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Review
. 2024 Apr 26:15:1354992.
doi: 10.3389/fimmu.2024.1354992. eCollection 2024.

CD44: a cancer stem cell marker and therapeutic target in leukemia treatment

Shuang Wu  1   2 , Yicheng Tan  1   2   3 , Fanfan Li  2   3   4 , Yixiang Han  2   3   5 , Shenghui Zhang  1   2   3   4 , Xiaofei Lin  4
Affiliations
Review

CD44: a cancer stem cell marker and therapeutic target in leukemia treatment

Shuang Wu et al. Front Immunol. .

Abstract

CD44 is a ubiquitous leukocyte adhesion molecule involved in cell-cell interaction, cell adhesion, migration, homing and differentiation. CD44 can mediate the interaction between leukemic stem cells and the surrounding extracellular matrix, thereby inducing a cascade of signaling pathways to regulate their various behaviors. In this review, we focus on the impact of CD44s/CD44v as biomarkers in leukemia development and discuss the current research and prospects for CD44-related interventions in clinical application.

Keywords: CD44; adhesion; biomarkers; clinical application; differentiation; homing; leukemia; migration.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Structural basis of CD44. (A) CD44 is encoded by 20 exons in mice but 19 exons in humans. Exon 6 coding for CD44 variant 1 (CD44v1) is lacking in humans. Except for orange color exons, the rest of exons always expressed as a standard form of CD44 (CD44s), and up to ten exon variants can be inserted by alternative splicing. Full-length CD44, CD44s, CD44v3, CD44v6, and CD44v8-10 are shown schematically. (B) Four domains of CD44 glycoprotein are six cysteine residues (located at the amino acid termini), a stem-like region, transmembrane domain, and cytoplasmic tail. And the variable domain is between six cysteine residues and stem -like region.
Figure 2
Figure 2
Mechanisms by which CD44 regulates the motility and adhesion. Binding of CD44 to HA can affect the intracellular system of backbone proteins and thus mediate cellular movement. CD44 connects to actin via the ERM as a bridge, and this process requires PKC activation as a prerequisite. It also recruits and activates c-Src, and regulates cell migration capacity by phosphorylating the actin Cortactin cytoskeletal protein tyrosine. After activation of Rho GTPase, two downstream factors, CDC42, and Rac1, regulate the cytoskeleton and cell membrane fold structure, respectively, thereby altering cell motility.
Figure 3
Figure 3
Involvement of CD44 in proliferation. (A) Binding of CD44 to HA can activate the PI3K-Akt pathway through RHO, and the activation of the Akt pathway can promote the increase of HAS2 synthase, which in turn can enhance the effect of CD44 and HA to form a positive cycle, overcoming apoptosis and maintaining cell survival. CD44 also binds to HA and activates the P38-MAPK pathway to enhance cell proliferation. Activation of the extracellular kinase ERK2 phosphorylates EIK-1 and ultimately promotes cell migration and proliferation. (B) CD44v6 forms a trimeric complex with Met and HGF and promotes Met activation. Furthermore, the interaction of the CD44 cytoplasmic tail with ERM proteins is required to activate the Ras-MAPK pathway. CD44v6-ECM binding also promotes PI3K/Akt pathway activation and Met transcription. Another protein, Merlin, competes with ERM at the intracellular end of CD44, and Merlin activation occurs after ERM protein inactivation. Merlin activation causes reorganization of the cortical actin cytoskeleton, prevents Ras activation and Ras-dependent signaling, and inhibits signaling by various receptor tyrosine kinases. The serine/threonine protein kinase PAK2 phosphorylates Merlin, but also leads to Merlin inactivation and inhibits its binding to CD44. The addition of high cell density or high molecular weight HA triggers the dephosphorylation of Merlin, leading to the formation of growth inhibitory complexes that limit cell proliferation. Therefore, ERM and Merlin proteins act as “switches” to control cell proliferation.
Figure 4
Figure 4
The cleavage of CD44. The ectodomain of CD44 is mainly cleaved by MMP (membrane-associated metalloproteases) to generate CD44 ECD. On the premise of previous process, CD44 ICD can be generated by intramembranous cleavage, which mediated by presenilin (PS)-dependent-γ-secretase. CD44 ICD can act as a signal transduction molecule to activate transcription.
Figure 5
Figure 5
Therapeutic measures concerning CD44. (A) Because of the high expression of CD44 molecules in target cells and their involvement in mechanisms such as anti-apoptosis of tumor cell proliferation, blocking the signaling pathways of relevant cellular activities by combating CD44 is a feasible therapeutic strategy. Primary treatments are the development of CD44-targeted drugs, immune-representative therapies such as the elimination of AML cells through CAR-T cells which associated with CD44v6 and the enhancement of therapeutic efficacy through the screening of drugs that can reduce the transcriptional expression of CD44 in combination with conventional chemotherapeutic agents. Finally, the binding of CD44 to HA can be interfered with by sCD44 and HA oligomers. (B) The high affinity between CD44 and HA can also be an important channel for drug delivery into the cell. Through the HA linkage, CD44 antibodies can be combined with drugs to form antibody-drug conjugates (ADCs), which can more efficiently target and attack highly CD44-expressing tumor cells.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by National Natural Science Foundation of China (No. 82072354), and Zhejiang Provincial Natural Science Foundation of China under Grant No. LTGD24C040008.
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