Background

Over the past decades, the conception that carcinoma represents a malignant disease type with both phenotypic and genetic heterogeneity has become completely accepted in the field of oncology. Although tremendous advancement has been achieved in precise management of this progressive disease [1,2,3], local invasion, distant metastasis and therapy resistance hinder survival improvement among tumor patients. A flurry of research has sprung up in order to throw light upon the underlying molecular mechanisms.

Cluster of differentiation 44 (CD44) is a complex transmembrane adhesion glycoprotein, and fundamentally associates with the pivotal component of the extracellular matrix (ECM) hyaluronic acid (HA) [4]. CD44 expresses in a variety of cell types in humans, including embryonic stem cells, differentiated cells and cancer cells [5]. Distinct alternative splicing during the transcription process produces two isoforms of CD44, including the standard isoform (CD44s) and CD44 variant isoforms (CD44v) [6].

Numerous studies have reported that CD44 not only prominently participates in normal cellular functions during physiological processes [7, 8], but also plays pivotal roles in pathological processes, especially tumors [9]. CD44 plays important roles in diverse physiological processes, such as organ development, diverse immune functions and haematopoiesis [10]. CD44-mediating processes include T cell differentiation, branching morphogenesis, proliferation, adhesion and migration [10]. For instance, loss-of-function of CD44 in mice contributed to abnormalities in bone-marrow colonization [11] as well as in the migration of lymphocytes to lymph nodes or the thymus [12]. As observed in pregnant mice, CD44-deletion impaired the preservation of lactation post-partum and accelerated uterine involution [13]. In another study, CD44 depletion suppressed the proliferation of smooth muscle cells in mice as comparison to wild-type controls [14].

It has been evident that CD44 as a surface biomarker of cancer stem cells (CSCs) and a vital regulatory factor of epithelial-mesenchymal transition (EMT) program is involved in the regulation of tumor initiation and development [6, 15,16,146]. This delivery nanoparticle could target tumor-specific CD44 molecule [146].

CD44 can be a target for HA-coated anti-tumor liposomes towards CSCs [147]. For instance, HA-coated cationic liposomes containing cabazitaxel (a tumor cell inhibitor) and silibinin (a CSC inhibitor), displayed enhanced cytotoxicity with low IC50, hampered cell migration, and triggered apoptosis among human prostate tumor cells with CD44 expression [147]. HA-coated nanoparticles containing anti-tumor drugs could also target CD44-positive cancer cells with high specialization and efficient drug delivery, refining the current anti-cancer management [148,149,150,151,152,153]. It has been observed that a rationally designed nanosystem containing gold nanostar/siRNA of heat shock protein 72/HA is endowed with the property of selectively sensitizing CD44-positive TNBC cells to hyperthermia, and improves the therapeutic accuracy and efficacy to TNBC with decreased unpleasant side effects both in vitro and in vivo [153]. As has also been displayed in Alamgeer M’s work, CD44s-positive small cell lung cancer cells benefit more from hyaluronic acid-irinotecan-carboplatin treatment [154].

As CD44 acts as the receptor for HA which can drive cancer migration, expansion, and metastasis [155], blocking HA-CD44 interaction by the degradation of HA or competitive suppression of CD44 might be also a promising strategy for tumor management. However, high spending and lack of specificity challenges [155]. For example, hyaluronidase which can accomplish the degradation of hyaluronic acid is difficult to be purified at the industrial level [155].

Conclusions

A growing body of evidence has demonstrated that CD44 is aberrantly up-regulated among diverse tumors in the forms of CD44s or CD44v. Herein, we aim at encapsulating the current understanding for CD44 structure and roles of CD44 during cancer initiation and progression. CD44 participates in the regulation of multiple signaling and pathways (Fig. 3), and in turn its expression is also regulated by a variety of molecules, such as transcription factors, microRNAs as well as post-translational modifications. CD44 exerts its effects on tumors mainly through stimulating signaling pathways that play vital roles in proliferation, apoptosis, EMT process and drug-resistance as well as activating transcription factors. However, the roles of diverse CD44 isoforms on cancer initiation and progression remain lack of further extensive investigation. Numerous studies demonstrate CD44 to be a potential therapeutic target among various cancers (Table 1). Potential therapeutic strategies targeting CD44-positive tumors via effectively blocking CD44, destroying HA-CD44 balance and increasing cellular concentration of anti-tumor drugs generate hope for anti-tumor drug development.

Fig. 3
figure 3

Signaling pathways which CD44 regulates. CD44v6 can enroll ERM proteins which can interact with VEGFR, contributing angiogenesis. CD44 activates AKT to promote the phosphorylation and nuclear translocation of MDM2, which blocks p53 genomic surveillance response. Subsequently, damaged hepatocytes escape from p53-mediated death, and carcinogen-induced mutations are maintained and transferred from parental cells to daughter cells, ultimately contributing to tumorigenesis. The combination of HA and CD44v6 promotes the phosphorylation of intracellular domain of CD44v6, which then activates Ras and FAK via Src and activates MAPK/ERK signaling. CD44v6 in combination with HA also promotes the PI3K/Akt signaling pathway and increases apoptosis. The intracellular tail of CD44v6 increases MMP2 and MMP9, which degrades ECM and promotes maturation of TGFβ. After binding to its receptor, TGFβ stabilizes β-catenin intracellularly via Smad3 together with activated Akt. Nucleus β-catenin stabilization enhances the expression of EMT-related genes and the gene encoding CD44v6. CD44v6 up-regulation enhances the expression of HA synthase genes, which promotes HA production. CD44 contributes to the dissociation of E-cadherin and β-catenin through suppression of E-cadherin, and then β-catenin translocates to nucleus

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Table 1 CD44-targeted therapy in some preclinical and clinical studies
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