Download CD44: Tumor Marker

CD44 as a potential diagnostic Tumor Marker
Abstract
CD44 is one of cellular protein intensively studied in relation to carcinogenesis in last
decade. It is found relatively altered during inflammatory responses and cellular malfunctioning
during tumor progression. Tumors of epithelial origin express CD44 in multiple isoforms
referred as variants. Some isoform were related to specific type of cancer cells. An increase of
CD44 specific isoforms was detected in certain leukemic proliferations. Most published data
indicated a partial involvement of CD44 in cancer cells either in invasiveness or selfrenewability. Nevertheless, none of them were certain about exact mechanism by which CD44
participate in growth of cancer or inflammatory response.
This review focuses on CD44 prevalence in cancer cell. It considers tumorigenic
behavior of cells that highly express CD44 as an early marker for neoplastic stem cell
proliferation. Multiple examples of tumor were discussed in this paper with an emphasis of two
solid tumors that are breast and colon cancer.
Introduction:
CD44 is a trans membrane glycoprotein that has various functions in cell division,
migration, adhesion and signaling. CD44 normally binds to its primary ligand hyaluronic acid
(HA). This binding thought to be responsible about cellular signaling and might regulating
other biological process within cells. Cells within a tissue interact either through intracellular
matrix (ICM) or through cellular junctions. CD44 as an adhesion molecule is enabling cell
communication by cell-cell signal transduction 1. Beside above-mentioned role, CD44 also
mediate the signal transduction of HER and MET receptor tyrosine kinases and work as a
platform for some growth factors as well as heparan sulphate proteoglycans 2.
CD44 with a molecular weight that is around 85-200 KDa, The studied trans-protein is
widely expressed almost over all body cell types. These cell surface glycoproteins can be
found in leukocytes, fibroblasts, epithelial, mesodermal and neuroectodermal cells 1. This
distribution makes it a great target to investigate since it has been found in many cancer stem
cells as well. CD44 prevalence in cancer cell attracts our attention to focus on its relation to
molecular onset of tumor progression. This study considers the tumorigenic behavior of cells
that highly express CD44 as an early marker for neoplastic stem cell proliferation. Multiple
examples of tumor were discussed in this paper with an emphasis of two solid tumors that are
breast and colon cancer
Genetic structure:
Scientists study CD44 genetic composition in human cells found that CD44 gene
located on the short arm of chromosome 11. It contains 50 KB of human DNA. CD44
chromosome is consisting of 20 exons that 12 of them have a role in splicing. Exons 1-5 give
rise of the constant region of the extracellular domain. Whereas 6-15 exons are encode for
variable side of extracellular domain. Proximal region of extracellular domain encoded by
exon 16 and 17. Exon 18 is a constant exon that encodes hydrophobic region and first 3
amino acid of cytoplasmic tail in CD44. Exon 19 is rich with A and T un-translated region
but it is believed that generate a 3aa short cytoplasmic tail. Last exon is the 20th, it participate
in the production of the long cytoplasmic tail of CD44.
Fig.1. CD44 molecular structure, a comparison diagrams between standard and variants.
This figure illustrates different exon of CD44.(Top) Green part shows constant region of mRNA included in
every possible variant. Other part (red) is variant exon that might be selected via alternative splicing of RNA.
(Bottom) shows the different domain of CD44 molecule. Trans-membrane domain, contain 269-289 a.a, then
extracellular domain where variant isoform is located with 292-300 a.a. Extracellular domain is forming the
binding site for hyaluronate acid. Extracellular domain structurally maintained by disulphide bond3.
CD44 Isoforms
CD44 has more than 20 isoform that generated out of RNA alternative splicing. These
isoform regulate and participate in cellular differentiation. The commonly known isoform are
only 12 isoforms. These isoforms known as variants and symbolize by “v”. The
nomenclature for it is CD44v#. These variant can be isolated out of any normal functioning
cells but also it can be observed in pathological cells. CD44H is a hematopoietic isoform
which also known as the standard isoform because it is the simplest isoform. CD44H or
CD44s is the most commonly distributed isoform. It expressed on all cell types of blood
including white blood cell and Natural killers. Another good example of the wide diversity of
CD44 isoforms is the CD44 E, which is weakly expressed by epithelial cells. Mononuclear
white blood cell also expresses an important isoforms CD44 R1 and R2, it also were isolated
out of granulocytes and some leukemia’s. However, specific CD44 variants have been found
highly expressed in certain cancer metastatic cells stem cells1. For example, CD44v6 is
suggested to be involved in breast and colorectal cancers 4. The observation overly expressed
certain variant with specific cancers can lead to a correlated relation in incidence. The high
frequency of variant CD44v6-v10 reported in metastatic growth, for instance, could indicate
that exon v6 boost metastasis of cancer cells especially in lymphoma 4, nevertheless its
function is not clear yet. Following is a table illustrates some biological functions of CD44
variants:
Table.1 CD44 variants and related biological functions 5
CD44 variant
Biological Function
CD44v1
Produces truncated protein as a result of premature termination of codon.
CD44v2
It function is not been identified in stem cells, CD44v2-10 overexpression been related
to metastatic tumors of SKHep1 cells.
CD44v3, 8-10
Is found in more than 90% of adenomas and colorectal carcinomas.
CD44v4
It mediates adhesion of breast cancer cells to endothelial monolayers through binding of
E-selectin
CD44v5
SRm160 and Sam64 (splicing co-activator) regulate CD44v5 expression during RNA
splicing. Reducing v5 expression in vitro is found to impair the invasiveness and
tumorgenicity in HeLa cells.
CD44v6
In colon cancer, CD44high associated with increase formation of sphere and betacatenin phosphorylation.
CD44v7
CD44v7+/+ in bone marrow stromal cells support homing of hematopoietic cell
progenitors. Indeed, treating CD44v7 with specific antibody promoting the production of
mononuclear cell and its proliferation into peripheral blood circulations.
CD44v8-10
Found to suppress Reactive Oxygen Species (ROS) induced activation of p38MAP cell
signaling pathway. Cells express CD44v8-10 resist antioxidant treatment. And more
efficiently enhance GSH synthesis.
CD44v9
CD44v9/HA binding is required for AR gene synthesis. CD44v9 and HGF interaction
promote phosphorylation of cMet and IGF1R (included in cell growth signaling).
CD44v10
It widely expressed by bone marrow stromal cells. CD44v10 promote progenitor cell to
maturate and differentiate into primary B cells. CD44v10 blocking antibody treatment
could provide a mobilization of progenitor cells and delay maturation.
Pathological role of CD44:
CD44 is found highly expressed in many diseases. It has been found in cancerous,
inflammatory and auto-immunological diseases. In order to find a precise relation of CD44 to
specific cancer, scientists deeply investigated CD44 isoforms to correlate specific isoform
with certain types of cancer stem cells and inflammatory immunological reactions. It has been
found that CD44 level raised in many tumor malignancy, chronic inflammatory reactions and
autoimmune dysfunctions. For example, CD44v6 have been associated with the
aggressiveness of human non-Hodgkin’s lymphomas1.
Immunological response is mediated through variety of cellular and soluble element. Tcell lymphocyte and dendritic cells are evolved with CD44 expression. CD44 engaged in rearrangement of cytoskeleton and adhesion of T-cell lymphocytes. TCR signaling pathway is
initiated by CD44 and associated tyrosine phospho-kinases p56lck/p59fyn 6.In dendritic
cells(DC), cross-linking of CD44 with mAb is promoting DC aggregation and maturation. It
also increases secretion of cytokines such as IL-8, TNF-alfa and IL-1beta. On the other hand,
treating DC with anti-CD44 mAb found to inhibit T cell activity in vitro 7. The binding of
MHC peptide with TCR is mediated through APC-T cell junction. These highly organized
junctions referred to as immunological synapses. Immunological synapse during allogeneic
binding between T cell and dendritic cells is recruiting CD44, which causes further activation
in T cell 6.
Binding of CD44 to its ligand HA regulates immuno-inflammatory response. For
instance, IL-5 is the major interleukin that responsible for eosinophilic inflammatory asthma,
interestingly, has been seen to promote the expression of CD44 in human eosinophil and in
murine B cell 1.
Moreover, scholars reveal that CD44 promotes homing of CSCs in many type of solid
tumor such in breast and prostate cancers. It mediates leukemia stem cells in homing to their
niches. Interestingly, CD44 expression was down regulated when CSCS introduced to cancer
suppressor elements such p53 and microRNA 34a 8.
CD44 interactions in stem cells:
The CD44 is a glycoprotein receptor that activated by the binding to its major ligand
HA. This binding regulates stem cells homing. In hematopoietic stem cells, CD44 mediate
these cells homing on bone marrow. Platelet derived growth factor stimulates mesenchymal
stems cell (MSCs) to produce more CD44 that facilitate cell traveling through extracellular
HA binding. This process is suggested to be helpful in recruitment of MSCs during tissue
development and healing 5.
CD44/HA binding seems to interact with different intrinsic niche factors. One common
pathway is the reaction with extracellular heparan sulphate. Heparan sulphate known to bind
with protein, give rise of heparan sulphate proteoglycan. Heparan sulphate moiety enables
CD44v3 to bind with factors such HGF, FGf2 and HB EGF 9. Growth factors mediate CD44
to link to tyrosine receptor kinase (RTKs) to work as cellular signals transducer. On the other
hand, CD44 could be also interacting with integrin. Integrin is a cell adhesion molecule
linking extracellular adhesion molecules to intracellular actin cytoskeleton 10. Integrin in
general found to have a role in cell-to-cell signaling, cell differentiation, proliferation and
migration. So, CD44 and integrin association in these bimolecular interactions could lead to
an assumption that CD44 mediate integrin functions in cell 5.
CSC is synthesizing HA (the primary ligand for CD44) to attract tumor-associated
macrophages (TAM) in the CSC niches 11. CSCs and TAMs produce oncogenic growth factor
PDGF-BB that keep tumor cell in a sustained proliferative phase. As a result, this interaction
recruits stromal cells into CSC niche. Stromal cells are known to produce multiple growth
factors that regulate stem cells activity and reproductively 5.
CD44s interaction with HA plays a crucial role in cell invasiveness. Flushing an in vitro
culture of breast cancer cells with HMW HA motivate invasion of tumor cells by 45%. That
conclude the availability of HA facilitates cells invasion. Cell invasion can be inhibited by preincubated the matrigel with anti-CD44s or HAOligo-6. This approach indicates that interaction
between HA and CD44 is pivotal in this process. The mechanism of how HA affects invasion
remains unclear. HA is found more concentrated in premalignant and malignant cell than normal
cells which support the theory that it has a role in cancer invasiveness 12.
CD 44 and Breast cancer
Breasts’ cancer cells show a remarkable heterogeneity and diversity among breast
cancers and within tumors. Examining breast cancer cell with a technique known as Gene
Expression Profiling, cancer cells show a diverse population of cell subtypes. The amount of
CD44 and another surface protein CD24 were both abnormally expressed in breast cancer
cells 2. CD44/CD24 ratio could be a guideline for early detection of a neoplastic growth in
human breast.
During last ten years, clinical studies investigate the reason for elevated expression of
CD44 found on the cell surface isolated of breast cancer patient. Most studies claims that
there was no “statistically significance” between CD44 overexpression and growth/metastasis
of Breast tumor. However, Fillmore & Kuperwasser, 2007 state that there is a correlation
between the irregularity of CD44+/CD24- ratio in breast cancer cells and the mesenchymal
like phenotype (MDA. MB231, SUM159 and SUM1315) they also suggested that CD44 is a
basal line cell like could be used as marker for cases with poor prognosis of breast cancer.
While CD24 expression was abundance in luminal differentiated type breast cancer 13.
By surfing on recent and old studies that shed lights on CD44 mal-functioning in breast
cancer, we find a discrepancy of the outcomes and justifications which can be referred to
discrepancies in techniques been used and/or sample storage/processing methods. In 2011,
study of Olsson et al.2 used more advanced molecular techniques including real time
polymerase chain reaction (RT-PCR) and Western blot were used to examine the associations
between the mRNA expression of CD44 isoforms and the cancer stem cell phenotypes CD44
of 151 frozen breast tumor samples. Unlike antibody antigen dependent assays, this technique
measures the level of various isoform in breast cancer stem cells. It founded a heterogeneous
expression of CD44 isoforms in different cell line of breast cancer. Surprisingly, CD44s
isoform were detected highly expressed in mesenchymal cell line. CD44 maintain important
role in different subtypes of breast cancer. It might acquire an oncogenic signaling pathway
since it have been found interfering with the expression of well-known oncogenic markers
such HER2, ER and PgR .
Since CD44+/CD24 - ratio is highly expressed in cancerous cells in general, it is also
important to investigate whether it has a role in chemotherapy resistance and relapsing of
breast cancer. Li and co-researchers14 conducted an experiment on human cancer breast cells
to identify the role of CD44 in breast cancer cells. Initially, breast cancer cell expressed high
level of CD44 and low CD24 level. By using conventional chemotherapy on in vitro, isolated
cancer cell has shown an increased expression of CD44+/CD24- and formation of
mammosphere but there is (non-statistically significant) reduce in expression when treated
with lapitine. That indicate an intrinsic chemical resistance of cells has a high expression of
CD44 14.
Receptor tyrosine kinase and CD44:
Receptor tyrosine kinase (RTKs) is a cellular surface receptor for many growth factors
and cytokines that regulates cellular proliferation and functioning. RTKs were sorted out as
critical key factors in initiation and development many cancers15. CD44 mediates and
promotes activity of RTKs in tumor cell. For example, in ovarian cancer binding of HA to
CD44/N-WASP is promoting ErbB2 kinase activity. As a result, beta-catenin phosphorylation
increases, then phosphorylated beta-catenin diffuses into the nucleus and bind to TCF/LEF
which promote the transcription16. Another example of growth factor/ CD44 intervention
found with transforming Growth Factor- 1ß (TGF-1ß) where CD44/EGFR interaction is
promoted by binding of HA (primary ligand for CD44). In turn, CD44/EGFR interaction
activates MAP-K/ ERK pathway leading to an increase TGF-ß1 dependent fibroblast
proliferation17. In insulin like growth factor receptor-1which responsible for uncontrolled
proliferation of cancer cell18. CD44v6 along with IGF1R mediate homing of multiple
myeloma cells to bone marrow18.
CD44/ RTKs signaling pathway regulates microRNAs expressions. Binding of CD44 to
HER2 elevates the expression of metastasis- associated protein type 1(MTA1) in gastric
cancer cells. MTA1 deacetylate H3 histone and silence the promoter region for miR139
leading to reduction in miR139 expression. In turn, that inhibits C-X-C receptor 4 20.All in
all; the rising in HER2/CD44 expression along with a reduction of miRNA 139/CXC4
expression could be a comprehensive element for gastric tumor’s growth and metastasis.
Above-mentioned examples indicate the influence of CD44 on RTKs physiocellular
activity. However, CD44 is not primary factor that activates RTK’s mutations but it has been
pointed out in many studies CD44 were isolated with RTKs in tumors of different origin.
CD44 in intestinal and Colon cancers:
In intestinal cancer stem cells CD44 variants 4-10 detected highly expressed in
intestinal cancers of mice. It is questionable whether CD44 variants regulate or has an effect
on the renewability of cancer stem cells in intestinal human cancers? CD44 standard isoform
(S) never has been isolated of CSC, however other variant of CD44 were massively found in
such tumors. Alternative splicing for CD44 mRNA produces many variants of CD44, which
makes it difficult for scientist to track down the exact function for each isoform on CSCs. For
example, CD44v4 that found to mediate cell adhesion to endothelial monolayer in breast
cancer5 has also been found in colon cancer with undetermined role. Indeed, multiple studies
use CD44 antibodies, which are not precise enough to sort out which exact variant initiate or
regulate CSCs differentiation in colon. Although scientists all agrees on the tumorigenicity of
CD44 but still the exact function of CD44 in tumor cell is not clear 8.
In 2011, Ishimoto and his co-researchers conducted experiments to investigate
oxidative stress resistance in CSCs in intestinal tumors. Normal Tumor cells posses a
defensive mechanism against oxidative free radicals that eradicate CSCs. Secretion of redox
enzymes and other anti-oxidant is one strategy CSCs uses to fight for its own survival.
Reduced glutathione (GSH) is another agent to protect cancer cell of oxidative anticancer
chemicals. Ishimoto et al 2011, assess these metabolites in intestinal CD44v and found them
high. That concludes, CD44v ROS resistance mechanism abrogates apoptosis and promotes
longer life span by fight against normal oxidative elements for such cells. The study
suggested that by targeting CD44v ROS defense mechanism scientist could exterminate
gastrointestinal cancers and force these cells to follow normal apoptotic cellular cycle 21.
CD44 and leukemia:
Normal hematopoietic cells proliferation in adult is occurring in bone marrow and some
of them undergo further maturation in other different organs. Evidence of recent studies
suggested that CD44 regulates normal hematopoietic cell proliferation. In vitro treating of
long-term bone marrow culture (LTC) cells with anti-CD44 antibodies during differentiation
stage shows a reduction in number of mature cell22 only feasible explanation for that is CD44
has a role in myeloid cell proliferation in bone marrow. Accordingly, we can assume that
CD44 mediates some micro-environmental functions of bone marrow.
Acute myeloid leukemia (AML) is characterized by extensive proliferation of blood
cells progenitor producing blast cells that functionally disabled to serve the body. The ligation
of CD44 activated mAbs and that can cause reverse blockage in the differentiation AML blast
in some myeloid leukemia subtypes such M1, 2,6. CD44 ligation with mAbs also could
inhibit the proliferation and induces apoptosis23. CD44 modulate the function of AML stem
cells and facilitate the proper homing of stem cell to niches of bone marrow
microenvironment. Binding of CD44 to HA or mAbs regulate many functions of
hematopoietic stem cells including differentiation of myeloid and lymphoid cells23,24.
CD44 as therapeutic target:
CD44 could be useful tool to abrogate cancer cell proliferation and metastasis. In cancer
hepatic cells, when treated with antisense oligonucleotide (ASO) a down regulation CD44
expression combined with increase in cellular apoptosis, which may reduce invasion and
metastasis of cancer25. CD44 down expression increases the chemo-sensitivity of hepatic
cancer cell to doxorubicin (anti-cancer chemotherapy). Therefore, CD44 is a potential target
for cancer therapy.
In patients with chronic cell leukemia (CLL), targeting CD44 expression in myeloid
cells could avoid immature proliferation of white blood cells. A recent study proposes that
treatment with single dose of 1 mg/kg anti-CD44 mAb causes a complete eradication of
engrafted chronic lymphoid leukemia cells 26. Antibody ligation to CD44 induces caspase
dependent apoptosis in “ZAP-70Pos” myeloid cells. However, treatment with mAb requires
close attention to avoid non-specific toxicity that might occur.
Ligation of specific antibody is a new way to enhance the success of chemotherapy in
patients with Acute Myeloid Leukemia. Cyclin dependent kinase inhibitor (p27) is a general
tumor suppressor factor. Ligation of CD44 with anti-CD44 monoclonal antibodies up
regulates the production of p27 in AML agent with CD44. Regardless the mechanism by
which AML blast is down regulated, increased level of p27 has been combined with better
outcomes of AML patient’s prognosis 27. An increase level of p27 seems to inhibit the
proliferation of primary cells of AML. Beside chemo radiotherapy, CD44 ligation could be a
synergistic treatment administered for leukemia patient to improve the overall treatment plan.
Leukemia stem cells (LSC) are suggested to be primary cause for relapsing of leukemic
cells after chemotherapy. Recently, many clinical trials review the effect of anti-CD44 agent
to assist in preventing remission of acute myeloid leukemia28. LSC homing in bone marrow
niches is assisted by CD44, i.e. cell adhesion molecule down-expression of CD44 could
impair LSC self-renewability and promote its sensitivity to chemotherapy.
An early recognition of any disease is promoting the chance of treatment and the
prognosis of cancer specifically. Cancer markers help healthcare providers to assess situation
in early stages of tumor growth. CD44 and it isoform seem to be good indicative marker for
certain cancer. CD44 isoform expression is found changing during prostate epithelial
differentiation29. Therefore, variant v3-v10, for example, can be marker of early stage of cell
differentiation in prostate cancer. By using immunomagnetic cell sorting technique, CD44
could be employed as a tool for separating basal from luminal prostate cell.
Conclusion:
Last decade, CD44 molecular interactions were intensively studied from different
points of view. Scientists explore the pathological role of CD44 in patients with different
types of tumor to find out how it could nourish cancer growth. Some studies were held in
vitro reveal a significant increase of CD44 variant. However, when these same variants were
studied in real patient a normal expression of CD44 was found. Hence, we cannot be positive
about the exact relation between cancer and overexpression of CD44 depending on study of
in vitro cell culture. In blood cancers, number of scholars investigate human lymphoma in
vivo has reported overexpression of certain variants of CD44. In breast and colon cancers,
CD44 could be used along with other parameter as a marker for early detection of tumor.
Beside of that, studying CD44 overexpression in murine tumor consider a weak evidence to
precisely determine role of CD44 in human.
Cancer biology indicates that not only one factor could lead to initiation of cancer;
multiple reasons are required to begin an uncontrolled cell division. Antibody inactivation of
CD44 in tumor cells could conclude the role of CD44 when reduction of tumor cell division
is monitored. Almost all recent researches claiming that an abnormal increase of CD44 has
been found in cancers cells without a clear explanation about the mechanism which carries on
this process. Therefore, referring CD44 as a viable reason for cancer progression require
further effort to discover the role CD44 completely.
Upon our review in this topic, we can expect many applications for CD44 in medicine.
CD44 could be a diagnostic marker for specific cancer cells. CD44 also can be employed as
therapeutic alternative that eradicating or sensitizing cancer cells for chemotherapy. We
believe CD44 require further investigating to be used as a successful marker for early
detection of multiple cancer cell lines.
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