CD44

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Encyclopedia of Cancer 2015

Synonyms

Cluster of differentiation 44; ECMRIII; gp90Hermes; H-CAM; Homing receptor; Hyaluronan receptor; pgp-1; Phagocytic glycoprotein-1

Definition

CD44 is a type I transmembrane glycoprotein, which exists in a large number of isoforms. The gene contains 20 exons within a region of ~60 kb on chromosome 11p13 in humans and on chromosome 2 at 56 cM in mice. CD44 is in close proximity to the recombination-activating genes Rag-1 and Rag-2.

Characteristics

CD44 is the major receptor for hyaluronic acid and  other  extracellular  matrix   molecules (fibronectin, laminin 5, collagen type IV, serglycin). The standard molecule is heavily glycosylated by Nand O-linked residues and chondroitin sulfate side chains, while some of the variant isoforms carry in addition heparan sulfate moieties, which can present various growth factors and chemokines (for local concentration and activation). The number of extra-cellular molecules that can associate with CD44 is ever growing, among them matrix metalloproteinase-7 (MMP-7) and matrix metalloproteinase-9 (MMP-9) inducing activation of latent transforming growth factor b (TGF-b)  and  hence  promote  invasion  and angiogenesis.  Further  associating  molecules are ErbB2 (HER-2/neu), EpCAM, E-selectin, CD8+ cytotoxic T-cells, and VLA-4 (Integrin a4b1). While c-met/? scatter factor receptor, c-kit/? stem cell factor receptor, osteopontin (OPN), and CD95 have specifically been shown to associate with CD44 variant isoforms, association with the other molecules has not been specified to a CD44 isoform. The association between VLA-4 (integrin a4b1) and CD44 directs cells into inflammatory regions, while the c-met/ CD44v6 interaction is required for c-met/scatter factor receptor signaling leading to Ras activation, and when CD44v6 associates with CD95, trimerization of the death receptor is prevented and hence apoptosis signaling is blocked (see Fig. 1).

Upon cellular activation, CD44 localizes to plasma membrane microdomains and associates (see Fig. 1) with nonreceptor tyrosine kinases lck and fyn,  smad-1, membrane-bound OPN, and Rho. Via ezrin (ERM protein), ankyrin, or annexin II, the cytoplasmic region of CD44 is linked to the cytoskeleton. CD44 is involved in the Wnt signaling pathway. P-glycoprotein, the product of the multidrug resistance (MDR) gene, has also been demonstrated to interact physically and functionally with CD44, thus promoting cell migration and invasion and possibly enforcing resistance to chemotherapy. The p-glycoprotein–CD44 interaction is the first hint of a functional association between MDR and metastasis formation, involving CD44. Further it is of importance that the presenilin-dependent g-secretase cleaves off the intracellular domain (ICD) of CD44, which then translocates to the nucleus and acts as a transcription factor for genes containing TPA (12-O-tetradecanoyl phorbol 13-acetate) response elements in their promoter. The ICD of CD44 promotes the fusion of macrophages, is localized in the nucleus of macrophages,  and  promotes  the  activation  of nuclear factor kappa (NF-k) B.

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Fig. 1. Multiprotein complexes can be formed between CD44 and various cell surface and various membrane-linked (top) and intracellular molecules (bottom)

Cellular and molecular regulation

The standard form of CD44 (CD44s) is expressed in almost all tissues and leukocytes and is encoded by exons s1–s10, yielding a product of 90 kDa. The variant isoforms (CD44v) are generated by alternative splicing of the nuclear RNA between exons s5 and s6 and are encoded by exons v2–v10 (exon v1 is silent in humans, but not in mice and rats). Combinations of different variant exons with the standard backbone result in numerous variant isoforms, with masses of 100–250 kDa. All the variant regions are located extracellularly and are highly hydrophilic. In contrast to the ubiquitous expression of CD44s, CD44v isoforms are expressed in a highly restricted manner in nonmalignant tissues: in early embryogenesis, stem cells of epithelia and hemopoiesis, activated leukocytes, and memory cells. However, in malignant tissues, CD44v isoforms are often upregulated, e.g., in carcinoma, various hematological malignancies, and in autoimmune lesions.

A positive feedback loop was identified which couples Ras activation with alternative splicing of the CD44 variant isoforms. The presence of CD44v6 then sustains Ras signaling, which is in turn important for cell cycle progression.

CD44 is implicated in various aspects of tumor  progression:  invasion,  migration,  and apoptosis blockade.

Clinical relevance

Originally identified by its metastasizing potential in rats, CD44v isoform expression was identified in various human tumors and correlated with clinical relevance. Upregulation of CD44v correlates with poor prognosis in gastric and colorectal carcinoma, non-small cell lung tumors, hepatocellular carcinoma, pancreatic cancer,   B-cell   chronic   lymphocytic   leukemia, ? multiple myeloma, non-Hodgkin lymphoma, and acute myeloblastic leukemia. Downregulation of CD44v correlates with poor prognosis  in  esophageal  squamous  cell  carcinoma,   bronchial   carcinoid   tumors,   ovarian neoplasms, uterine cervical tumors, transitional cell bladder tumors, and prostate cancers, while downregulation of CD44s correlates with amplification of MYCN and is indicative for an unfavorable outcome in neuroblastoma patients. In breast  carcinoma,  controversial  data  between CD44v expression and survival were established and need further evaluation.

Elevated serum levels of CD44v have prognostic value for gastric and colon carcinoma and non-Hodgkin lymphoma, which are indicative for a poor prognosis.

An emerging new field (although hypothesized some 150 years ago) is the area of cancer-initiating cells, also termed cancer stemlike cells. They exist as a small population in every tumor and determine the capability of the tumor to grow and propagate. In tumors of the Brms1, the pancreas, the prostate, the head and neck, the brain (glioblastoma), and in the blood system (leukemia), the cancer-initiating cells are CD44+. A major goal currently is to identify specific markers (stem cell markers) that enable to distinguish  between  normal,  benign tissue  stem  cells  and  those  that  are  cancer-initiating.

CD44 is also strongly upregulated in inflammatory lesions of patients with autoimmune diseases (inflammatory bowel disease (Crohn’s disease), multiple sclerosis, rheumatoid arthritis).

References

Cheng C, Yaffe MB, Sharp PA (2006) A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev 20:1715–1720

Jin L, Hope KJ, Zhai O et al (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12:1167–1174

Martin TA, Harrlison G, Mansel RE et al (2003) The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol 46:165–186

Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Biol 4:33–45

Ponti D, Zaffaroni N, Capelli C et al (2006) Breast cancer stem cells: an overview. Eur J Cancer 42:1219–1224

Zeilstra J, Joosten SP, van Andel H, Tolg C, Berns A, Snoek M, van de Wetering M, Spaargaren M, Clevers H, Pals ST (2014) Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling. Oncogene 3(5):665-70


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