Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target

Abstract

The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell's fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including self-renewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications.

Significance: Mounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer are summarized. The current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications are also discussed.

Keywords: Biomarker; CD44; Cancer stem cell; Splicing variants; Therapeutic target; Tumor microenvironment.

Figure 1.

Diagrammatic structure of CD44 gene and protein. (A): Schematic structures of CD44 gene and pre-mRNAs. CD44 consists of several exons (top panel); some are constant region exons that are used in every CD44 mRNA and protein (yellow boxes), and others are variant exons (pink boxes) that are used in the CD44 splicing variant (CD44v) mRNAs and proteins (lower three panels), whereas the standard CD44 (CD44s) does not contain any variant exon. (B): CD44 protein structural domains. The CD44 protein is composed of an extracellular link domain; a stalk-like region in the extracellular domain close to the transmembrane region, where the variant exon products (red) are inserted; the TM; and the ICD. Abbreviations: ICD, intracellular cytoplasmic domain; TM, transmembrane region; UTR, untranslated region.