CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells.

TL;DR: Recent observations have shown that CD44 intracellular domain (CD44-ICD) is related to the metastatic potential of breast cancer cells, however, the underlying mechanisms need further elucidation.

Abstract: CD44 is a cell surface adhesion receptor that is highly expressed in many cancers and regulates metastasis via recruitment of CD44 to the cell surface. Its interaction with appropriate extracellular matrix ligands promotes the migration and invasion processes involved in metastases. It was originally identified as a receptor for hyaluronan or hyaluronic acid and later to several other ligands including, osteopontin (OPN), collagens, and matrix metalloproteinases. CD44 has also been identified as a marker for stem cells of several types. Beside standard CD44 (sCD44), variant (vCD44) isoforms of CD44 have been shown to be created by alternate splicing of the mRNA in several cancer. Addition of new exons into the extracellular domain near the transmembrane of sCD44 increases the tendency for expressing larger size vCD44 isoforms. Expression of certain vCD44 isoforms was linked with progression and metastasis of cancer cells as well as patient prognosis. The expression of CD44 isoforms can be correlated with tumor subtypes and be a marker of cancer stem cells. CD44 cleavage, shedding, and elevated levels of soluble CD44 in the serum of patients is a marker of tumor burden and metastasis in several cancers including colon and gastric cancer. Recent observations have shown that CD44 intracellular domain (CD44-ICD) is related to the metastatic potential of breast cancer cells. However, the underlying mechanisms need further elucidation.

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MINI REVIEW
published: 07 March 2017
doi: 10.3389/fcell.2017.00018
Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 March 2017 | Volume 5 | Article 18
Edited by:
Mitsugu Fujita,
Kindai University, Japan
Reviewed by:
Sumit Sahni,
University of Illinois at Chicago, USA
Sigrid A. Langhans,
Alfred I. duPont Hospital for Children,
USA
*Correspondence:
Meenakshi A. Chellaiah
mchellaiah@umaryland.edu
Specialty section:
This article was submitted to
Cell Adhesion and Migration,
a section of the journal
Frontiers in Cell and Developmental
Biology
Received: 03 January 2017
Accepted: 21 February 2017
Published: 07 March 2017
Citation:
Senbanjo LT and Chellaiah MA (2017)
CD44: A Multifunctional Cell Surface
Adhesion Receptor Is a Regulator of
Progression and Metastasis of Cancer
Cells. Front. Cell Dev. Biol. 5:18.
doi: 10.3389/fcell.2017.00018
CD44: A Multifunctional Cell Surface
Adhesion Receptor Is a Regulator of
Progression and Metastasis of
Cancer Cells
Linda T. Senbanjo and Meenakshi A. Chellaiah
*
Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, MD, USA
CD44 is a cell surface adhesion receptor that is highly expressed in many cancers and
regulates metastasis via recruitment of CD44 to the cell surface. Its interaction with
appropriate extracellular matrix ligands promotes the migration and invasion processes
involved in metastases. It was originally identified as a receptor for hyaluronan or
hyaluronic acid and later to several other ligands including, osteopontin (OPN), collagens,
and matrix metalloproteinases. CD44 has also been identified as a marker for stem cells
of several types. Beside standard CD44 (sCD44), variant (vCD44) isoforms of CD44 have
been shown to be created by alternate splicing of the mRNA in several cancer. Addition
of new exons into the extracellular domain near the transmembrane of sCD44 increases
the tendency for expressing larger size vCD44 isoforms. Expression of certain vCD44
isoforms was linked with progression and metastasis of cancer cells as well as patient
prognosis. The expression of CD44 isoforms can be correlated with tumor subtypes
and be a marker of cancer stem cells. CD44 cleavage, shedding, and elevated levels
of soluble CD44 in the serum of patients is a marker of tumor burden and metastasis
in several ca ncer s including colon and gastric cancer. Recent observations have shown
that CD44 intracellular domain (CD44-ICD) is related to the metastatic potential of breast
cancer cells. However, the underlying mechanisms need further elucidation.
Keywords: CD44, cancer, metastasis, hyaluronic acid, migration, angiogenesis, invasion, CD44-ICD
CD44 INTRODUCTION
CD44 is a transmembrane glycoprotein also referred t o as P-glycoprotein 1. It is encoded by a
single gene on chromosome locus 11p13 (
Underhill, 1992; Iczkowski, 2010). CD44 is ubiquitously
expressed throughout th e body and has a molecular weight of 85–200 kDa (Bas akran, 2015). The
standard CD44 (sCD44) is the conserved form with a molecular weight of about 85–90 kDa
protein which is made of transcription of exons 1–5 a nd 16–20 that are spliced togeth er (Rall
and Rustgi, 1995; Rudzki and Jothy, 1997). The primary domains of CD44 are the extracellular
domain (or ectodomain), the transmembrane domain, and the intracellular domain/cytoplasmic
domain (
Iczkowski, 2010). The extracellular domain interacts with the external microenvironment
and senses stimuli in the external microenvironment (Underhill, 1992). The transmembrane
domain provides an avenue for interacting with co-factors and adaptor proteins as well as
directing lymphocyte homing (
Underhill, 1992; Williams et al., 2013). CD44 intracellular domain
(CD44-ICD) has a short-tail and long-t ail configuration with functions in nuclea r loc a lizat ion and

Senbanjo and Chellaiah Role of CD44 in Metastasis
transcription mediation (Okamoto et al., 2001; Williams et al.,
2013). Our current understanding of the dual role of CD44 in
cancer progression is summarized in Figure 1 below.
ISOFORMS OF CD44
Multiple isoforms of CD44 can be generated due to insertion of
alternative exons at specific sites within the extracellular domain
(
Cichy and Puré, 2003). The variant isoforms of CD44 (CD44v)
comprises of exon 6–15 spliced at various sites between exons 5
and 16 of the standard isoform (
Goodison et al., 1999; Zeilstra
et al., 2014). The expression of distinct CD44 isoforms appears
to be necessary for the progression of human tumors (Günthert
et al., 1995; Wang et al., 2009). One or multiple splice variants
and standard CD44 may be expressed in cancer cells. There
is an increased chance of expressing larger isoforms like that
of CD44v8-10 in pancreatic cancers (Rall and Rust gi, 1995)
and CD44v6 in colorectal cancer (Yamane et al., 1999). The
expression of CD44v6 is well-known as a useful marker of tumor
progression and prognosis in colorectal cancer (Yamane et al.,
1999). In cultured supernatants from prostate cancer cell lines
derived from bone metastasis (PC3), soluble CD44, and variant
6 isoform (v6) was identified, however, it was not identified in
lymph node metastatic prostate cancer cell line (LNCaP,
Stevens
et al., 1996; Desai et al., 2009; Gupta et al., 2012). The switch from
standard CD44 to CD44v6 improved survival and adhesion in
prostate cancer (PC3) cells (Gupta et al., 2013b). The expression
of CD44v6 in colorectal cancer is enhanced by cancer stem cells
expression (Todaro et al., 2014).
CD44 EXPRESSION IN NORMAL AND
TUMOR CELLS
The ubiquitous transmembrane cell surface mole cule CD44
is widely distributed in normal adult and fetal tissues. CD44
standard isoform was originally isolated from hematopoietic cells
but now it is found in a variety of tissues e.g., central nervous
system, lung, and epidermis. In comparison, the distribution
of CD44 variant isoforms is restricted and expressed on a
selection of epithelial cells (
Sneath and Mangham, 1998). The
isoforms with restricted distribution and exon sequence may
have different functions as compared to the standard isoform
of CD44. Keratinocytes, macrophages, and sele ct epithelial cells
express the variant CD44 (CD44v) isoforms and are present on
tissues at various stages of development (
Sneath and Mangham,
1998). In normal tissues, the import ance of CD44 is vit al in th e
regulation of hyaluronic metabolism, activation of lymphocytes,
and release of cytokines. However, targeting of CD44 resulting in
its loss leads to the disruption of hyaluronic metabolism, wound
healing, and keratinocyte proliferation (Yu and Stamenkovic,
1999). Among many of CD44 functions, one is to make ce ll
lines that are non-metastatic become more metastatic (Heider
et al., 1993). The details that confer CD44 metastatic potential in
human malignancies is t he subject of further elucidation. Prostate
cells that are benign express higher CD44 variant 5 isoforms
(CD44v5), whereas neoplastic prostate cells express hig her levels
of CD44s (
Dhir et al., 1997; Desai et al., 2009; Gupta et al., 2013a).
FIGURE 1 | CD44 transmembrane receptor function. CD44, a
multifunctional receptor can control biological functions involved in cancer cell
dissemination and metastasis. CD44 can be sequentially cleaved by
membrane type 1 matrix metalloprotease (MT1-MMP) and then presenilin-1/γ
secretase induced by ligands [osteopontin (OPN), hyaluronic acid (HA), etc]
binding. Cleavage produces (1) extracellular domain (ECD ) fragment. (2)
CD44β like peptide or transmembrane domain (TMD), and (3) CD44
intracellular domain (ICD) fragment. CD44—ICD translocates into the nucleus
to activate transcription of genes important in metastasis and cell survival.
Adapted from
Thorne et al., 2004.
Various breast c a ncer cells show abnormal expression of CD44
including heterogeneously expressing CD44 isoforms (Basakran,
2015).
CD44 RECEPTOR-LIGAND INTERACTION
CD44 is known to interact with various ligands and this
interaction is crucial for its many cellular functions (
Goodison
et al., 1999
). There are several well-known ligands of CD44
including hyaluronic acid (HA), osteopontin (OPN), collagens,
and matrix metalloproteinases (MMPs) (Goodison et al., 1999).
CD44 effects on cell migration and growth are dependent on its
specificity to ligands (Weber et al., 1996).
Hyaluronan (HA)
HA is a glycosaminoglycan that is a ubiquitous component
of the extracellular membrane. It is considered the major
ligand for CD44 and can bind CD44v isoforms that are
ubiquitously expressed. Through binding of CD44, HA can
activate cytoskeleton and matrix metalloproteinases (MMPs)
signaling involved in tumor progression (
Bourguignon et al.,
2014). Multiple regions of the c ytoplasmic domain of CD44 can
promote enhancement of HA binding, however, the role of the
cytoplasmic domain in mediating the binding does not require a
specific amino acid sequence in T-lymphoma cells (
Perschl et al.,
1995). HA can exist in high molecular weight or low molecular
weight form due to cleavage into varying sizes. In breast cancer
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Senbanjo and Chellaiah Role of CD44 in Metastasis
cell lines, high molecular weight HA is involved in tumorigenesis,
antiangiogenic and anti-inflammatory responses. However, low
molecular weight HA has been shown to promote cell motility,
CD44 cleavage and angiogenesis. Therefore, the size of HA
ligand is important for th e biological function (Louderbough and
Schroeder, 2011).
Osteopontin (OPN)
Several studies have demonstrated an elevated expression of
OPN in highly invasive met astatic human cancers (
Tuck et al.,
2007). Integrin αvβ3 and CD44 are receptors for OPN and
can interact with α
v
β
3
through its functional arginine-glycine-
aspartic acid (RGD) cell binding sequence (Thalmann et al., 1999;
Desai et al., 2007). Prostate cancer growth and progression is
shown to be mediated by paracrine and autocrine signaling of
OPN (Thalmann et al., 1999). CD44-OPN interaction induces
cell migration out of the bloodstream to sites of inflammation.
The migration of cells and subsequent invasion at distant sites
involves a complex sequence of events (Weber et al., 1996).
Variant CD44 isoforms bind to OPN independent of RGD
sequences present at the N-terminal domain of CD44 (
Katagiri
et al., 1999). OPN binding to CD44 variants/bet a1-containing
integrin promotes cell spreading, motility, and chemotactic
behavior in rat pancreatic carcinoma (Katagiri et al., 1999).
OPN increases surface expression of standard CD44 (sCD44)
in osteoclasts and both sCD44 and variant isoforms in human
melanoma and PC3 cells (Chellaiah et al., 2003; Samanna et al.,
2006; Desai et al., 2007). Osteopontin regulation of surface
expression of CD44v6 and sCD44 was observed in breast and
hepatocellular cancer cells (Gao et al., 2003; Khan et al., 2005).
Matrix Metalloproteases (MMPs)
Matrix metalloproteinases (MMPs) are important extracellular
matrix proteins that are involved in degradation of the
extracellular matrix. They are also important during
development, wound healing, bone resorption, and angiogenesis
(
Paiva and Granjeiro, 2014). There is evidence suggesting that
MMP-9 and CD44 associate in mouse and human tumor cells
resulting in MMP9 activity localization on the cell surface (Yu
and Stamenkovic, 1999; Gupta et al., 2013a). The interaction of
CD44 and proteolytic form of MMP-9 is particularly involved
in the invasion of prostate cancer cells (PC3) derived from bone
metastases (Desai et al., 2007). Therefore, the ability of CD44 to
localize proteolytically active MMP-9 to th e tumor cell surface is
important for tumor invasion (Yu and Stamenkovic, 1999).
CD44 ROLE IN MIGRATION/INVASION,
ANGIOGENESIS, AND BONE METASTASIS
Migration and Invasion
CD44 receptor has the potential to integrate adhesive and
signaling activities to modulate migration/invasion processes
during cancer progression (
Lokeshwar et al., 1995). The
mechanisms by which CD44 receptors mediate migration,
proliferation, survival of tumor cells through HA-mediated
signaling have been widely studied (
Bourguignon et al., 1998,
2001, 2004; Kuniyasu et al., 2001; Wang and Bourguignon,
2006a,b; Wang et al., 2009). Changes in cell shape and formation
of adhesive structures are regulated by the dynamic regulation
of the actin cytoskeleton. The dynamic regulation of the actin
cytoskeleton and t he specialized structures involved in migration
are regulated by the temporal and spatial localization of actin-
binding proteins (
Chellaiah et al., 2000; Linder and Aepfelbacher,
2003; Desai et al., 2008). The surface expression of CD44 along
with its interaction with matrix metalloproteinase 9 (MMP9)
on the surface of the cell results in secretion of active MMP9,
migration, and invasion of PC3 cells (Desai et al., 2007, 2008;
Gupta et al., 2013a). Disruption of CD44/MMP9 interaction
on the cell surface reduces migration and invasion of PC3
cells. When MMP9 i s knockdown, CD44 expression switches to
variant 6 (v6) isoform. This results in a less invasive phenotype
due to lack of expression of sCD44 and inability to form
invadopodia (Gupta et al., 2013a). CD44v6 expression inversely
correlates with pathologic stage and disease progression and
positively correlates with PSA-free survival in prostate cancer
(
Ekici et al., 2002). However, expression of CD44v6 in non-
metastatic rat carcinoma cells has been shown to convert them
into metastatic cells and promote tumor progression (Günthert
et al., 1991; Seiter et al., 1993). Furthermore, CD44v3 has
been shown to upregulate the function of cytoskeleton through
ankyrin to activate the actomyosin contractile complex in order
to mediate cell migration in head and neck squamous carcinoma
cell line. Transfection of v3 cDNA into non-expressing cell lines
also resulted in a significant incre ase in cell migration but not
proliferation (Franzmann et al., 2001; Wang et al., 2007 ). CD44
variants have also been shown to function as a co-receptor for the
activation of growth-promoting tumor receptor tyrosine kinases
(
Orian-Rousseau et al., 2002, 2007).
Angiogenesis
The formation of new blood vessels (angiogenesis) is required
for tumor cell to disseminate and migrate to distant organs.
Past studies have identified CD44 expression on endothelial
cells (
Liesveld et al., 1994; Xu e t al., 1994) and this controls
the formation of blood vessels (Trochon et al., 1996; Savani
et al., 2001). Inhibition of CD44 therefore results in impaired
formation of vessel-like networks (Savani et al., 2001; C ao et al.,
2006). Endothelial cells were found in increased numbers in
prostate cancer tissues in relation to normal tissues (Wang
et al., 2013). When CD44-null mice was used to study in
vivo angiogenic responses, wound healing and vascularization
were both impaired in matrigel implants. Therefore, metastasis
formation is also linked to vascular CD44 expression (
Cao et al.,
2006). Adhesion of cancer cells to vasculature and enhanced
expression of CD44 (CD44s and/or CD44v) by angiogenic
factors (e.g., VEGF) produced by tumor cells might lead to
facilitated extravasation via angiogenesis. Furthermore, the role
of CD44 in tumor angiogenesis is enhanced by its binding to
immobilized HA (Griffioen et al., 1997). CD44 variants are shown
to have binding domains for various growth factors including
vascular endothelial growth factor (VEGF), heparin-binding
basic fibroblast growth factor and heparin binding epidermal
growth factor (
Bourguignon et al., 1998, 1999; Kalish et al., 1999).
Analysis of tissue microarray and lysates of prostatic tumor cells
showed that OPN and VEGF expression was more pronounced
in prostate cancer as compared to benign or normal prostate
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Senbanjo and Chellaiah Role of CD44 in Metastasis
tissues. It was suggested that an increase in micro vessel number
and expression of CD44 might be useful diagnostic markers of
metastasis of breast cancer (Ozer et a l., 1997).
Bone Metastasis
Breast and prostate cancer cells ability to metastasize to bone
is based on their ability to arrest on, adhere to, and extravasate
across the bone marrow endothelium into the underlying bone
matrix (
Draffin et al., 2003). In prostate cancer cells, the selective
adhesion of these cells to bone marrow epithelium is based on the
role of adhesive properties of integrin receptors. Prostate cancer
cells have been involved in strong interaction with the bone
marrow endothelial cells (Draffin et al., 2004). There currently
exists a dissension between clinical and experimental data in
literature re garding t he importance of sCD44 in breast cancer
disease progression. A recent study suggests that breast cancer
models show the expression of CD44 stand ard and variant
isoforms which increase disease-progressing and metastatic
behavior (
McFarlane et al., 2015). HA and CD44 co-localize in the
bone marrow sinusoidal epi thelium, which is a site of metastasis
of breast cancer. This suggests the contribution of HA-CD44
to the efficiency of distant metastasis to bone in breast cancer
cells (McFarlane et al., 2015). Cells producing low levels of CD44
have lower ability to form tumor sphere in vitro. Furthermore,
CD44 is a marker for cancer stem cells (Jaggupilli and Elkord,
2012; Cho et al., 2015; Stivarou and Patsavoudi, 2015) and CD44
expressing cancer stem cells increases the likelihood of bone
metastases through its interaction with HA. Therefore, CD44-
HA interaction could be a potential target for reducing bone
metastases. CD44 signaling in prostate cancer cells has also
been shown to regulate key proteins (i.e., RANKL and MMP9)
involved in osteoclast differentiation and tumor metastasis
(
Gupta e t al., 2012). Runx2 is a master transcription factor with
important roles in osteoblast differentiation. Transcription of
many osteoblast and bone formation related factors such as OPN,
osteocalcin, and collagen type I are regulated by Runx2 (Akech
et al., 2010).
ROLE OF CD44 AS A TRANSCRIPTIONAL
FACTOR
Proteolytic cleavage that occurs at the extracellular domain
releasing soluble CD44 has long been recognized. However,
recent studies have shown that CD44 can undergo further
sequential proteolytic processing by membrane type 1 matrix
metalloproteases (MT1-MMP) and presenilin-1/y-secretase to
produce the extracellular domain and intracellular domain
(ICD) fragments. Presenilin-1/y-secretase cleavage occurs at the
intramembrane site releasing two cleavage products of ∼25 and
∼16 kD a size. The 12 kDa ICD translocates to the nucleus to
activate transcription of several proteins including CD44 itself
(
Okamoto et al., 2001; Nagano and Saya, 2004; Thorne et al.,
2004). Consequently, if t his cleavage can be inhibited through
metalloprotease inhibitors, it can serve as a therapeutic way of
preventing tumor progression and metastasis (
Nagano and Sa ya,
2004). The translocation of CD44-ICD to the nucleus initiates
the process of transcriptional regulation via it binding to novel
promoter response element thereby regulating transcription of
several genes that are involved in cell survival during stress,
inflammation, oxid ativ e glycolysis, tumor invasion (
Okamoto
et al., 2001; Miletti-González et al., 2012 ).This sug gests a
mechanism for the multifunctional role of CD44 in cancer
cell metastasis and metabolism (Miletti-González et al., 2012).
Nuclear translocation of the intracellular domain also shown to
interact with stemness factors (C ho et al., 2015). CD44-ICD is
linked with the regulation of MMP-9 gene i n prostate and bre ast
cancer cells through its interaction with the transcriptional factor
RUNX2 (Miletti-González et al., 2012).
CONCLUSIONS
The multifunctional glycoprotein CD44 can undergo alternative
splicing events to produce CD44 variant isoforms that are more
restricted in their distribution as compared to the standard CD44
isoforms (
Rall and Rustgi, 1995). The ubiquitously expressed cell
surface protein is primarily involved in aggregation, migration,
and activation of cells, these functions are mediated through
the adhesive properties of CD44 (Heider et al., 1993). Initially
described for hematopoietic stem cells, it has since been
confirmed as a marker of cancer stem cells (Bourguignon et al.,
1998). CD44 interacts with a variety of ligands and can undergo
sequential proteolytic processing resulting in the generation of
CD44-ICD. CD44-ICD is k nown to translocate into the nucleus
to activate gene transcription (Okamoto et al., 1999). Though the
information provided here provides a c omprehensive review of
the literature thus far, there exists some discourse in the effect of
ICD as the main modulator of metastatic events in cancers. To
further substantiate CD44’s effect in metastasis, research into the
specifics will need to be completed to address this.
AUTHOR CONTRIBUTIONS
LS and MC drafted the manuscript and equally contributed in
editing and rewriting final contents.
FUNDING
This work was supported by a research grant to MC from the
National Institute of Health - National Institute of Arthritis and
Musculoskeletal and Skin Diseases (5R01AR066044).
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Frontiers in Cell and Developmental Biology | www.frontiersin.org 5 March 2017 | Volume 5 | Article 18