The normal structure and function of CD44 and its role in neoplasia.

CD44 is a transmembrane glycoprotein, the variant isoforms of which are coded for by alternative splicing, with the most prolific isoform being CD44 standard. CD44 is found in a wide variety of tissues including the central nervous system, lung, epidermis, liver, and pancreas, whereas variant isoforms of CD44 (CD44v) appear to have a much more restricted distribution. Variants of CD44 are expressed in tissues during development, including embryonic epithelia. Known functions of CD44 are cellular adhesion (aggregation and migration), hyaluronate degradation, lymphocyte activation, lymph node homing, myelopoiesis and lymphopoiesis, angiogenesis, and release of cytokines. The functions of CD44 are principally dependant on cellular adhesion in one setting or another. The role of CD44 in neoplasia is less well defined, although metastatic potential can be conferred on non-metastasising cell lines by transfection with a variant of CD44 and high levels of CD44 are associated with several types of malignant tumours. The physiological functions of CD44 indicate that the molecule could be involved in the metastatic spread of tumours. Many studies have investigated the pattern of CD44 distribution in tumours and some observations suggest that certain cells do not use CD44 in tumorigenesis or in the production of metastases. However, the data are extremely conflicting, and further studies are needed to establish the prognostic value of CD44 and its variant isoforms. The precise function of CD44 in the metastatic process and the degree of involvement in human malignancies has yet to be established fully.

[1]  F. Reinholt,et al.  Osteopontin--a possible anchor of osteoclasts to bone. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[2]  V. Combaret,et al.  CD44--a new prognostic marker for neuroblastoma. , 1993, The New England journal of medicine.

[3]  W. Carter,et al.  Identification of multiple cell adhesion receptors for collagen and fibronectin in human fibrosarcoma cells possessing unique alpha and common beta subunits , 1987, The Journal of cell biology.

[4]  I. Stamenkovic,et al.  Identification of hyaluronic acid binding sites in the extracellular domain of CD44 , 1993, Journal of Cell Biology.

[5]  C. Meijer,et al.  Adhesion molecules in the prognosis of diffuse large-cell lymphoma: expression of a lymphocyte homing receptor (CD44), LFA-1 (CD11a/18), and ICAM-1 (CD54). , 1990, Leukemia.

[6]  S. Jalkanen,et al.  A lymphoid cell surface glycoprotein involved in endothelial cell recognition and lymphocyte homing in man , 1986, European journal of immunology.

[7]  T. Yue,et al.  Osteopontin-stimulated vascular smooth muscle cell migration is mediated by beta 3 integrin. , 1994, Experimental cell research.

[8]  I. Stamenkovic,et al.  CD44 is the principal cell surface receptor for hyaluronate , 1990, Cell.

[9]  R. Midura,et al.  Expression of CD44 isoforms in human prostate tumor cell lines , 1996, The Prostate.

[10]  R. Hyman,et al.  CD44 can be activated to function as an hyaluronic acid receptor in normal murine T cells , 1992, European journal of immunology.

[11]  K. Bennett,et al.  CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor , 1995, The Journal of cell biology.

[12]  S. Jalkanen,et al.  Biochemical properties of glycoproteins involved in lymphocyte recognition of high endothelial venules in man. , 1988, Journal of immunology.

[13]  P. Herrlich,et al.  Retardation of metastatic tumor growth after immunization with metastasis‐specific monoclonal antibodies , 1990, International journal of cancer.

[14]  S. Fox,et al.  Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms. , 1994, Cancer research.

[15]  J. Sleeman,et al.  The role of CD44 splice variants in human metastatic cancer. , 1995, Ciba Foundation symposium.

[16]  J. R. de los Toyos,et al.  Lymphocyte recognition of high endothelium: antibodies to distinct epitopes of an 85-95-kD glycoprotein antigen differentially inhibit lymphocyte binding to lymph node, mucosal, or synovial endothelial cells , 1987, The Journal of cell biology.

[17]  J. Bos,et al.  A PCR-based method for the analysis of human CD44 splice products. , 1993, PCR methods and applications.

[18]  S. Zigmond.  Cell locomotion and chemotaxis. , 1989, Current opinion in cell biology.

[19]  K. Bennett,et al.  Regulation of CD44 binding to hyaluronan by glycosylation of variably spliced exons , 1995, The Journal of cell biology.

[20]  J. Figge,et al.  Restricted patterns of CD44 variant exon expression in human papillary thyroid carcinoma. , 1996, Cancer research.

[21]  L. Wahl,et al.  Dual role of the CD44 molecule in T cell adhesion and activation. , 1989, Journal of immunology.

[22]  V. Hascall,et al.  Cell surface heparan sulfate proteoglycans. , 1992, The Journal of biological chemistry.

[23]  P. Herrlich,et al.  A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps , 1993, The Journal of cell biology.

[24]  R. Schulte,et al.  Binding of hyaluronic acid to lymphoid cell lines is inhibited by monoclonal antibodies against Pgp-1. , 1990, Experimental cell research.

[25]  X. Chen,et al.  Hyaluronic acid-induced lymphocyte signal transduction and HA receptor (GP85/CD44)-cytoskeleton interaction. , 1993, Journal of immunology.

[26]  C. Bouvier,et al.  Automated and quantitative immunocytochemical assays of CD44v6 in breast carcinomas. , 1997, Human pathology.

[27]  M. Culty,et al.  Binding and degradation of hyaluronan by human breast cancer cell lines expressing different forms of CD44: Correlation with invasive potential , 1994, Journal of cellular physiology.

[28]  W. Carter,et al.  Human keratinocytes express a new CD44 core protein (CD44E) as a heparan-sulfate intrinsic membrane proteoglycan with additional exons , 1991, The Journal of cell biology.

[29]  C. Kainz,et al.  Immunohistochemical and serological evaluation of CD44 splice variants in human ovarian cancer. , 1995, British Journal of Cancer.

[30]  D. S. Webb,et al.  LFA-3, CD44, and CD45: physiologic triggers of human monocyte TNF and IL-1 release. , 1990, Science.

[31]  S. Gansauge,et al.  Differential expression of CD44 splice variants in human pancreatic adenocarcinoma and in normal pancreas. , 1995, Cancer research.

[32]  I. Stamenkovic,et al.  CD44 hyaluronate binding influences growth kinetics and tumorigenicity of human colon carcinomas. , 1995, Oncogene.

[33]  W. Carter,et al.  Structural homology between lymphocyte receptors for high endothelium and class III extracellular matrix receptor. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Martin Hofmann,et al.  A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells , 1991, Cell.

[35]  Brian Seed,et al.  A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family , 1989, Cell.

[36]  P. Kincade.  Molecular interactions between stromal cells and B lymphocyte precursors. , 1991, Seminars in immunology.

[37]  C. Underhill,et al.  The hyaluronate receptor is preferentially expressed on proliferating epithelial cells , 1989, The Journal of cell biology.

[38]  M. Denis,et al.  H blood group antigen carried by CD44V modulates tumorigenicity of rat colon carcinoma cells. , 1994, Cancer research.

[39]  H. Liao,et al.  The transmembrane hyaluronate receptor (CD44): multiple functions, multiple forms. , 1991, Cancer cells.

[40]  William,et al.  Characterization of the class III collagen receptor, a phosphorylated, transmembrane glycoprotein expressed in nucleated human cells. , 1988, The Journal of biological chemistry.

[41]  K. Oritani,et al.  Glycosylation of CD44 negatively regulates its recognition of hyaluronan , 1995, The Journal of experimental medicine.

[42]  P. Comoglio,et al.  The hyaluronate receptor is identical to a glycoprotein of Mr 85,000 (gp85) as shown by a monoclonal antibody that interferes with binding activity. , 1987, The Journal of biological chemistry.

[43]  M. Blue,et al.  Mechanism of peripheral T cell activation by coengagement of CD44 and CD2. , 1992, Journal of immunology.

[44]  R. Savani,et al.  Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. , 1994, The EMBO journal.

[45]  M. Glimcher,et al.  Receptor-Ligand Interaction Between CD44 and Osteopontin (Eta-1) , 1996, Science.

[46]  W. Jiang,et al.  In-vitro models of cancer invasion and metastasis: recent developments. , 1994, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[47]  P. Herrlich,et al.  Expression of CD44 isoforms carrying metastasis-associated sequences in newborn and adult rats. , 1993, European journal of cancer.

[48]  B. Caillou,et al.  CD44 contributes to T cell activation. , 1989, Journal of immunology.

[49]  G. Tarone,et al.  Aggregation of macrophages and fibroblasts is inhibited by a monoclonal antibody to the hyaluronate receptor. , 1988, Experimental cell research.

[50]  B. Toole,et al.  Common pattern of CD44 isoforms is expressed in morphogenetically active epithelia , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[51]  G. Hommel,et al.  Expression and prognostic value of the CD44 splicing variants v5 and v6 in gastric cancer , 1997, The Journal of pathology.

[52]  T. Urano,et al.  Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorectal cancer patients. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  J. Narula,et al.  Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody. , 1994, Cancer research.

[54]  M. Amiot,et al.  The hematopoietic and epithelial forms of CD44 are distinct polypeptides with different adhesion potentials for hyaluronate‐bearing cells. , 1991, The EMBO journal.

[55]  C. Underhill,et al.  CD44: the hyaluronan receptor. , 1992, Journal of cell science.

[56]  T. Bauknecht,et al.  Increasing incidence of CD44v7/8 epitope expression during uterine cervical carcinogenesis , 1996, International journal of cancer.

[57]  T. Oegema,et al.  A cell surface chondroitin sulfate proteoglycan, immunologically related to CD44, is involved in type I collagen-mediated melanoma cell motility and invasion , 1992, The Journal of cell biology.

[58]  M. von Knebel Doeberitz,et al.  Expression of CD44 splice variants in normal respiratory epithelium and bronchial carcinomas: no evidence for altered CD44 splicing in metastasis. , 1996, Oncogene.

[59]  Q. He,et al.  Requirements for hyaluronic acid binding by CD44: a role for the cytoplasmic domain and activation by antibody , 1992, The Journal of experimental medicine.

[60]  I. Hart,et al.  Isolation and characterization of human melanoma cell variants expressing high and low levels of CD44. , 1991, Cancer research.

[61]  B. Pessac,et al.  Cell Aggregation: Role of Acid Mucopolysaccharides , 1972, Science.

[62]  K. Friedrichs,et al.  CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. , 1995, Cancer research.

[63]  S. Jalkanen,et al.  Regulated expression of exon v6 containing isoforms of CD44 in man: downregulation during malignant transformation of tumors of squamocellular origin , 1993, The Journal of cell biology.

[64]  H. Cantor,et al.  Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo , 1990, The Journal of experimental medicine.

[65]  F. Watt,et al.  Altered expression of CD44 isoforms in squamous‐cell carcinomas and cell lines derived from them , 1996, International journal of cancer.

[66]  A. Datta,et al.  The complex CD44 transcriptional unit; alternative splicing of three internal exons generates the epithelial form of CD44. , 1992, Biochemical and biophysical research communications.

[67]  S. Molica,et al.  Increased serum levels of soluble CD44 standard, but not of variant isoforms v5 and v6, in B cell chronic lymphocytic leukemia , 1997, Leukemia.

[68]  P. Herrlich,et al.  CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. , 1991, Cancer research.

[69]  T. Urano,et al.  Expression of CD44 Variant Exons 8‐10 in Gastric Cancer , 1995, Japanese journal of cancer research : Gann.

[70]  P. Herrlich,et al.  CD44 variant exon epitopes in primary breast cancer and length of survival , 1995, The Lancet.

[71]  C. Underhill.  Interaction of hyaluronate with the surface of simian virus 40-transformed 3T3 cells: aggregation and binding studies. , 1982, Journal of cell science.

[72]  P. Herrlich,et al.  A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells. , 1993, Cancer research.

[73]  I. Stamenkovic,et al.  Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development , 1994, The Journal of experimental medicine.

[74]  E. Haber,et al.  Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury. , 1996, The Journal of clinical investigation.

[75]  B. Toole,et al.  The cell surface hyaluronate binding sites of invasive human bladder carcinoma cells. , 1987, Biochemical and biophysical research communications.

[76]  T. Fan,et al.  Angiogenesis in a delayed revascularization model is accelerated by angiogenic oligosaccharides of hyaluronan. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[77]  P. Kincade,et al.  Antibody‐induced activation of the hyaluronan receptor function of CD44 requires multivalent binding by antibody , 1993, European journal of immunology.

[78]  S. Kumar,et al.  The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity. , 1989, Experimental cell research.

[79]  S. Weissman,et al.  The core protein of epican, a heparan sulfate proteoglycan on keratinocytes, is an alternative form of CD44. , 1992, The Journal of investigative dermatology.

[80]  P. Herrlich,et al.  Activated human lymphocytes and aggressive non-Hodgkin's lymphomas express a homologue of the rat metastasis-associated variant of CD44 , 1993, The Journal of experimental medicine.

[81]  P. Herrlich,et al.  Participation in normal immune responses of a metastasis-inducing splice variant of CD44. , 1992, Science.

[82]  C. Underhill,et al.  The role of hyaluronic acid in intercellular adhesion of cultured mouse cells. , 1978, Experimental cell research.

[83]  B. Zetter,et al.  Adhesion molecules in tumor metastasis. , 1993, Seminars in cancer biology.

[84]  C. Soria,et al.  Evidence of involvement of CD44 in endothelial cell proliferation, migration and angiogenesis in vitro , 1996, International journal of cancer.

[85]  M. Zahalka,et al.  Lymph node (but not spleen) invasion by murine lymphoma is both CD44- and hyaluronate-dependent. , 1995, Journal of immunology.

[86]  G. Dougherty,et al.  To metastasize or not? Selection of CD44 splice sites , 1995, Nature Medicine.

[87]  M. Telen,et al.  CD44--a molecule involved in leukocyte adherence and T-cell activation. , 1989, Immunology today.

[88]  C. Mackay,et al.  Expression and modulation of CD44 variant isoforms in humans , 1994, The Journal of cell biology.

[89]  P. Goodfellow,et al.  The gene, MIC4, which controls expression of the antigen defined by monoclonal antibody F10.44.2, is on human chromosome 11 , 1982, European journal of immunology.

[90]  G. Mengod,et al.  Murine cell surface glycoproteins. Characterization of a major component of 80,000 daltons as a polymorphic differentiation antigen of mesenchymal cells. , 1981, The Journal of biological chemistry.

[91]  B. Toole,et al.  Receptors for hyaluronate on the surface of parent and virus-transformed cell lines: binding and aggregation studies. , 1981, Experimental cell research.

[92]  D. Tarin,et al.  Evaluation of CD44 transcription variants in human digestive tract carcinomas and normal tissues , 1996, International journal of cancer.

[93]  J. Isaacs,et al.  CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. , 1997, Cancer research.

[94]  C. Figdor,et al.  De-novo expression of CD44 and survival in gastric cancer , 1993, The Lancet.

[95]  K. Miyake,et al.  Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long- term bone marrow cultures , 1990, The Journal of experimental medicine.

[96]  C. Isacke,et al.  Phosphorylation of CD44 in vivo requires both Ser323 and Ser325, but does not regulate membrane localization or cytoskeletal interaction in epithelial cells. , 1992, The EMBO journal.

[97]  G. Screaton,et al.  CD44 and cancer screening , 1993, The Lancet.

[98]  T. Hardingham,et al.  Proteoglycans: many forms and many functions , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[99]  B. Toole,et al.  Physical characteristics of hyaluronate binding to the surface of simian virus 40-transformed 3T3 cells. , 1980, The Journal of biological chemistry.

[100]  W. Carter,et al.  Isolation and DNA sequence of a cDNA clone encoding a lymphocyte adhesion receptor for high endothelium. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[101]  C. Isacke,et al.  The cytoplasmic tail of CD44 is required for basolateral localization in epithelial MDCK cells but does not mediate association with the detergent-insoluble cytoskeleton of fibroblasts , 1993, The Journal of cell biology.