ReviewCD44 polymorphisms and its variants, as an inconsistent marker in cancer investigations
Introduction
According to published data, there were 1,762,450 new cases and 880,606 thousand cancer deaths in the United States of America in 2019 [1]. Despite recent advancements in cancer therapy and increased knowledge of tumor biology, cancer remains the second main cause of global mortality. Studies have shown that environmental, genetic, and epigenetic factors have been the major causes of cancer [2]. Given the existence of approximately 210 different types of cancer, identifying versatile markers to understand the origin and the stage of cancer plays a crucial role in the treatment and prevention of cancer progression [3]. Additionally, to investigate the involved molecular mechanisms and signaling pathways in different kinds of cancer, targeting, isolation, and examination of cancer cells and the identification of CSCs behavior are highly required. CSCs are known as tumor-initiating cells that possess a specific function in tumor recurrence, metastasis, heterogeneity and therapeutic resistance [4,5]. CSCs reside in tumor niche. The tumor niche is a distinct region within the microenvironment of tumor that maintains properties of CSCs (morphological, physiological, behavioral and phenological) and protects them from the immune system [6]. There are several theories regarding the origin of CSCs; the first theory believes that CSCs is the result of genetic mutation or environmental alteration in normal stem cell. The second theory suggests that genetic or heterotypic alteration in somatic stem cell convert them to CSCs [7]. Isolation of CSCs based on a universal surface marker is a necessary step for cancer therapy. A common component stem cell niche is CD44 glycoprotein. So, it has been considered as a target for CSCs tracking [8].
Until now, various classes of markers such as soluble blood markers, cell surface markers, and internal cell markers have been identified to check out and study the changes and molecular patterns of the dreaded cancer cells in order to achieve the above-mentioned goals [[9], [10], [11]]. These markers are mostly glycoproteins such as CD10, CD24, CD26, CD133, CD166, and CD326 [[12], [13], [14]]. Genetic abnormalities (leading to modifications of tumor suppressors such as p53 and BRCA), oncogenes (Bcr-Abl and Ras), and gene derivatives such as microRNAs have also been accounted for efficient tumor markers [[15], [16], [17]].
CD44, a polymorphic transmembrane glycoprotein, is one of the important markers of malignant cells in different types of tumor and has attracted substantial attention in a variety of research areas, mostly because of its essential role in mediating cell-cell and cell-matrix interactions and also its association with malignant processes and cancer dissemination. This multi-structural and multifunctional receptor is highly expressed in many cancer cells. This receptor lacks kinase property and plays a crucial role in various vital cellular functions including, cell migration, binding, and cellular division [18,19]. Studies have shown that this receptor is also involved in the process of invasion and metastasis of cancer cells. Hyaluronic acid (HA), metalloproteases, and collagens are ligands associated with this receptor. Notch1, TGFβ2, and STAT3 are involved in CD44 related signaling pathways. Interaction of CD44 with HA leads to the activation of this receptor. CD44 by activation and inducing the expression of MMPs, plays an important role in the occurrence of metastasis. Activation of CD44 induced Ras, MAPK, and PI3K signaling pathways too [20].
Several investigations have shown that CD44 is the most common CSC’s marker and have reported its substantial role in regulating CSC stemness properties and communicating with tumor microenvironment [21,22]. Evidence suggests that different CD44 variants and more specifically CD44v, is a promising prognostic biomarker and a therapeutic target for many malignant solid tumors. Studies in recent years have examined the association of specific SNPs in the CD44 gene with cancer risk; however, the importance of these findings is not well-established [23]. In this paper we aimed to give an overview of the recent scientific reports concerning the association of CD44 polymorphisms with cancer progression in different types of tumor and tried to evaluate the significance of CD44 and discussed whether or not it could be a prognostic marker in cancer development.
Section snippets
Biological characteristics of CD44
CD44 is a major component of the ECM and a co-receptor for many growth factors and cytokines [24]. CD44 gene is composed of two groups of exons (two groups consisting of 20 exons) and is located at the short arm of chromosome 11. One group includes exons 1–5 and exons 16–20 (Fig. 1) which are expressed together, and the other group consists of exons 6–15 [25,26]. CD44 plays a significant role in matrix cell adhesion and signal transduction. This receptor is also involved in hematopoiesis and
Molecular functions of CD44
Most of the reported functions for CD44 in the cell can be described by its three roles. First, CD44 acts as a ligand-binding receptor that interacts with the ECM and extracellular soluble components. These interactions can either have a passive adhesive function or result in intracellular signaling and triggering cellular responses. For example, CD44 binds to hyaluronan, which the affinity of this protein for hyaluronan seems to be modulated from inside the cells. This modulation of binding
CD44 and cancer physiopathology
CD44 is one of the most important factors in tumorigenesis. CD44 is involved in many biological pathways such as apoptosis, chemotherapy resistance, metastasis, angiogenesis, and proliferation [34]. CD44 by regulating different classes of cellular factors affects apoptosis cascades in cancer cells. The anti-apoptotic effects of CD44 at different stages of the cell cycle have been observed frequently [35]. Evaluation of apoptotic resistance manifestations in head and neck cancer stem cells has
The role of noncoding RNAs on CD44 expression
Although the regulation of cancer pathways at the molecular level especially in CSCs is not well-established, recent findings on noncoding RNAs have opened up a new window into better understanding the involved mechanisms. Different investigations have suggested that noncoding RNAs may play critical roles in normal stem cell functions and tumor development by regulating CSCs behaviors. The ability of these RNAs to target CSCs and to regulate cancer-related genes, signaling, and transcriptional
Colorectal cancer
A large number of studies were focused on the effect of CD44 polymorphisms in cancer incidence, and this receptor is known as a reliable marker for predicting colorectal metastases and survival. In a research concerning the effects of CD44 rs8193 C > T polymorphism in a group of patients with colon cancer, it was shown that the minor allele of CD44 rs8193 C > T was significantly associated with increased tumor recurrence time. The results of this study indicated that this polymorphism in CD44
CD44, a valuable surface marker for cancer cells targeting
CD44 targeting may be a successful approach in the diagnosis and treatment of cancer. CD44 could be used along with other parameters as markers to characterize the population of cancer cells in various types of tumors. Among the various markers used for specific targeting of CD44, there are; antibodies, peptides, aptamers, and nanoparticles [177]. The cytotoxicity and antitumor efficacy of a humanized monoclonal antibodies specific for CD44 (RG7356) in chronic lymphocytic leukemia (CLL) and
Conclusion
Despite the considerable developments in cancer therapy, this disease is still the first responsible for hundreds of thousands of deaths worldwide. A significant number of patients still suffer from chemo-resistance and disease recurrence that has led to decreased survival rates among them. The expanding body of evidence implicating the role of CD44 polymorphisms with the risk of cancer incidence revealed the essential role of this gene and its variants in tumor initiation, progression, and
Declaration of Competing Interest
The authors report no conflict of interest.
References (186)
- et al.
Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis
Mol. Oncol.
(2007) - et al.
Evolving role of uPA/uPAR system in human cancers
Cancer Treat. Rev.
(2008) - et al.
The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?
Cell Stem Cell
(2015) - et al.
Cancer stem cells
Int. J. Biochem. Cell Biol.
(2012) - et al.
BC200 RNA: an emerging therapeutic target and diagnostic marker for human cancer
Mol. Cells
(2018) - et al.
Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis
Cell
(2012) - et al.
Ras related oncogene protein as a tumor marker in transitional cell carcinoma of the bladder
J. Urol.
(1987) - et al.
Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors
Am. J. Pathol.
(2002) - et al.
The biology and role of CD44 in cancer progression: therapeutic implications
J. Hematol. Oncol.
(2018) - et al.
Multiple variants of the human lymphocyte homing receptor CD44 generated by insertions at a single site in the extracellular domain
J. Biol. Chem.
(1992)
CD44 co-stimulates apoptosis in thymic lymphomas and T cell hybridomas
Cell. Immunol.
CD44 promotes resistance to apoptosis in human colon cancer cells
Exp. Mol. Pathol.
Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression
Cell
Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters
BMC Cancer
The biology and role of CD44 in cancer progression: therapeutic implications
J. Hematol. Oncol.
Down-regulated expression of CD44 variant 6 in oral squamous cell carcinomas and its relationship to regional lymph node metastasis
Int. J. Oral Maxillofac. Surg.
Reduced expression of CD44 variant 9 is related to lymph node metastasis and poor survival in squamous cell carcinoma of tongue
Oral Oncol.
Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2
J. Biol. Chem.
CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth
Cancer Cell
Initiation and maintenance of gastric cancer: a focus on CD44 variant isoforms and cancer stem cells
Cell. Mol. Gastroenterol. Hepatol.
The CD44 variant induces K562 cell acquired with resistance to adriamycin via NF-κB/Snail/Bcl-2 pathway
Med. Hypotheses
Elevated levels of soluble CD44 are associated with advanced disease and in vitro proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia
Leuk. Res.
Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells
J. Biol. Chem.
Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185HER2 and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth
J. Biol. Chem.
De-methylation of miR-148a by arsenic trioxide enhances sensitivity to chemotherapy via inhibiting the NF-κB pathway and CSC like properties
Exp. Cell Res.
let-7 regulates self renewal and tumorigenicity of breast cancer cells
Cell
MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes
Nat. Commun.
Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells
cell
Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer
Cancer Cell
Schmittgen TD. miR-221 regulates CD44 in hepatocellular carcinoma through the PI3K-AKT-mTOR pathway
Biochem. Biophys. Res. Commun.
miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines
Biochem. Biophys. Res. Commun.
miR-106b modulates cancer stem cell characteristics through TGF-β/Smad signaling in CD44-positive gastric cancer cells
Lab. Investig.
Cancer statistics, 2019
CA Cancer J. Clin.
Cancer stem cells: a review from origin to therapeutic implications
J. Cell. Physiol.
Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity
Clin. Dev. Immunol.
Cancer stem cells: implications for cancer therapy
Oncology (Williston Park, N.Y.)
Cancer stem cells as key drivers of tumour progression
J. Biomed. Sci.
Exosomal TRIM3 is a novel marker and therapy target for gastric cancer
J. Exp. Clin. Cancer Res.
CD10 as a novel marker of therapeutic resistance and cancer stem cells in head and neck squamous cell carcinoma
Br. J. Cancer
CD44+ CD133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma
Cancer Biol. Ther.
Tumor markers in breast cancer-evaluation of their clinical usefulness
Coll. Antropol.
Serum miR-20a is a promising biomarker for gastric cancer
Biomed. Rep.
CD44: from adhesion molecules to signalling regulators
Nat. Rev. Mol. Cell Biol.
CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?
Nat. Rev. Cancer
Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells
Tumour Biol.
The role of CD44 and cancer stem cells
Methods Mol. Boil. (Clifton, NJ)
Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target
Stem Cells Transl. Med.
CD44 as a cancer stem cell marker and its prognostic value in patients with ovarian carcinoma
J. Obstet. Gynaecol.
CD44 cell adhesion molecules
Mol Pathol.
Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons
Proc. Natl. Acad. Sci. U. S. A.
Cited by (22)
New insights in aptamer-targeted nanoliposomes for the treatment of breast cancer
2023, Journal of Drug Delivery Science and TechnologyStructural evolution of Delta lineage of SARS-CoV-2
2023, International Journal of Biological MacromoleculesCitation Excerpt :As well as small molecules production costs are lower [105]. Given that residue displacement alter the function [106,107] and affinity of proteins to interact with other molecules [108], at this step of study the impact of B.1.617.2 Spike mutations on its interaction ability with desired compounds has been investigated. Based on the National Institutes of Health website (https://clinicaltrials.gov/), various small molecule inhibitors were proposed as possible treatments for SARS-CoV-2 [109,110].
Development of a Prognostic Model of Glioma Based on Pyroptosis-Related Genes
2022, World NeurosurgeryCitation Excerpt :There are known to be 2 kinds of immune checkpoint of great concern. In many cancers, including glioma, many studies have proved that they play an important role in the proliferation, invasion, and migration of tumor cells, and are promising therapeutic targets for malignant tumors.27,28 Therefore, patients in the high-risk group identified by the model of pyroptosis should be treated with more aggressive immunotherapy.
Implementation of docking, molecular dynamics and free energy to investigate drug potency of novel BCR-ABL<sup>T315I</sup> inhibitors as an alternative to ponatinib
2021, Computational ToxicologyCitation Excerpt :Given that experimental values of ADMET parameters are available for ponatinib, all of these were obtained from the DrugBank server. Today, large pharmaceutical companies spend a lot of money on designing and producing effective drugs to target cancer cells [51,52]. One of the main challenges that affect the performance of cancer treatment protocols is the occurrence of mutations in the genome that result is increased stability of oncoproteins [53].