European Journal of Pharmacology 903 (2021) 174147

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Review

The role of CD44 in cancer chemoresistance: A concise review

Zohreh Yaghobi a, b, Aliakbar Movassaghpour c, Mehdi Talebi c, Mahdi Abdoli Shadbad a,
Khalil Hajiasgharzadeh a, Shiva Pourvahdani a, b, Behzad Baradaran a, b, d, *
a
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
b
Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
c
Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
d
Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: CD44 is a cell surface adhesion molecule, which is overexpressed on cancer stem cells. The interaction of CD44
Chemoresistance with hyaluronan is responsible for tumor development, metastasis, and expression of the chemoresistant
Cancer stem cells phenotype. The overexpression of CD44 impedes the cytotoxic effect of chemotherapy medications in various
CD44
cancers. Therefore, the high expression of CD44 is associated with a poor prognosis in affected patients. This high
Multidrug resistance
expression of CD44 in various cancers has provided an ample opportunity for the treatment of patients with
chemoresistant malignancy. This review aims to demonstrate the various cross-talk between CD44 and intra­
cellular and extracellular factors and highlight its role in developing chemoresistant tumors in some troublesome
cancers.

1. Introduction cassette transducer is ATP-binding cassette (ABC) (Ghaffari et al., 2018).

Cancer is one of the leading causes of morbidity and mortality
worldwide. It has been estimated that 1 in 8 men and 1 in 10 women will
develop malignancy in a lifetime (Bray et al., 2018). Chemotherapy is
currently the most effective treatment for patients with cancer.
Chemotherapy was the first therapy that tumoral cells responded to it
effectively (Liu, 2009). However, the emergence of chemoresistant tu­
mors has posed a daunting challenge for the treatment of affected pa­
tients. As cancer stem cells (CSCs) can regenerate whole neoplasia
following treatment, CSCs have limited the efficacy of chemotherapy
(Cabrera, 2015; Liu, 2009). The reason for their ability to develop
chemoresistance owes to the fact that they are often static during
chemotherapy (Shirmohamadi et al., 2020).
Fibroblasts and extracellular matrix components of tumor microen­
vironments, e.g., fibronectin, laminin, collagen, osteopontin, and hya­
luronan, have been implicated in the development of CSCs (Morath
et al., 2016). Identifying their surface marker, their related intracellular
signalings, and the cross-talk between tumor microenvironment and
CSCs can be essential for introducing new strategies to treat affected
patients. These markers can be grouped into two categories, i.e., CD
molecules and ATP cassette transducers. The recognized CDs of CSCs are
CD44, CD133, and CD24, and the identified membrane of the ATP
ABC protein, which is known as an ATP-dependent transporter, is also
expressed in non-tumoral cells. The well-known compound of this group
is P-glycoprotein, which has a well-established role in developing the
chemoresistant phenotype in various cancers (Gottesman and Pastan,
1993; Liu, 2009; Tarling et al., 2013). ABC transporters, which are
widely expressed in various tissues, can lead to the efflux of drugs.
Moreover, these transporters contribute to the absorption, distribution,
excretion, and toxicity of xenobiotics (Durmus et al., 2013). Since the
multidrug resistance (MDR) of cancer cells can protect the tumoral cells
against many toxic drugs, cancer cells counteract the inhibitory effect of
most chemotherapeutic medications (Liu, 2009). In some previous
studies, CSCs were isolated in various cancers and successfully identi­
fied. Some of the well-known CSC markers which have prognostic value
include CD24, CD133, CD44, and CD166 (Senel et al., 2017). CD44 is the
cell surface molecule of CSCs in colorectal, ovarian, gastric, pancreatic,
head and neck, and breast cancer (Hu and Fu, 2012). CD44 serves as an
essential adhesion receptor for extracellular matrix components, e.g.,
hyaluronic acid, and can interact with collagen, osteopontin, and matrix
metalloproteinases (Kupsa et al., 2015).
Hyaluronan (also hyaluronate or hyaluronic acid), has a negative
charge and a very large linear polysaccharide. Hyaluronan is an
important component of the microenvironment in cancer cells and is

* Corresponding author. Immunology Research Center, Tabriz University of Medical Sciences, Golgasht St., Tabriz, 5166614766, Iran.
E-mail address: baradaranb@tbzmed.ac.ir (B. Baradaran).

https://doi.org/10.1016/j.ejphar.2021.174147
Received 14 November 2020; Received in revised form 28 April 2021; Accepted 30 April 2021
Available online 5 May 2021
0014-2999/© 2021 Elsevier B.V. All rights reserved.
Z. Yaghobi et al.
involved in determining progression and tumor prognosis (Skandalis
et al., 2014). Hyaluronan interactions are involved in metastasis and
tumor growth. The main receptor for hyaluronan is on the cell surface of
the CD44 molecule. Interactions of hyaluronan with CD44 promoting
transporter activities, signaling pathways, and resistance to therapy. Of
course, these interactions are vital for both malignancy and normal cells.
The binding of hyaluronan to CD44 in cancer cells leads to indirect or
direct interaction of CD44 with signaling receptors such as transforming
growth factor-β (TGF-β) receptor type I and, epidermal growth factor
receptor (EGFR) ErbB2, which activates these receptors.
CD44-hyaluronan binding influences the activity of a variety of down­
stream signaling pathways, particularly PI3 kinase-Akt pathways and
MAP kinases, resulting in chemical resistance, invasion, tumor cell
proliferation, motility, and survival (Toole, 2009). CD44 has been
implicated in metastasis, chemoresistance, and tumor development
(Morath et al., 2016). The inhibition of CD44 has been associated with
Fig. 1. The structure of ABC carrier protein.
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European Journal of Pharmacology 903 (2021) 174147
enhanced chemosensitivity of tumoral cells (Wu et al., 2015). Further­
more, CD44 can up-regulate the gene expression of MDR and pave the
road for developing chemoresistant tumoral cells (Zoeller, 2015).
Although there have been considerable advances in developing
chemotherapy medications, cellular protection mechanisms against
toxic medications have limited the efficacy of this approach. A better
understanding of drug resistance biology can pave the road for devel­
oping new approaches for patients with chemoresistant tumors. There­
fore, this review aims to demonstrate the role of CD44 in developing
chemoresistant tumor cells in some troublesome cancers.
2. MDR and the mechanism of resistance
Since the membrane transporters regulate the movement of mole­
cules across the plasma membrane, their interactions with chemo­
therapy medications are associated with the efficacy of anti-cancer
Z. Yaghobi et al.
medications (Huang, 2007). The two main groups of these transporters
are ABCs and solute transporters, which affect the pharmacokinetics of
chemotherapy medications (Huang, 2007). The ABCs can result in the
efflux of drugs and reduce the intracellular accumulation of chemo­
therapy drugs. As solute transporters are associated with the uptake of
anti-cancer medications, they increase the chemosensitivity of tumoral
cells. The development of chemoresistant tumors might be associated
with reduced activity of solute transporters (Liu, 2009). Since MDR
protects cells against toxic medications, MDR can also contribute to
chemoresistance development. This protection mechanism is present in
normal stem cells and CSCs (Liu, 2009).
The ABCB1, also referred to as P-glycoprotein or MDR1, contains
1280 amino acids (KDa170), two binding sites to ATP, and 12 membrane
domains (Hrycyna, 2001). The aberrant expression of the MDR1 gene
has been found in about 50% of cancers, which facilitates chemo­
resistance development (Hrycyna, 2001; Huang, 2007). Since ABC
family proteins have the nucleotide-binding domain, they can utilize
ATP to propel the efflux of intracellular chemotherapy medications (Liu,
2009). Most members of this family have a transmembrane region,
which is composed of six helical membranes. The transmembrane region
is a binding site for transferring anti-cancer medications from the
cytoplasm (Liu, 2009) (Fig. 1). Based on the structure of the trans­
membrane region and nucleotide-binding domain, the ABC family is
divided into seven subfamilies, i.e., class A to G. Three out of 49 mem­
branes of this family are known as MDR (Stavrovskaya and Stromskaya,
2008) (Fig. 1). These three proteins are P-glycoprotein, MDR-related
protein, and breast cancer resistance protein. P-glycoprotein, which is
encoded by the ABCB1 gene, is a transmembrane glycoprotein with
1280 amino acids (Gottesman and Pastan, 1993). P-glycoprotein re­
duces the intracellular concentration of many anti-cancer medications,
e.g., tyrosine kinase inhibitors (Durmus et al., 2013). Moreover,
P-glycoprotein transports cationic and neutral hydrophobic compounds,
e.g., the natural products daunorubicin, actinomycin D, vinblastine,
doxorubicin, vincristine, etoposide, and paclitaxel (Liu, 2009). Two
ATPs are necessary for the efflux of chemotherapy drugs; these ATPs
allow the initiation of the next drug transport cycle (Ambudkar et al.,
2003; Liu, 2009) (Fig. 2). Furthermore, MDR transporters are respon­
sible for constitutive drug resistance of the normal tissue stem cells.
Indeed, CSCs retains the essential properties of this protective mecha­
nism (Donnenberg and Donnenberg, 2005; Liu, 2009). MDR-related
protein (MRP) is another membrane of this family, which is similar to
P-glycoprotein; however, its amino terminus has more five membrane
regions than P-glycoprotein (Gottesman et al., 2002). The natural sub­
strates for MRP1 are neutral hydrophobic chemotherapy medications,
anionic hydrophobic drugs, and their conjugates with glutathione, sul­
fate, and glucuronate. These substrates play a substantial role in trans­
porting chemotherapeutic medications (Borst et al., 1999). Some
membranes of this family, e.g., MRP2, MRP3, and MRP6, require amine
terminals with five membrane regions. There is a structural similarity
between P-glycoprotein and MRP7, MRP5, and MRP4 (Borst et al.,
2000). MDR (Multidrug resistance) is one of the important factors in
Fig. 2. The drug is transported by P-gp by hydrolysis of ATP molecules.
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European Journal of Pharmacology 903 (2021) 174147
increasing resistance to chemical drugs, often associated with increased
expression of ATP-binding cassette (ABC) transporter. As well, the
interaction of hyaluronan and CD44 induced MDR and P-glycoprotein
expression and activation of the PI3K/Akt pathway. Besides, the
PI3K/Akt pathway modulated both P-glycoprotein activity and MDR
functions (Liu et al., 2009).
3. CD44 and cancer stem cells
CSCs have unique capabilities such as angiogenesis, metastasis, self-
renewal, relapse, and drug resistance (Nagano et al., 2013). The most
important CSC cell surface markers in tumors are CD166, CD24, CD44,
CD133, CD29, and EpCAM (CD326). The most prevalent of these
markers is CD44 (Ailles and Weissman, 2007). CD44 glycoprotein is a
surface marker of normal and cancer cells that are overexpressed in
tumor cells because it is an extracellular matrix adhesion protein and
plays an important role in metastasis, adhesion, and migration (Jothy,
2003). The cytoplasmic tail of CD44 is of special importance in signal
transmission. Through the cytoplasmic tail, it can interact with cyto­
skeletal elements such as ankyrin, spectrin, and actin. CD44 triggers
signaling cascades and regulation of some intracellular biological pro­
cesses after interacting with its primary ligand (HA) hyaluronic acid
(Basakran, 2015). Through interaction with HA, it plays a role in cell
adhesion and motility (Marhaba and Zöller, 2003). Interaction of CD44
with its ligand (HA) regulates the inflammatory response. For example,
CD44 expression is increased in mouse cells and human cells in eosin­
ophilic inflammatory asthma. In many types of tumors, such as prostate
and breast cancer, CD44 expression in the CSC, promotes homing
(Basakran, 2015). Different types of CD44 isoforms are expressed in
cancer cells with epithelial origin (Basakran, 2015). As mentioned,
different isoforms of CD44 are expressed in cancer cells, each of which
causes a specific activity, e.g, the CD44v3 isoform after interacting with
the pro-form of heparin-binding epidermal growth factor-like growth
factor activates this factor with the help of MMP7. Protein or the stan­
dard CD44 isoform (CD44s) activates the TGFb receptor (TGFbRII) and
the SMAD downstream signaling system by interacting with phosphor­
ylated ERM (ezrin/radixin/moesin) or CD44v9 and CD44v6 interact
with FAS, they inhibit programmed cell death promote (Nagano et al.,
2013). The most important association of CD44 is with ERM proteins
(ezrin, radixin, moesin). ERM is important in regulating cell shape and
protein uptake in plasma membranes and cell migration (Bretscher
et al., 2002). Importantly, the cytoplasmic tail of CD44 is associated with
phosphotyrosine kinases (PTKs), fyn, and lyn also plays a role in signal
transduction in cells due to its association with phosphokinases (Taher
et al., 1996). One of the characteristics of cancer cells is resistance to
radiotherapy and chemotherapy, which is due to the protective mech­
anisms against stress caused by reactive oxygen species. In CSCs, CD44v
enhances defense against reactive oxygen species, which in turn pro­
motes chemical resistance, tumor growth, and metastasis to cancer cells
(Nagano et al., 2013). Therefore, CD44 can be considered as a diagnostic
marker for certain cancer cells and acceptable for cancer progression,
Z. Yaghobi et al.
and expect a lot of applications examine medical treatment for the CD44
marker. Research emphasizes the importance of CD44 as a potentially
attractive surface marker and receptor for therapeutic purposes, espe­
cially in tumors with increased CD44 expression (Naor et al., 2002).
4. CD44 and drug resistance
CD44 is the most common cancer stem cell receptor whose over­
expression is associated with metastasis, resistance, and tumor recur­
rence. Evidence suggests that CD44 is overexpressed in many types of
tumors (Ryoo et al., 2018). CD44 was first identified as a member of the
cartilage transplant protein family (Stamenkovic et al., 1989; Zöller,
2011). CD44 is a transmembrane glycoprotein that contributes to tumor
migration, invasion, and survival (Cichy and Puré, 2003). Even though
the human CD44 is encoded by 19 exons and mice CD44 is encoded by
20 exons, the first and last five exons are common (Chen et al., 2018).
Although CD44 is encoded by a single gene on chromosome 11 (Wu
et al., 2015), alternative splicing of RNA is responsible for different
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European Journal of Pharmacology 903 (2021) 174147
CD44 isoforms (Zoeller, 2015). These isoforms are known as the stan­
dard form of CD44 (CD44s), which are expressed in most tissues. The
alternative assembling of intermediate exons with ten common exons in
the standard CD44 isoforms creates v series isoforms of CD44 (Chen
et al., 2018). Although many cells express CD44s on their cell surface,
the cancerous cells express both CD44s and CD44v on their cell mem­
brane (Zoeller, 2015). The extracellular domain of CD44 gives rise to the
(V1–V10) isoforms (Chen et al., 2018) (Fig. 3). Furthermore,
post-translational modifications, e.g., glycosylation and the attachment
of glycosaminoglycans, lead to the additional structural diversity of
CD44 (Cichy and Puré, 2003). The glycosylation of CD44 plays a critical
role in binding to fibrin and fibrinogen (Kupsa et al., 2015).
Hyaluronan (HA) is one of the most valid extracellular signaling
molecules, and, CD44 is the most important cell surface receptor for HA
(Lee and Spicer, 2000). This glycosaminoglycan located in the extra­
cellular matrix is important in wound healing, inflammation, embryonic
development, and cancer resistance. HA interacts with various cell
surface receptors, including intracellular signaling pathways such as the
Fig. 3. (A) CD44 gene contains 20 exons.
Alternative splicing gives rise to CD44s and
CD44v. (B) CD44 protein consists of a short
C-terminal cytoplasmic domain, a trans­
membrane domain, and seven extracellular
domains, which contain an N-terminal HA-
binding link-homology module and stem
region. 1 is an N-terminal signal sequence,
exons 2 and 3 are a link module that binds to
HA, exons 4, 5, 16, and 17 compose a stem
region, exon 18 makes up a single-pass
transmembrane domain, and exon 20 forms
a cytoplasmic domain.
Z. Yaghobi et al.
tyrosine kinase receptor pathway, the hyaluronan-mediated motility
receptor, CD44, to increase proliferation, survival, and resistance to
cancer cell treatment (Price et al., 2018). HA interacts with cancer stem
cell marker CD44 promotes adhesion, migration, cell proliferation, and
chemotherapy resistance. A study of cancer cells has shown that HA
interacts with CD44 to activate Nanog and STAT-3 pathway then pro­
mote SOX2, REX1, and MDR1 expression (Price et al., 2018). Taken
together, HA/CD44 with targeting ankyrin/cytoskeleton function and
Nanog-Stat-3 signaling pathways may be a novel strategy to reducing
chemotherapy resistance in some tumor cells (Bourguignon et al., 2008).
Furthermore, HA-CD44 interaction can activate several important
signaling pathways by activating mediators such as the Rac1 GTPase and
Rho. CD44 plays an important role in the reorganization of the actin
cytoskeleton and src-related tyrosine kinases, ErbB2 tyrosine kinase, and
nuclear factor-κB (NF-κB) (Lee and Spicer, 2000). One of the important
signals in increasing CD44 expression is Rho signaling (Desai et al.,
2007). Also, most studies have considered HA functions at the cellular
level or within the ECM, but evidence suggests that HA may have new
functions inside the cell. IHABP4, P32, the hsp90 associated kinase
chaperone protein cdc37, and RHAMM are four intracellular
HA-binding proteins (IHABPs). RHAMM (receptor for HA-mediated
motility) plays an important role in activating Ras and src signaling.
IHABP4 and P32 may have a function in intracellular signaling or RNA
processing. IHABP4 has a sequence identity to single-stranded DNA-­
binding proteins and RNA (Das et al., 1997; Lee and Spicer, 2000).
As mentioned above, increased expression of CD44 is associated with
resistance to radiotherapy and chemotherapy. In some malignant cells,
decreased CD44 gene or protein expression enhances the response rate
to cancer treatment (Wu et al., 2015). In hepatocellular carcinoma, the
functional inhibition of CD44 with decreased levels of anti-apoptotic
proteins (MCL-1 and Survivin) has sensitized tumoral cells to
sorafenib-induced cell death in TGF-β dependent fashion (Fernando
Fig. 4. (A) CD44 is activated by high molecular weight hyaluronan (HA) or by phosphorylated ezrin, radixin and moesin (ERM), the molecule increases on the cell
surface. However, the interaction of CD44 with low molecular mass HA causes the MDR protein to internalize, leading to a significant decrease in drug resistance. (B)
CD44 to HA regulate the expression of P300 and its acetyltransferase activity. It then enhances the acetylation of β-catenin and NFκB-p65. After activation of
β-catenin and NFκB act as factors affecting transcription in MDR1.
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European Journal of Pharmacology 903 (2021) 174147
et al., 2015). It has been demonstrated that the CD44 molecule can
induce chemoresistance in breast cancer (Li et al., 2008; Yuan, 2011).
Furthermore, paclitaxel-resistant ovarian cancer cells have shown an
increased CD44 expression level compared to paclitaxel-sensitive cancer
cells (Gao et al., 2015). CSCs with CD44high/CD24low antigen on the cell
surface have been more resistant to chemotherapy and radiotherapy.
Also, CD44 inhibition reduces cancer proliferation and progression in
bladder cancer T24-L cells (Wu et al., 2013).
The expression of CD44 isoforms contributes to drug resistance in
many cancers (Wei et al., 2014). In head and neck squamous cell car­
cinoma, targeting overexpressed CD44v3 on the tumoral cells with an­
tibodies has reduced tumoral proliferation and resistance to cisplatin
(Wang et al., 2007). Since CD44v6 can form a pre-metastatic niche for
tumoral cells, this isoform develops chemoresistant tumors (Orian-­
Rousseau and Ponta, 2015). In prostate cancer, knockdown of CD44v6
has inhibited the tumor invasion and increased sensitivity to chemo­
therapy. Moreover, CD44 induces the epithelial-mesenchymal transition
and regulates the Wnt/β-catenin and PI3K/Akt/mTOR signaling
pathway in prostate cancer (Ni et al., 2014). Since CD44v3-hyaluronan
up-regulates the microRNA-302 transcription and Oct4-Sox2-Nanog
signaling pathway, CD44v3-hyaluronan interaction substantially in­
creases the expression of MDR (Lilly Y. W. Bourguignon et al., 2012).
Furthermore, CD44v3-hyaluronan interaction increases the expression
of Nanog, which up-regulates microRNA-21 and MDR1 expression.
Indeed, this interaction inhibits apoptosis and augments the tumor
development in breast cancer (Bourguignon et al., 2009). Since
CD44v3-hyaluronan interaction up-regulates the expression of MDR1, it
contributes to the development of chemoresistant tumors. Moreover, the
interaction of CD44 with HA activates the PI3K pathway, which subse­
quently up-regulates HA and MDR expression (Misra et al., 2005)
(Fig. 4). As CD44v3-hyaluronan interaction can regulate the expression
of P300 and its acetyltransferase activity, this can enhance the
Z. Yaghobi et al.
acetylation of β-catenin and NFκB-p65. Following the activation of
β-catenin and NF-κB, the expression of MDR1 is up-regulated (Zoeller,
2015). The interaction of CD44 with high-molecular-weight hyaluronan
increases the MDR expression, which leads to drug resistance. However,
the interaction of CD44 with low-molecular-mass hyaluronan in­
ternalizes the MDR protein (Zöller, 2011) (Fig. 5). Due to the pivotal role
of CD44 in tumor development, the following sections aim to review the
role of CD44 isoforms and their identified signaling pathways in some
troublesome cancers (Table 1). In the next section, we discuss in more
detail the role of CD44 in the chemoresistance of each cancer type.
5. Cancers and CD44
5.1. Breast cancer and CD44
Since breast cancer stem cells can resist radiation and chemotherapy,
there is an urgent need to find new strategies to overcome this resis­
tance. Recent findings have shown that there is an increase in the level of
CD44high/CD24-/low/Lin- in patients treated with chemotherapy or
radiotherapy (Dave and Chang, 2009). Studies have shown over­
expression or silencing CD44 increases or decreases the expression of
nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) (a key regulator of
antioxidant genes). NRF2 protein expression plays a pivotal role in
regulating drug resistance and cellular reactive oxygen species. Reactive
oxygen species expression increases resistance against treatment and
causes maintenance and survival (Ryoo et al., 2018). Since MDR1 in­
creases hyaluronan production in malignant cells, MDR1 can mediate
resistance to chemotherapy (Misra et al., 2003). The interaction of CD44
with hyaluronan activates the PI3K/Akt signaling pathway, which
augments the activity of MDR1 in breast cancer and induces resistance to
doxorubicin. In breast cancer, the interaction of CD44 with hyaluronan
stimulates the ErbB2 signaling pathway, which propels the PI3K/Akt
signaling pathway. The activation of the PI3K/Akt signaling pathway
Fig. 5. CD44 interacts with its cellular surface ligand (hyaluronic acid); it activates the 3-kinase (PI3K)/AKT signaling pathway and then increases the activity of P-
glycoprotein in breast cancer cells resistant to doxorubicin. In another study, hyaluronic acid, PI3K and ErbB2 increased the expression of MDR1 in the cell by
creating a positive feedback loop.
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European Journal of Pharmacology 903 (2021) 174147
confers drug-resistant and anti-apoptotic features to tumoral cells via
hyaluronan production. Therefore, there is a positive feedback loop
between the PI3K pathway and hyaluronan, which shields the cancer
cells from chemotherapy (Misra et al., 2005). CD44v6 can stimulate the
PI3K signaling pathway. Besides, CD44v6 is positively associated with a
poor prognosis in breast cancer. CD44v6 contributes to apoptosis
resistance and metastasis via the PI3K/AKT pathway (Yu et al., 2010).
These findings help to produce specific antibodies against human
CD44v6 and are a good target for the treatment of various types of
epithelial cancers (Heider et al., 2004). The interaction of CD44 with
hyaluronan activates Nanog, which up-regulates the expression of
MDR1 in Stat-3 dependent manner. Moreover, CD44-hyaluronan pro­
motes the binding of MDR-1 to ankyrin and facilitates the efflux of
doxorubicin and paclitaxel in breast and ovarian cancer cells. Thus,
targeting this pathway can be a promising approach for overcoming the
chemoresistance in breast and ovarian cells (Bourguignon et al., 2008).
Since the FKBPL(FK506-binding protein-like) and its peptide derivative,
AD-01, can inhibit CD44, it can disrupt the Oct4, Nanog, and angiogenic
signaling pathways, which decreases the stemness of CSCs and increases
the sensitivity of tumoral cells to treatment (McClements et al., 2013)
(Fig. 6). In other studies, protein transforming growth factor-beta
(TGFβ) may regulate the CD44 signaling pathway, and activation of
the TGFβ protein may increase CD44 protein expression in cells. Sarkar
et al. found that rhPRG4 (recombinant human PRG4) (Proteoglycan 4, a
glycoprotein, contributes to friction-reducing and anti-adhesive prop­
erties) inhibits the TGFβ-Hyaluronan-CD44 signaling pathway in cancer
cells, and reducing CD44 activity (Sarkar et al., 2019). Also, another
study inhibited the CD44 signaling pathway in breast cancer cells using
the molecular mechanisms of methyl sulfonyl methane and allicin. As a
result, it increased apoptosis in the cells (Sarkhani et al., 2017). How­
ever, the role of CD44 in breast cancer stem cells as a potential thera­
peutic target needs further investigation.
Z. Yaghobi et al. European Journal of Pharmacology 903 (2021) 174147

Table 1
The significance and function of CD44 isoforms.
CD44 Biological functions Cancer types References
isoforms

CD44s Tumor progression Breast cancer Brown et al.

(2011)
CD44s Metastasis, Tumor Pancreatic cancer L. Li et al. (2014)
growth, low survival
rate
CD44v3 Tumor cell growth, Head and neck Wang et al.
migration squamous cell (2007)
carcinoma
CD44v3 Overexpressed in Head and neck Reategui et al.
tumor tissue, Migration squamous cell (2006)
carcinoma
CD44v5-v6 Tumor progression Colorectal cancer Vizoso et al.
(2004)
CD44v5-v6 Invasion Primary ovarian (Schröder et al.
cancer and lymph n.d.)
node
CD44v6 Association with liver Pancreatic cancer Rall and Rustgi
metastasis, Metastasis (1995)
CD44v6 Metastasis Colon cancer Todaro et al.
(2014)
CD44v6 Epithelial phenotype Prostate cancer Hernandez et al.
cells expression (2015)
CD44v6 Tumorigenic and Prostate cancer Ni et al. (2014)
chemoresistance
CD44v6 Migration, metastasis, Colorectal (Todaro et al.,
advanced stage of adenocarcinomas 2014; Wielenga
tumor et al., 1993)
CDv6 Reduced survival Acute myeloid Legras et al.
leukemia (1998)
CD44v6, Liver metastasis, Pancreatic cancer Z. Li et al. (2014)
CD44v9 Correlates with lymph
node metastasis
CD44 3v, Prognosis Hodgkin’s Terpe et al.
6v, and lymphomas (1994)
9v
CD44v9 Prognosis, low survival Multiple myeloma Günthert et al.
rate (1997)
CD44v8- Lung metastasis Breast cancer Yae et al. (2012)
10
CD44v8- Tumor initiation Gastric cancer Lau et al. (2014)
10

5.2. Ovarian cancer and CD44

Fig. 6. Nanog leads to the activation and transcription of Stat-3 and the
It has shown that ovarian cancer stem cells have high self-renewal
transfer of a multi-drug gene, the expression of the MDR1 gene (p-
and low differentiation capacity. Therefore, they can develop glycoprotein).
advanced tumors, which are resistant to chemotherapy (Lai, 2010). In
previous research, the CD44, one of the cell surface adhesion molecules,
of CD44 has been associated with increased expression of
has been reported as a marker of cancer stem cells in ovarian cancer.
microRNA-199a and reduced expression of the multidrug resistance
CD44 is associated with cell-matrix, and cell-cell interactions through
gene in ovarian cancer stem cells (Cheng et al., 2012). Furthermore,
interactions with hyaluronate (major ligand) and other extracellular
microRNA-199a, via targeting the CD44 molecule, can reduce the in­
receptors (Cheng et al., 2012). There is considerable evidence that
vasion and proliferation of CD44+ CD117+ ovarian cancer both in vivo
CD44v6, one of the major types of CD44, increases tumor metastasis by
and in vitro. More investigations are needed to elucidate the association
binding to hyaluronic acid, and CD44v6 is significantly associated with a
between CD44 and microRNA-199a in maintaining multidrug-resistant
high TMN stage in ovarian cancers (Lin and Ding, 2017). As well CD44 is
features and stemness phenotype in ovarian cancer stem cells (Cheng
of particular importance in signal transmission, cytoskeletal rearrange­
et al., 2012). The combination of MDR1 small interfering RNA (siRNA)
ment, cell migration, lymphocyte homing, and tumorigenesis (Lin and
with paclitaxel has considerably inhibited the function of P-glycoprotein
Ding, 2017). In a meta-analysis study on the importance of CD44, a total
and the tumor development in ovarian cancer cells (Yang et al., 2015).
of 2161 patients from 18 articles were included. Data suggest that CD44
However, the pathological and the clinical value of this marker in
molecule expression in ovarian cancers is dramatically associated with a
ovarian cancer remains controversial.
high TMN stage. Diagnosis of the CD44 marker may be effective in
diagnosing the prognosis and pathology of ovarian cancer patients (Lin
and Ding, 2017).
5.3. Pancreatic cancer and CD44
Since ovarian cancer stem cells are associated with metastasis and
tumor relapse, it is critical to introduce a new target therapy based on
Since this highly metastatic cancer has no primary symptoms and
the intracellular signaling pathways of CD44 (Cheng et al., 2012). It has
shows chemoresistant features, this devastating cancer is the fourth
been demonstrated that the up-regulated level of microRNA-199a can
leading cause of cancer-related mortality (Pan et al., 2016). Among
suppress CD44 both in mRNA and protein levels. Besides, the inhibition
cancers, pancreatic cancer has the worst survival rate. The high

7
Z. Yaghobi et al.
resistance to chemo- and radiation therapy is one of the important fea­
tures of pancreatic cancer (Long et al., 2011). Specified, CD44 glyco­
protein is overexpressed in pancreatic cancer stem cells (a target of HA)
(Kesharwani et al.). In a study by Wang et al. A subgroup of cells isolated
from Panc-1 cells was identified and named as stem cells such as
pancreatic cancer. These stem cells, such as Panc-1, showed high levels
of CD44, CD133, Nestin, and Oct4. Compared with Panc-1 cells, stem
cells such as Panc-1 are resistant to gemcitabine and show high levels of
MDR1 expression (Pan et al., 2016). CD44 is one of the most important
markers of cancer stem cells that have been identified and has various
functions in proliferation, survival, migration, return home, apoptosis,
and cell adhesion (Williams et al., 2013). The cytoplasmic tail of CD44
has regions for linkers to ERM proteins and ankyrin (Wang et al., 2016).
In another study, knockdown of CD44 expression in pancreatic cancer
cells downregulation of p-ERK and p-AKT along with reduced ability to
migrate and proliferate (Li et al., 2015). Mutations, aberrant gene
expression, deregulation of signaling pathways (such as NF-κB, Notch,
Akt, and apoptotic pathways) cause drug resistance in pancreatic cancer
cells. Studies have shown that the level of CD44s in pancreatic cancer
cells is significantly higher than normal cells. The use of the anti-CD44s
monoclonal antibody, H4C4, plays a role in reducing metastasis,
recurrence, and growth of pancreatic xenograft tumors in mice after
radiation therapy. Anti-CD44 in pancreatic cancer cells inhibits cell
proliferation and survival signaling by reducing the expression of
self-renewing genes such as Nanog, Sox-2, and Rex-1 (Li et al., 2015).
Following the exposure to a high-dose of gemcitabine, CD44+ cells have
substantially expressed MDR1 that regenerates new neoplasia. However,
the administration of anti-CD44 treatment and verapamil have over­
come the chemoresistance of pancreatic cancer cells (Hong et al., 2009).
Consistent with this, CD44 has been implicated in the colonization and
tumor development in gemcitabine-resistant pancreatic cancer cells
(Chen et al., 2018). Moreover, CD44+/LIN28B+ pancreatic CSCs have
been substantially resistant to gemcitabine, cisplatin, hydrochloride,
and growth inhibition (Ercan, G., Karlitepe, A., & Ozpolat, 2017). Based
on the data, verapamil (Verapamil is an inhibitor of ABC transporters)
and CD44 knock-down by antisense RNA can overcome drug resistance
in pancreatic cancer (Hong et al., 2009). Indeed CD44 is an essential
maker in CSC of pancreatic cancer (Pan et al., 2016). Pancreatic cancer
cells express some isoforms of CD44. The most predominant isoform is
CD44v6, which plays a considerable role in the metastasis of pancreatic
cancer (Castella et al., 1996; Rall and Rustgi, 1995). CD44v6 is the
cornerstone of the oncogenic pathway of c-Met/HGF in pancreatic
cancer, and CD44v6 inhibition suppresses the MEK/ERK oncogenic
pathway (Orian-Rousseau, 2002; Yousefi et al., 2012). Besides, the
presence of the cytoplasmic tail of CD44 is required for signal trans­
duction from c-Met activated to MEK and Erk (Orian-Rousseau, 2002).
Increased expression and activation of c-Src and c-Met are also impor­
tant in drug resistance (Long, Zhang et al., 2011). It has been reported
that the inhibition of NF-κB in CD44+ cancer stem-like cells can repress
the chemoresistance of pancreatic cancer stem-like cells (Kesharwani
et al.). Krüppel-like factor 4 (KLF4) is a transcription factor. KLF4 can act
as a tumor suppressor (Park et al., 2019). Research has shown that there
are three potential KLF4 binding sites in the CD44 promoter region.
KLF4 has a negative effect on pancreatic cancer metastasis by sup­
pressing CD44 signaling (Yan et al., 2016). Using ABC transporter in­
hibitors or therapy against the CD44 can be a good option to overcome
the drug resistance of cancer cells (Hong et al., 2009).
5.4. Head and neck cancer and CD44
Epidermal factor growth factor receptor-mediated pathways are
essential for tumor development in head and neck squamous cell car­
cinoma (Thomas et al., 2003). The interaction of CD44 with hyaluronan
promotes epidermal growth factor receptor (EGFR)-regulated pathways,
which leads to chemoresistance in head and neck squamous cell carci­
noma (Wang and Bourguignon, 2011, 2006). Indeed this complex
8
European Journal of Pharmacology 903 (2021) 174147
promotes resistance to some chemotherapeutic medications, e.g.,
doxorubicin, methotrexate, autopsied, and cisplatin (Wang and Bour­
guignon, 2011). This interaction also mediates oncogenic signaling
pathways and facilitates tumor invasion and metastasis (Turley et al.,
2002). Since cisplatin induces apoptosis via interrupting the Akt
pathway, it is one of the effective chemotherapy medications for patients
with head and neck squamous cell carcinoma (Wang and Bourguignon,
2011).
As well as by activating the signaling phosphatidylinositol 3 (PI-3)
kinase and Rho kinase promote invasion, migration, cisplatin resistance
and HNSCC proliferation (Torre et al., 2010). Phosphatidylinositol 3
kinase mediates various cellular activities, such as stimulating prolif­
eration, promoting tumor cell survival, and suppressing apoptosis (Torre
et al., 2010). Also, HA and CD44 activate the Rho kinase pathway and
PI-3 kinase and ultimately activate carcinogenic signaling and cisplatin
resistance. Examining this pathway could be a new strategy for treating
HNSCC (Torre et al., 2010). The hyaluronan-mediated chemoresistance
can limit the efficacy of cisplatin in head and neck squamous cell car­
cinoma. Since hyaluronan mediates this chemoresistance via
EGFR-mediated pathways, the administration of MAPK inhibitors can
abolish this chemoresistance (Wang and Bourguignon, 2006). Apart
from the EGFR, hyaluronan can drive the phosphorylation of ERK1 and
ERK2, which leads to tumor development. In line with this, ERK and
EGFR inhibitors substantially have reduced hyaluronan-mediated ERK
and EGFR phosphorylation, tumor migration, tumor growth, and
chemotherapy resistance (Wang and Bourguignon, 2006).
Several studies indicate, microRNAs (small RNA molecules with
~20–25 nucleotides) plays an important role in the pathogenesis and,
cell survival and chemoresistance of Head and Neck Squamous Cell
Carcinoma (HNSCC) (Asadzadeh et al., 2019; L Y W Bourguignon et al.,
2012). The results show that HA interaction with CD44, induces
Nanog-Stat-3 (also phosphorylated tyrosine Stat-3) complex formation,
then nucleation transfer and regulates miR-21 production. Stat-3 bind­
ing site controls transcription of miR-21 (L Y W Bourguignon et al.,
2012). Induction of the Nanog/Stat-3-dependent signaling pathway
leads to decreased expression of inhibitors of the apoptosis family of
proteins (IAPs), decreased tumor suppressor protein (PDCD4) as well as
chemical resistance in the tumor cell. Treatment of HNSCC cells with
Nanog- and/or Stat-3-specific small interfering RNAs (siRNAs) or spe­
cific anti-miR-21 inhibitor reduces inhibitors of the apoptosis protein
and increases cell survival and drug resistance (L Y W Bourguignon
et al., 2012). In another study, miR-520b prevented HNC malignancy by
targeting the CD44 molecule. MiR-520b reduces the expression of
multiple stemness regulators (Nestin, Twist, Nanog, and Oct4).
MiR-520b sensitizes cells to radiation and chemotherapy drugs.
MiR-520b may be considered as a therapeutic target (Lu et al., 2017).
5.5. Colorectal cancer and CD44
Colorectal cancer is a highly prevalent malignancy, and its meta­
static cells commonly invade lung and liver tissues (Lotfipour et al.,
2011; Villeneuve and Sundaresan, 2009). CD44 isoforms have also been
implicated in the invasion and relapse of colorectal cancer (Bates et al.,
2001). CD44v9 mRNA expression in circulating tumor cells has been
associated with a worse prognosis in patients with colorectal cancer.
This is probably due to the ability of CSCs to evade the anti-tumoral
immune response and their chemoresistant phenotype. Indeed, the
expression level of mRNA CD44v9 can serve as a valuable indicator for
chemoresistance, prognosis, and relapse in patients with colorectal
cancer. Moreover, CD44 can stimulate the src-family tyrosine kinase Lyn
(Katoh et al., 2015). The up-regulated expression of dominant-active
Lyn has been associated with stimulating the PI3K/Akt pathway and
chemoresistant phenotype. Indeed the CD44 overexpression can sup­
press cell apoptosis and pave the road for tumor development (Bates
et al., 2001). Currently, a known pathway for cell survival in response to
several stimuli, including cell adhesion and growth factors, signaling
Z. Yaghobi et al.
pathway the serine/threonine kinase Akt (Dudek, 1997).
Ezrin, as one of the ERM family, can interact with p85, which is a
regulatory subunit of PI3K. Mutations in ezrin can disrupt the activation
of Akt, which leads to apoptosis (Bates et al., 2001; Tsukita et al., 1994).
The ERM protein also serves as a bridge between the plasma membrane
and the actin cytoskeleton. Indeed, these proteins contain an
actin-binding domain, which is toward the COOH-terminal, and a
conserved FERM domain, which is near the NH2 terminus. The FERM
domain interacts with some transmembrane adhesion molecules, e.g.,
CD44 (Bates et al., 2001). The interaction of ezrin with CD44 might be a
critical step, which is involved in activating the Akt pathway. Moreover,
the CD44 cytoplasmic domain shows low interaction for ERM proteins
under physiological ionic strength conditions (Bates et al., 2001; Tsu­
kita, 1997). The CD44 cytoplasmic domain binds to various cellular
skeletal proteins, which trigger different signaling pathways. Richard
et al. have shown that the inhibition of CD44, which has been pre­
dominately from standard isoforms, has halted Lyn activation (Bates
et al., 2001). In colorectal cancer, the overexpression of dominant-active
Lyn kinase has been associated with chemoresistance in PI3K/Akt
dependent manner (Bates et al., 2001). The CD44 molecule can be
inhibited using CD44-specific siRNA. CD44-siRNA transfection resulted
in increased apoptosis and decreased adhesion, cell viability. It has been
suggested that the main cause of apoptosis is the activation of caspase-3
by CD44 siRNA (Subramaniam et al., 2007). Also, CD44 knockdown
using shRNA (short-hairpin RNA) against CD44, reduces CD44 expres­
sion, then inhibits cell proliferation, invasion, migration, and apoptosis
were increased of the cancer cell. CD44 inhibition reduces the phos­
phorylation of some proteins such as GSK3β, Akt, PDK1, and β-catenin
levels. Reduce phosphorylated Akt led to cell cycle arrest (Park et al.,
2012). In another study, the use of Hibiscus sabdariffa (HPE) in human
CRC cell DLD-1, HPE altered the cytoskeletal structure of the cell,
decreased the MMP-2, MMP-9, and uPA expression, and suppressed FAK
and CD44/c-MET signaling in cells. Other findings indicate that HPE can
inhibit the metastasis of DLD-1 cells. It is suggested that the use of HPE
may be beneficial in patients receiving chemotherapy (Huang et al.,
2018).
5.6. Leukemia and CD44
Leukemia stem cells have several unique characteristics, such as
expression of stem cell surface markers, an activator of transcription
(STAT) pathway (STAT3 is an important transcription factor that regu­
lates proliferation, inhibits apoptosis, and cell growth), and the Janus
kinases (JAKs), which can interfere with hematopoietic stem cells dif­
ferentiation (Kanna et al., 2018). The only permanent treatment for
leukemia is the removal of leukemic stem cells (LSCs), a type of undif­
ferentiated cell that produces leukemic clones (Thapa and Wilson,
2016). Chemotherapy is one of the most effective therapy for patients
with acute myeloid leukemia (AML) (Yousefi et al., 2016). However, the
side effects of tyrosine kinase inhibitor drugs, e.g., skin rashes, vomiting,
nausea, diarrhea, heartburn, cardiac toxicity, muscle cramps, head­
aches, liver disorders, and pulmonary toxicity, might not bring desired
outcomes in affected patients (Briot et al., 2018; Montalban-Bravo and
Garcia-Manero, 2015). Therefore, new treatments should have the
highest response rate with the lowest side effects.
CD44 is a cell surface adhesion molecule and was first identified as
the home receptor of lymphocytes (Zoeller, 2015). CD44 was initially
recognized on hematopoietic stem cells, but research showing it on
leukemia- and cancer-initiating cells are also being reported. CD44s and
CD44v are both involved in maintaining the characteristics of stem and
cancer cells, including proliferation, migration, invasion, and relative
resistance of apoptosis and embedding in a niche. HA is placed in the
extracellular matrix after production by hyaluronic synthase. The major
HA receptor is CD44 cell hyaluronan and CD44 both are involved in drug
resistance. MDR gene expression is associated with CD44 activation
(Zoeller, 2015). Cell interactions via adhesion molecules, e.g., CXCR4
9
European Journal of Pharmacology 903 (2021) 174147
and CD44, are essential for AML development (Kupsa et al., 2015). The
adhesion of AML cells to the surrounding cells is one of the reasons for
developing chemoresistance in patients with AML (Becker, 2012; Meads
et al., 2009). CD44 is a cell surface receptor that is highly expressed in
AML cells (Aldehaiman, 2018). The interaction of CD44 with hyalur­
onan substantially contributes to tumor cell migration, adhesion, and
tumor cell survival (Gutjahr et al., 2015).
The interaction of CD44v3-HA in the cell can form the Oct4-Sox2-
Nanog complex and cause miR-302 transcription and expression of
drug resistance (Lilly Y. W. Bourguignon et al., 2012). Signaling induced
by CD44-HA interaction leads to nuclear translocation of Nanog and
miR-21 transcription and expression of the MDR1 gene (Bourguignon
et al., 2009). In another study, the interaction of CD44 with HA activates
signaling pathways such as transforming growth factor-β receptor type 1
(TGBβR1) and receptor tyrosine kinases (ErbB2 and EGFR) in the
plasma membrane (Toole and Slomiany, 2008) also mediates Ras family
GTPase or Src family (Bourguignon et al., 2008). Interaction HA with
CD44 causes the complex formation of several adapter proteins such as
Vav2, Grb2, and Gab-1, and also activates the path Ras, Rac1, and RhoA
(Bourguignon et al., 2008, 2004). These receptors activate protein ki­
nases (MAPKs) and PI3 kinases that result in the survival, proliferation
of tumor cells, invasion, migration, and chemoresistance (Bourguignon
et al., 2008). High molecular weight (HMW) hyaluronan activates CD44,
then connected actin and ERM (Ezrin/Radixin/Moesin) as result CD44
stabilizes MDR1 expression (Zoeller, 2015). The PI3K/Akt signaling
pathway is responsible for developing chemoresistance and tumor
development in patients with AML (Chen et al., 2015; Gadhoum et al.,
2016). Since increased expression of CD44v6 is associated with
short-term survival in AML patients, this marker can serve as a valuable
prognostic tool in patients with AML (Legras et al., 1998). Moreover, the
interaction of CD44 with hyaluronan is involved in the chemoresistance
of lymphoblastic leukemia and acute T cell lymphoid leukemia. This
interaction also leads to the development of myeloid leukemia (Hoofd
et al., 2016; Morath et al., 2016). The adhesion property of the CD44
molecule also confers the chemoresistant phenotype to adult T-cell
leukemia/lymphoma (Miyatake et al., 2013). Furthermore, treating the
B-cell chronic lymphocytic leukemia with CD40L has conferred
anti-apoptotic properties to tumoral cells (Kitada et al., 1999). Jin et al.
with transplanting human AML cells into non-obese diabetic-severe
combined immune deficient (NOD-SCID) and using mAb specific to
CD44 (H90) efficiently and selectively eradicated AML LSCs (Jin et al.,
2006). Also, A3D8 (The anti-CD44 monoclonal antibody) via the locking
PI3K/Akt pathway induces apoptosis or differentiation in acute myeloid
leukemia (AML) (Chen et al., 2015). Results show Targeting CD44 with
siRNA/CD44 (siRNA targeted CD44) causes increases apoptosis,
decreased proliferation, and resistance to ADM and ARA-C. Also, the
knockdown of CD44 decreases c-Myc and Bcl-2 synthesis (over­
expression of c-Myc and Bcl-2 in tumor cells are also increasing che­
moresistance) (Wang et al., 2014). Therefore, the availability of an
FDA-approved CD44 monoclonal antibody can now provide an ample
opportunity to treat patients with AML.
5.7. Gastric cancer and CD44
One of the malignancies with high prevalence and mortality in
developing countries is gastric cancer (GC) (Hong et al., 2019). GC is the
second most common cause of cancer death worldwide (Hartgrink et al.,
2009). Many tumor oncogenes or suppressors have been identified as
key players in the poor prognosis and tumorigenesis of GC, under­
standing specific molecular mechanisms and discovering new regulators
could be new therapeutic goals (Hong et al., 2019). One of the CSC
markers is CD44 (Kodama et al., 2017). GCs with CD44 expression can
generate spheroid colonies. In general, cancer cells (CD44+) tend to
migrate and invasion be more resistant to treatment (Sun et al., 2013).
CD44+ cells are related to important genes including cyclooxygenase 2
(COX-2) and MMP-1 (metalloproteinase-1), MMP-2, epidermal growth
Z. Yaghobi et al.
factor receptor (EGFR) genes, in various types of human cancers
including GC which may result in the formation of new tumors, migra­
tion, and resistance. An important feature of CD44 is that CD44 is a
hyaluronic acid receptor and is also able to interact with other ligands,
including MMPs and collagens (Sun et al., 2013). CD44 interacts with
hyaluronic acid to enhance intracellular signaling, including migration,
cell adhesion, and drug resistance. Advanced GCs are CD44v6 positive
(Kodama et al., 2017). CD44v6-positive patients have a poorer prognosis
(Yamaguchi et al., 2002). CD44v9-positive cells are also more potent in
suppressing the production of reactive oxygen species, CD44v9 interacts
with a glutamate-cysteine transporter binds and suppresses reactive
oxygen species resulting in drug resistance (Kodama et al., 2017; Tsu­
gawa et al., 2012). Also, H. pylori (Helicobacter pylori) infection can in­
crease GC risk. H. pylori infection can increase the expression of CD44v9
and CD44v6 in gastric carcinomas and gastric adenomas (Jang et al.,
2011). Inhibition of CD44 by shRNA reduced the production of smaller
tumors and spheroid colony formation in SCID mice (Takaishi et al.,
2009). There is evidence that miRNAs are important molecules in
regulating the response of cancer cells. For example, miR-145 (tumor-­
suppressive miRNA) via targeting the CD44 3′ UTR, inhibit CD44
expression and decreases chemical resistance (Zeng et al., 2017).
5.8. Gallbladder cancer, bile duct tumors, and CD44
Bile duct and gallbladder tumors are invasive adenocarcinomas that
arise from extrahepatic and intrahepatic bile ducts or the epithelial
lining of the gallbladder (Kawamoto et al., 2007). Due to late diagnosis
and lack of palliative care and adequate treatment methods, the prog­
nosis of bile duct tumors is mostly poor (Pahernik et al., 1998). Un­
derstanding the mechanisms that lead to cellular resistance may be more
effective in developing new treatments for bile duct cancer (BDC). CD44
is a cellular and multi-structural surface marker. It is involved in cell
differentiation, cell proliferation, angiogenesis, cell migration, and
presentation of chemokines, cytokines, and growth factors to specific
receptors and activation of some signaling pathways (Naor et al., 2002).
It was found in a study of invasive bile duct tumor cholangiocarcinoma
(CCA) patients with (CD44+) expression in biliary epithelia had a
shorter survival rate than patients with negative CD44 biliary epithelia
(Kunlabut et al., 2012). Many CD44 isoforms are widely expressed ac­
cording to cell type (Kunlabut et al., 2012). CD44s, CD44v (variant
isoforms) is related to metastasis, tumor growth, and prognostic. CD44s
+ cells increased invasiveness and chemotaxis in vitro. CD44s increase
the expression of transcription factors ZEB1 and ZEB2, which mediate
EMT (epithelial-mesenchymal transition) (Miwa et al., 2017; Tanno
et al., 2004). Often in BDC, Serine/Threonine Kinase AKT signaling
pathway increases resistance cell and inhibition of AKT activity may
have a positive effect in BDC patients treated with radiation (Tanno
et al., 2004).
6. Anti-CD44 monoclonal antibodies
Cancer recurrence, drug resistance, proliferation, and metastasis are
also major problems for cancer patients. Today, scientific advances have
been made in the treatment of cancer through immunotherapy with
monoclonal antibodies (mAbs). mAbs purposefully identify tumor cells,
resulting in toxicity they have less compared to chemotherapy drugs.
CD44 is known as one of the most common and important markers
associated with CSC, which plays an important role in causing malig­
nancy and resistance to chemical drugs in tumors such as breast, colon,
pancreas, and head and neck (Al-Hajj et al., 2003; Dalerba et al., 2007).
Anti-CD44 monoclonal antibodies can play a pivotal role in the control
and progression of cancer cells. For example, in acute myeloid leukemia
(AML), a malignant clonal disease, with the complication of abnormal
production of immature myeloid cells, monoclonal antibodies (mAbs,
H90, and A3D8) induced cell differentiation by inhibiting CD44 antigen.
In addition to differentiating AML cell lines, these mAbs can inhibit their
10
European Journal of Pharmacology 903 (2021) 174147
proliferation or even induce apoptotic (Gadhoum et al., 2004). Also,
CD44 antibodies were used to inhibit some processes such as lympho­
cyte migration, lymphohemopoiesis, and tumor metastasis (Zheng et al.,
1995). In another study of lung diseases, the use of anti-CD44 antibodies
on fibroblast cells increased apoptosis in cells by disrupting the adhesion
of fibroblasts to the substratum (Henke et al., 1996).
7. Conclusion
CD44, as a surface marker of CSCs, is responsible for epithelial-
mesenchymal transition, tumor development, and altering the cellular
cytoskeleton. CD44 can induce a chemoresistant phenotype in malig­
nant cells because CD44 up-regulates the expression of MDR, which is
responsible for the efflux of intracellular cytotoxic medications. There­
fore, targeting CD44 can provide an ample opportunity for overcoming
chemoresistance in various cancers.
Funding source
This study received no specific grant from any funding bodies.
Author contribution to study
ZY and BB devised the main conceptual ideas. ZY, MAS and KH wrote
the initial draft of the manuscript. ZY prepared the figures. AM, MT, SP,
and BB reviewed and edited the manuscript. BB supervised the study.
Author agreement
Enclosed please find a manuscript entitled “The role of CD44 in
cancer chemoresistance: a concise review”. On behalf of my coauthors, I
declare that:
1. All authors participated actively in the study and have read and
approved the manuscript.
2. The study complies with current ethical considerations.
3. The work reported has not been published previously nor is it
under consideration for publication elsewhere.
4. None of the authors has any conflicts of interest relating to this
work or its publication.
We would appreciate if you could consider our manuscript for pub­
lication in European Journal of Pharmacology.
Declaration of competing interest
The authors declare that there are no conflicts of interest.
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