Chen et al. Journal of Hematology & Oncology (2018) 11:64 https://doi.org/10.1186/s13045-018-0605-5 REVIEW Open Access The biology and role of CD44 in cancer progression: therapeutic implications Chen Chen1, Shujie Zhao2, Anand Karnad2,4 and James W. Freeman1,2,3,4* Abstract CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy. Keywords: CD44, Cancer, Signaling transduction, Tumorigenicity, Epithelial to mesenchymal transition (EMT), Cancer therapy Background conformational changes that allow binding of adaptor CD44 is a family of non-kinase, single span transmem- proteins or cytoskeletal elements to intracellular do- brane glycoproteins expressed on embryonic stem cells mains that in turn activate various signaling pathways and in various levels on other cell types including con- leading to cell proliferation, adhesion, migration, and nective tissues and bone marrow [1, 2]. CD44 expression invasion [7, 8]. CD44s and various CD44v isoforms have is also upregulated in subpopulations of cancer cells and overlapping and distinct functional roles. CD44v iso- is recognized as a molecular marker for cancer stem forms have additional binding motifs that promote the cells (CSC) [3]. In humans, CD44 is encoded by 19 interaction of CD44 with molecules in the microenvir- exons with 10 of these exons constant in all isoforms. onment [9]. CD44v isoforms can act as co-receptors by The standard form of CD44 (CD44s) is encoded by the binding/sequestering growth factors on the cell surface ten constant exons. CD44 variant isoforms (CD44v) is and presenting these to their specific receptors [10]. generated by alternative splicing and possess the ten Cancer cells that undergo an epithelial to mesenchymal constant exons and any combination of the remaining transition (EMT) acquire stem cell-like properties and nine variant exons [4, 5]. show an increase in CD44 expression [11]. Moreover, The main ligand for CD44 is hyaluronic acid (HA), an cancer cells with an EMT phenotype show increased in- abundant component of the extracellular matrix (ECM) vasiveness and are more resistant to chemotherapy [12]. that is expressed by stromal and cancer cells [6]. HA The clinicopathological impacts of CD44s and its binds the CD44 ligand binding domain inducing isoforms in promoting tumorigenesis suggest that CD44 may be a molecular target for cancer therapy (13). In * Correspondence: [email protected] addition, the established role of CD44 in maintaining 1 Department of Cell Systems & Atanomy, University of Texas Health Science stemness and the function of cancer stem cells in tumor Center at San Antonio, San Antonio, TX, USA 2Department of Medicine, Division of Hematology and Oncology, University regeneration following therapy suggests that CD44 may of Texas Health Science Center at San Antonio, San Antonio, TX, USA also be an important prognostic marker. Therapeutic Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Journal of Hematology & Oncology (2018) 11:64 Page 2 of 23 strategies that target CD44 or reduce CD44 expression CD44v isoforms can be inserted as a single variant are in various stages of clinical development [13–15]. exon or combined with other variant exons that code These strategies include CD44 neutralizing antibodies, for peptides located in the juxta membrane domain. tumor delivery of shRNAs, ectodomain mimics, and The encoded CD44 peptide can be further modified aptamers [14, 16–18]. Thus, an important area of inves- by N- and O-linked glycosylation and glycosaminogly- tigation is to further define the functional roles of CD44 canation by addition of heparin sulfate or chondroitin isoforms in cancer and to determine the potential bene- sulfate [20, 21]. CD44 has extracellular domains, a fits of targeting these CD44 isoforms or their signaling membrane-proximal region, a transmembrane domain, pathways for cancer therapy. and a cytoplasmic tail [22]. An illustration of the CD44 gene showing CD44s and CD44v exons and the Structure and function of CD44 functional domains and the position of peptides Exon composition and functional domains of CD44 coded by variant exons are illustrated in Fig. 1. CD44, a non-kinase transmembrane proteoglycan, is a single-chain glycoprotein encoded by one gene located CD44 ligands and interacting molecules on chromosome 11 in humans and on chromosome 2 in CD44 binds to several ligands including hyaluronic mice. The CD44 gene is comprised of 19 exons in acid (HA), osteopontin (OPN) [23], chondroitin [24], humans and 20 in mice; a homolog of exon 6 or variant collagen [25], fibronectin [26], and serglycin/sulfated 1 is not found in humans [19]. The first five and the last proteoglycan [27]. five exons are constant and encode the shortest isoform HA is the most specific ligand for CD44 activation. of CD44 (85–95 kDa) called CD44 standard (CD44s). All isoforms of CD44 possess a HA-binding domain The middle nine exons can be alternatively spliced and located in N-terminal region of the extracellular do- assembled with the ten exons contained in the CD44 main (Fig. 1). HA is a major extracellular matrix standard isoform and are referred to as CD44 variant component expressed by stromal and tumor cells. HA isoforms (CD44v). is a linear glycosaminoglycan consisting of repeating Fig. 1 CD44 protein and gene structure. a Four domains of CD44 glycoprotein are presented with correponding colors: ligand binding domain, variable domain, transmembrane domain, and cytoplasmic tail. b CD44 is encoded by 20 exons in mice but 19 exons in humans. Exon 6 coding for CD44 variant 1 (CD44v1) is lacking in humans. Green color exons are always expressed as a standard form of CD44 (CD44s), and up to nine exon variants can be inserted by alternative splicing. Full-length CD44, CD44s, CD44v3, CD44v6, and CD44v8-10 are shown schematically Chen et al. Journal of Hematology & Oncology (2018) 11:64 Page 3 of 23 disaccharide units of D-glucuronic acid and N-acetyl- in cancer-associated fibroblasts (CAF). TGF-β receptor- D-glucosamine and is expressed in various molecular dependent SMAD signaling transduction regulated VCAN sizes up to 107 kDa. HA binding to CD44 causes expression in CAFs. Upregulated VCAN promoted the conformational changes favoring the binding of adaptor motility and invasion of ovarian cancer cells by upregu- molecules to the intracellular cytoplasmic tail of CD44 lating expression of CD44 and receptor of hyaluronic leading to cell signaling that enhances cell adhesion, acid-mediated motility (RHAMM) [38]. Thus, inter- migration, and proliferation [7]. The pathways activated rupting HA-CD44 binding through VCAN may change through CD44-HA binding include Ras, MAPK, and PI3K the proteoglycan enrichment in the tumor lesion to [28]. CD44 binding to HA is cell specific and depends on reduce tumor growth or metastasis in cancers. the activation state of CD44; when HA interacts with Osteopontin (OPN) also binds to CD44 inducing cell CD44, CD44 proteins exist in three scenarios: non-bound signaling that mediates tumor progression and metasta- to HA, non-bound to HA unless activated by physio- sis [23]. The expression of OPN and CD44v6 correlated logical stimuli, or constitutive binding to HA [29]. In positively in 159 non-small cell lung cancers [39]. Strong breast tumor cells, HA activation of CD44 leads to the ex- correlation of OPN and CD44 expression was detected pression of multidrug resistance gene (P-glycoprotein) in 243 gastric cancer patients’ tissues [40]. OPN shared a and anti-apoptotic gene Bcl expression, which promotes perivascular expression pattern with CD44 and pro- tumor cell proliferation and survival [30]. Pancreatic can- moted glioma stem cell-like phenotypes. OPN promotes cer cells (MiaPaCa-2) secrete hyaluronidases abundantly