Review
CD44 polymorphisms and its variants, as an inconsistent marker in cancer investigations

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Abstract

Among cell surface markers, CD44 is considered the main marker for identifying and isolating the cancer stem cells (CSCs) among other cells and has attracted significant attention in a variety of research areas. Many studies have shown the essential roles of CD44 in initiation, metastasis, and tumorigenesis in different types of cancer; however, the validity of CD44 as a therapeutic or diagnostic target has not been fully confirmed in some other studies. Whereas the association of specific single nucleotide polymorphisms (SNPs) in the CD44 gene and related variants with cancer risk have been observed in clinical investigations, the significance of these findings remains controversial. Here, we aimed to provide an up-to-date overview of recent studies on the association of CD44 polymorphisms and its variants with different kinds of cancer to determine whether or not it can be used as an appropriate candidate for cancer tracking.

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.

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