) have been determined in gliomas and play vital roles in driving tumor growth due to their competency in self-renewal and proliferation. Studies of gliomas have recognized CSCs via specific markers. This review comprehensively examines the current knowledge of the most significant CSCs markers in gliomas in general and in glioblastoma in particular and specifically focuses on their outlook and importance in gliomas CSCs research. We suggest that CSCs should be the superior therapeutic approach by directly targeting the markers. In addition, we highlight the association of these markers with each other in relation to their cascading pathways, and interactions with functional miRNAs, providing the role of the networks axes in glioblastoma signaling pathways.

The World Health Organization has classified glioblastoma as a grade IV tumor, the highest grade. Despite improvements in neurosurgery, chemotherapy, and radiation therapy, glioblastoma remains one of the most resistant tumors, and it consistently recurs. Glioblastoma cells that co-express the cancer stem cell biomarkers CD44 and CD133 play a crucial role in glioblastoma progression, as they possess the capacity to initiate tumors, self-renew, invade, and disseminate, ultimately leading to therapeutic resistance and recurrence. Simultaneous targeting of both biomarkers can impair essential glioblastoma cell processes, facilitating significant progress in alternative therapeutic techniques to improve the survival rate of glioblastoma patients. This review summarizes the roles that CD44 and CD133 play in various malignancies, the involvement of single and combined expression of CD44 and CD133 in worsening the prognosis for glioblastoma patients, and emphasizes that targeting both would be a viable treatment approach for glioblastoma.