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  • Review Article
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CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?

Key Points

  • CD44, the major hyaluronan (HA) receptor, makes abundant use of alternative splicing and can be located in glycolipid-enriched microdomains (GEMs). The extracellular and the cytoplasmic domains can associate with a large array of molecules.

  • Cancer-initiating cells (CICs; also known as cancer stem cells) constitute a minor population of cells within a tumour, but are frequently essential for tumour maintenance and progression. CICs can be enriched by so-called CIC markers, the most common of which is CD44.

  • CD44 can contribute to the activation of stem cell regulatory genes and can be a target of these genes, but there is, at present, no compelling evidence that CD44 has a central role in self-renewal and maintenance of pluripotency.

  • CD44 binding to HA has an important role in haematopoietic stem cells (HSCs) and leukaemia-initiating cells (LICs) and probably CIC homing and adhesion. HA binding-induced changes in CD44 membrane localization and conformation trigger the association and activation of multiple signal transduction molecules and of proteases, which supports migration.

  • CD44 accounts for the homing and settling of adult stem cells (ASCs), as well as metastasizing tumour cells and CICs in the niche, is actively involved in niche assembly through its effect on HA secretion and degradation, mainly owing to its activity as a catcher of chemokines, growth factors and matrix-degrading enzymes.

  • The HA–CD44 and HA–CD44v interactions have a central role in receptor tyrosine kinase (RTK)-induced activation of anti-apoptotic pathways and actively promote tumour cell and possibly CIC survival through their associations with multidrug resistance genes. Importantly, activation of signalling pathways initiated by the tumour matrix could be inhibited by HA degradation, by competition with small HA fragments, by CD44 blockade or by CD44 knockdown, whereas a blockade of an individual RTK did not recapitulate all of the effects observed on inhibition of CD44–HA binding.

Abstract

Can an abundantly expressed molecule be a reliable marker for the cancer-initiating cells (CICs; also known as cancer stem cells), which constitute the minority of cells within the mass of a tumour? CD44 has been implicated as a CIC marker in several malignancies of haematopoietic and epithelial origin. Is this a fortuitous coincidence owing to the widespread expression of the molecule or is CD44 expression advantageous as it fulfils some of the special properties that are displayed by CICs, such as self-renewal, niche preparation, epithelial–mesenchymal transition and resistance to apoptosis?

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Figure 1: CD44 gene and protein structure.
Figure 2: The engagement of CD44 in HSC and CIC homing and migration.
Figure 3: The contribution of CD44 to matrix assembly.
Figure 4: The involvement of CD44 in epithelial–mesenchymal transition.
Figure 5: The CD44–RTK cooperation and CIC apoptosis resistance.
Figure 6: CICs, CD44 and drug resistance.

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References

  1. Gallatin, W. M., Weissman, I. L. & Butcher, E. C. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature 304, 30–34 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Günthert, U. et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65, 13–24 (1991). First report on CD44 splice variants and their importance for metastatic potential.

    Article  PubMed  Google Scholar 

  3. Naor, D., Wallach-Dayan, S. B., Zahalka, M. A. & Sionov, R. V. Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin. Cancer Biol. 18, 260–267 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Ratajczak, M. Z. Cancer stem cells--normal stem cells “Jedi” that went over to the “dark side”. Folia Histochem. Cytobiol., 43, 175–181 (2005).

    CAS  PubMed  Google Scholar 

  5. Fábián, A., Barok, M., Vereb, G. & Szöllosi, J. Die hard: are cancer stem cells the Bruce Willises of tumor biology? Cytometry A 75, 67–74 (2009).

    Article  PubMed  Google Scholar 

  6. Allan, A. L., Vantyghem, S. A., Tuck, A. B. & Chambers, A. F. Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis. 26, 87–98 (2006–2007).

    Article  CAS  PubMed  Google Scholar 

  7. Sales, K. M., Winslet, M. C. & Seifalian, A. M. Stem cells and cancer: an overview. Stem Cell Rev. 3, 249–255 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Conway, A. E. et al. A Pluripotency and Self-Renewal Program Controls the Expansion of Genetically Unstable Cancer Stem Cells in Pluripotent Stem Cell-Derived Tumors. Stem Cells Oct 2. [Epub ahead of print] (2008).

  9. Adams, J. M. & Strasser, A. Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res. 68, 4018–4021 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, J. C. Good cells gone bad: the cellular origins of cancer. Trends Mol. Med. 16, 145–151 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Kuçi, S. et al. Adult stem cells as an alternative source of multipotential (pluripotential) cells in regenerative medicine. Curr. Stem Cell Res. Ther. 4, 107–117 (2009).

    Article  PubMed  Google Scholar 

  12. Stamenkovic, I., Amiot, M., Pesando, J. M. & Seed, B. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell 56, 1057–1062 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Goldstein, L. A. et al. A human lymphocyte homing receptor, the hermes antigen, is related to cartilage proteoglycan core and link proteins. Cell 56, 1063–1072 (1989). References 12 and 13 describe cloning of CD44 and characterization of CD44 as a member of the link protein family

    Article  CAS  PubMed  Google Scholar 

  14. Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C. B. & Seed, B. CD44 is the principal cell surface receptor for hyaluronate. Cell 61, 1303–1313 (1990). First description of HA as the major receptor for the leukocyte-homing molecule CD44.

    Article  CAS  PubMed  Google Scholar 

  15. Screaton, G. R., Bell, M. V., Jackson, D. G., Cornelis, F.B., Gerth, U. & Bell, J.I. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc. Natl Acad. Sci. USA 89, 12160–12164 (1992). First description of the complete intron–exon organization of the human CD44 gene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Idzerda, R. L., Carter, W. G., Nottenburg, C., Wayner, E. A., Gallatin, W. M. & St. John, T. Isolation and DNA sequence of a cDNA clone encoding a lymphocyte adhesion receptor for high endothelium. Proc. Natl Acad. Sci. USA 86, 4659–4663 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Goldstein, L. A. & Butcher, E. C. Identification of mRNA that encodes an alternative form of H-CAM (CD44) in lymphoid and nonlymphoid tissues. Immunogenetics 32, 389–397 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Peach, R. J., Hollenbaugh, D., Stamenkovic, I. & Aruffo, A. Identification of hyaluronic acid binding sites in the extracellular domain of CD44. J. Cell Biol. 122, 257–264 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Ishii, S., Ford, R., Thomas, P., Nachman, A., Steele, G. Jr. & Jessup, J. M. CD44 participates in the adhesion of human colorectal carcinoma cells to laminin and type IV collagen. Surg. Oncol. 2, 255–264 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Jalkanen, S. & Jalkanen, M. Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. J. Cell Biol. 116, 817–825 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Konstantopoulos, K. & Thomas, S. N. Cancer cells in transit: the vascular interactions of tumor cells. Annu. Rev. Biomed. Eng. 11, 177–202 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Toyama-Sorimachi, N. & Miyasaka, M. A novel ligand for CD44 is sulfated proteoglycan. Int. Immunol. 6, 655–660 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Greenfield, B. et al. Characterization of the heparan sulfate and chondroitin sulfate assembly sites in CD44. J. Biol. Chem. 274, 2511–2517 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Screaton, G. R., Bell, M. V., Bell, J. I. & Jackson, D. G. The identification of a new alternative exon with highly restricted tissue expression in transcripts encoding the mouse Pgp-1 (CD44) homing receptor. Comparison of all 10 variable exons between mouse, human, and rat. J. Biol. Chem. 268, 12235–12238 (1993).

    CAS  PubMed  Google Scholar 

  25. Okamoto, I. et al. Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J. Cell Biol. 155, 755–762 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kalnina, Z., Zayakin, P., Silina, K. & Liné, A. Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 42, 342–357 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Neame, S. J. & Isacke, C. M. The cytoplasmic tail of CD44 is required for basolateral localization in ephitelial MDCK cells but does not mediate association with the detergent-insoluble cytoskeleton of fibroblasts. J. Cell Biol. 121, 1299–1310 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Ruiz. P., Schwärzler, C. & Günthert, U. CD44 isoforms during differentiation and development. Bioessays 17, 17–24 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Bennett, K. L. et al. CD44 isoforms containing exon v3 are responsible for the presentation of heparin-binding growth factor. J. Cell Biol. 128, 687–698 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Orian-Rousseau, V. & Ponta, H. Adhesion proteins meet receptors: a common theme? Adv. Cancer Res. 101, 63–92 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Tremmel, M. et al. A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis. Blood 114, 5236–5244 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Lesley, J., Hyman, R. & Kincade, P. W. CD44 and its interaction with extracellular matrix. Adv. Immunol. 54, 271–335 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Liu, D. & Sy, M. S. Phorbol myristate acetate stimulates the dimerization of CD44 involving a cysteine in the transmembrane domain. J. Immunol. 159, 2702–2711 (1997).

    CAS  PubMed  Google Scholar 

  34. Oliferenko, S. et al. Analysis of CD44-containing lipid rafts: Recruitment of annexin II and stabilization by the actin cytoskeleton. J. Cell Biol. 146, 843–854 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Föger, N., Marhaba, R. & Zöller, M. Raft associated interaction of CD44 with the cytoskeleton. J. Cell Science 114, 1169–1178 (2001). Describes for the first time the importance of the GEM localization of CD44 as a co-receptor in signal transduction and cytoskeleton organization.

    PubMed  Google Scholar 

  36. Lokeshwar, V. B., Fregien, N. & Bourguignon, L. Y. Ankyrin-binding domain of CD44(Gp85) is required for the expression of hyaluronic acid-mediated adhesion function. J. Cell Biol. 126, 1099–1109 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Fehon, R. G., McClatchey, A. I. & Bretscher, A. Organizing the cell cortex: the role of ERM proteins. Nature Rev. Mol. Cell Biol. 11, 276–287 (2010).

    Article  CAS  Google Scholar 

  38. Mori, T., Kitano, K., Terawaki, S., Maesaki, R., Fukami, Y. & Hakoshima, T. Structural basis for CD44 recognition by ERM proteins. J. Biol. Chem. 283, 29602–29612 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stamenkovic, I. & Yu, Q. Merlin, a “Magic” Linker between Extracellular Cues and Intracellular Signaling Pathways that Regulate Cell. Motility, Proliferation, and Survival. Curr. Protein Pept. Sci. 11, 471–484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Virchow, R. L. K. in Cellular Pathology (ed.Hirschwald A), Berlin (1858).

    Google Scholar 

  41. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994). Definition of leukemia-initiating cells by their growth in SCID mice.

    Article  CAS  PubMed  Google Scholar 

  42. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Elenbaas, B. et al. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 15, 50–65 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Ponti, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Med. 7, 1028–1034 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Lobo, N. A., Shimono, Y., Qian, D. & Clarke, M. F. The Biology of Cancer Stem Cells. Annu. Rev. Cell. Dev. Biol. 23, 675–688 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Tárnok, A., Ulrich, H. & Bocsi, J. Phenotypes of stem cells from diverse origin. Cytometry A 77, 6–10 (2010).

    Article  PubMed  Google Scholar 

  49. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Huangfu, D. et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnol. 26, 1269–1275 (2008).

    Article  CAS  Google Scholar 

  51. Suzuki, H. I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S. & Miyazono, K. Modulation of microRNA processing by p53. Nature 460, 529–533 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Kashyap, V. et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 18, 1093–1108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cerdan, C. & Bhatia, M. Novel roles for Notch, Wnt and Hedgehog in hematopoesis derived from human pluripotent stem cells. Int. J. Dev. Biol. 54, 955–963 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Kwong, L. N. & Dove, W. F. APC and its modifiers in colon cancer. Adv. Exp. Med. Biol. 656, 85–106 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wielenga, V. J. et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am. J. Pathol. 154, 515–523 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bourguignon, L. Y., Spevak, C. C., Wong, G., Xia, W. & Gilad, E. Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J. Biol. Chem. 284, 26533–26546 (2009). Provides evidence for the involvement of CD44 in production of the oncogene miRNA-21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hao, J. et al. Co-expression of CD147 (EMMPRIN), CD44v3–10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression. Br. J. Cancer 103, 1008–1018 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Huang, Q. et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nature Cell Biol. 10, 202–210 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Skotheim, R. I. & Nees, M. Alternative splicing in cancer: noise, functional, or systematic? Int. J. Biochem. Cell Biol. 39, 1432–1449 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Srebrow, A. & Kornblihtt, A. R. The connection between splicing and cancer. J. Cell Sci. 119, 2635–2641 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Blick, T. et al. Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J. Mammary Gland Biol. Neoplasia 15, 235–252 (2010).

    Article  PubMed  Google Scholar 

  63. Bhat-Nakshatri, P. et al. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer 10, 411 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Smart, N. & Riley, P. R. The stem cell movement. Circ. Res. 2008 May 23;102(10), 1155–1168.

    Article  CAS  PubMed  Google Scholar 

  65. Almond, A. Hyaluronan. Cell. Mol. Life Sci. 64, 1591–1596 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Toole, B. P. Hyaluronan: from extracellular glue to pericellular cue. Nature Rev. Cancer 4, 528–539 (2004). Excellent Review on the close functional connection between HA and its receptor CD44.

    Article  CAS  Google Scholar 

  67. Lapidot, T., Dar, A. & Kollet, O. How do stem cells find their way home? Blood 106, 1901–1910 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Miyake, K., Medina, K. L., Hayashi, S., Ono, S., Hamaoka, T. & Kincade, P. W. Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long-term bone marrow cultures. J. Exp. Med. 171, 477–488 (1990).

    Article  CAS  PubMed  Google Scholar 

  69. Lundell, B. I., Mccarthy, J. B., Kovach, N. L. & Verfaillie, C. M. Activation of beta1 integrins on CML progenitors reveals cooperation between beta1 integrins and CD44 in the regulation of adhesion and proliferation. Leukemia 11, 822–829 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Ratajczak, M. Z. et al. Heterogeneous populations of bone marrow stem cells--are we spotting on the same cells from the different angles? Folia Histochem. Cytobiol. 42, 139–146 (2004).

    PubMed  Google Scholar 

  71. Avigdor, A. et al. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 103, 2981–2989 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Liu, J. & Jiang, G. CD44 and hematologic malignancies. Cell. Mol. Immunol. 3, 359–365 (2006).

    CAS  PubMed  Google Scholar 

  73. Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Med. 12, 1167–1174 (2006). Provides convincing evidence that the CD44–niche interaction is required for AML–CIC survival.

    Article  PubMed  CAS  Google Scholar 

  74. Krause, D. S., Lazarides, K., von Andrian, U. H. & Van Etten, R. A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nature Med. 12, 1175–1180 (2006). Defines CD44 as the homing receptor for CML (see also reference 73).

    Article  CAS  PubMed  Google Scholar 

  75. Zöller, M., Rajasagi, M., Vitacolonna, M. & Luft, T. Thymus repopulation after allogeneic reconstitution in hematological malignancies. Exp. Hematol., 35, 1891–1905 (2007).

    Article  PubMed  CAS  Google Scholar 

  76. Colmone, A., Amorim, M., Pontier, A. L., Wang, S., Jablonski, E. & Sipkins, D. A. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322, 1861–1865 (2008). Convincing demonstration that CICs usurp and modulate stem cell niches so that the niche no longer fulfils the requirement of ASCs.

    Article  CAS  PubMed  Google Scholar 

  77. Ropponen, K. et al. Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res. 58, 342–347 (1998).

    CAS  PubMed  Google Scholar 

  78. Kim, H. R. et al. Hyaluronan facilitates invasion of colon carcinoma cells in vitro via interaction with CD44. Cancer Res. 64, 4569–4576 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Siegelman, M. H., Stanescu, D. & Estess, P. The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion. J. Clin. Invest. 105, 683–691 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lesley, J., English, N. M., Gál, I., Mikecz, K., Day, A. J. & Hyman, R. Hyaluronan binding properties of a CD44 chimera containing the link module of TSG-6. J. Biol. Chem. 277, 26600–26608 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Lamontagne, C. A. & Grandbois, M. PKC-induced stiffening of hyaluronan/CD44 linkage; local force measurements on glioma cells. Exp. Cell Res. 314, 227–236 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Thomas, L., Byers, H. R., Vink, J. & Stamenkovic, I. CD44H regulates tumor cell migration on hyaluronate-coated substrate. J. Cell Biol. 118, 971–977 (1992).

    Article  CAS  PubMed  Google Scholar 

  83. Oliferenko, S., Kaverina, I., Small, J. V. & Huber, L. A. Hyaluronic acid (HA) binding to CD44 activates Rac1 and induces lamellipodia outgrowth. J. Cell Biol. 148, 1159–1164 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bustelo, X. R. Regulatory and signaling properties of the Vav family. Mol. Cell Biol. 20, 1461–1477 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bourguignon, L. Y., Singleton, P. A., Zhu, H. & Diedrich, F. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J. Biol. Chem. 278, 29420–29434 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Bourguignon, L. Y. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin. Cancer Biol. 18, 251–259 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Marhaba, R., Freyschmidt-Paul, P. & Zöller, M. In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance. Eur. J. Immunol. 36, 3017–3032 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Nagano, O. & Saya, H. Mechanism and biological significance of CD44 cleavage. Cancer Sci. 95, 930–935 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Nagano, O. et al. Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2+) influx and PKC activation. J. Cell Biol. 165, 893–902 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nakamura, H. et al. Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase. Cancer Res. 64, 876–882 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Sugahara, K. N. et al. Chondroitin sulfate E fragments enhance CD44 cleavage and CD44-dependent motility in tumor cells. Cancer Res. 68, 7191–7199 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Okamoto, I. et al. Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors. Am. J. Pathol. 160, 441–447 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jung, T. et al. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11, 1093–1105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Desai, B., Ma, T., Zhu, J. & Chellaiah, M. A. Characterization of the expression of variant and standard CD44 in prostate cancer cells: identification of the possible molecular mechanism of CD44/MMP9 complex formation on the cell surface. J. Cell. Biochem. 108, 272–284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bourguignon, L. Y. et al. CD44v(3, 8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells. J. Cell. Physiol. 176, 206–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Yu, Q. & Stamenkovic, I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 13, 35–48 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wilson, T. J., Nannuru, K. C., Futakuchi, M., Sadanandam, A. & Singh, R. K. Cathepsin G. enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappaB ligand. Cancer Res. 68, 5803–5811 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Hill, A., McFarlane, S., Johnston, P. G. & Waugh, D. J. The emerging role of CD44 in regulating skeletal micrometastasis. Cancer Lett. 237, 1–9 (2006).

    CAS  Google Scholar 

  99. Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).

    PubMed  PubMed Central  Google Scholar 

  100. Wilson, T. J., Nannuru, K. C. & Singh, R. K. Cathepsin G-mediated activation of pro-matrix metalloproteinase 9 at the tumor-bone interface promotes transforming growth factor-beta signaling and bone destruction. Mol. Cancer Res. 7, 1224–1233 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Pelletier, L. et al. Gamma-secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells. Cancer Res. 66, 3681–3687 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Wolpert, L. One hundred years of positional information. Trends Genet. 12, 359–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Li, L. & Neaves, W. B. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 66, 4553–4557 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Diaz-Flores, L. Jr., Madrid, J. F., Gutierrez, R., Varela, F., Alvarez-Argüelles, H. & Diaz-Flores, L. Adult stem and transit-amplifying cell location. Histol. Histopathol. 21, 995–1027 (2006).

    PubMed  Google Scholar 

  105. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Hendrix, M. J., Seftor, E. A., Seftor, R. E., Kasemeier-Kulesa, J., Kulesa, P. M. & Postovit, L. M. Reprogramming metastatic tumour cells with embryonic microenvironments. Nature Rev. Cancer 7, 246–255 (2007).

    Article  CAS  Google Scholar 

  107. Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Williams, D. A. & Cancelas, J. A. Leukaemia: niche retreats for stem cells. Nature 444, 827–828 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Stern, R. Association between cancer and “acid mucopolysaccharides”: an old concept comes of age, finally. Semin. Cancer Biol. 18, 238–243 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Girish, K. S. & Kemparaju, K. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci. 80, 1921–1943 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Kuhn, N. Z. & Tuan, R. S. Regulation of stemness and stem cell niche of mesenchymal stem cells: implications in tumorigenesis and metastasis. J. Cell. Physiol. 222, 268–277 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nature Rev. Mol. Cell Biol. 10, 75–82 (2009).

    Article  CAS  Google Scholar 

  113. Itano, N. & Kimata, K. Altered hyaluronan biosynthesis in cancer progression. Semin. Cancer Biol. 18, 268–274 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Klingbeil, P., Marhaba, R., Jung, T., Kirmse, R., Ludwig, T. & Zöller, M. CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance. Mol. Cancer Res. 7, 168–179 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Adamia, S., Maxwell, C. A. & Pilarski, L. M. Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer. Curr. Drug Targets. Cardiovasc. Haematol. Disord. 5, 3–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Jung, T. Molekulare Grundlagen des Beitrags varianter CD44-Isoformen zur Apoptoseresistenz und Präparation einer prämetastatischen Nische. PhD Thesis, 2010, Karslruhe Institute of Technology, Karlsruhe, Germany.

    Google Scholar 

  117. Zhang, J., Ren, H., Yuan, P., Lang, W., Zhang, L. & Mao, L. Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells. Cancer Res. 66, 18–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Pucci, S., Mazzarelli, P., Nucci, C., Ricci, F. & Spagnoli, L. G. CLU “in and out”: looking for a link. Adv. Cancer Res. 105, 93–113 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Peerschke, E. I., Yin, W. & Ghebrehiwet, B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol. Immunol. 47, 2170–2175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Couchman, J. R. Transmembrane Signaling Proteoglycans. Annu. Rev. Cell Dev. Biol. 26, 89–114 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Wai, P. Y. & Kuo, P. C. Osteopontin: regulation in tumor metastasis. Cancer Metastasis Rev. 27, 103–118 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Berdiaki, A., Nikitovic, D., Tsatsakis, A., Katonis, P., Karamanos, N. K. & Tzanakakis, G. N. bFGF induces changes in hyaluronan synthase and hyaluronidase isoform expression and modulates the migration capacity of fibrosarcoma cells. Biochim. Biophys. Acta 1790, 1258–1265 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. van der Voort, R. et al. Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. J. Biol. Chem. 274, 6499–6506 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Sherman, L., Wainwright, D., Ponta, H. & Herrlich, P. A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth. Genes Dev. 12, 1058–1071 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yu, W. H., Woessner, J. F. Jr., McNeish, J. D. & Stamenkovic, I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev. 16, 307–323 (2002). One of the first descriptions of the cooperativity between proteoglycan activities of CD44, MMPs, growth factors and their receptors with tyrosine kinase activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kim, M. S. et al. Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells. Cancer Res. 65, 686–691 (2005).

    CAS  PubMed  Google Scholar 

  127. Weber, G. F. Molecular mechanisms of metastasis. Cancer Lett. 270, 181–190 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nature Med. 12, 657–664 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Weber, G. F., Bronson, R. T., Ilagan, J., Cantor, H., Schmits, R. & Mak, T. W. Absence of the CD44 gene prevents sarcoma metastasis. Cancer Res. 62, 2281–2286 (2002).

    CAS  PubMed  Google Scholar 

  130. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Barnhart, B. C. & Simon, M. C. Metastasis and stem cell pathways. Cancer Metastasis Rev. 26, 261–271 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ponta, H., Sherman, L. & Herrlich, P. A. CD44: from adhesion molecules to signalling regulators. Nature Rev. Mol. Cell Biol. 4, 33–45 (2003).

    Article  CAS  Google Scholar 

  133. Marhaba, R. & Zöller, M. CD44 in cancer progression: adhesion, migration and growth regulation. J. Mol. Histol. 35, 211–231 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ahmed, N., Abubaker, K., Findlay, J. & Quinn, M. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr. Cancer Drug Targets. 10, 268–278 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Wong, N. A. & Pignatelli, M. Beta-catenin--a linchpin in colorectal carcinogenesis? Am. J. Pathol. 160, 389–401 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Toole, B. P. & Slomiany, M. G. Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Semin. Cancer Biol. 18, 244–250 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Yoshihara, S. et al. A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells. FEBS Lett. 579, 2722–2726 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Uchino, M. et al. Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. BMC Cancer 10, 414 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Takahashi, E. et al. Tumor necrosis factor-alpha regulates transforming growth factor-beta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction. J. Biol. Chem. 285, 4060–4073 (2010). Elaborates in an in vivo model of fibrosis the contribution of the HA–CD44–moesin complex to EMT via TNFα.

    Article  CAS  PubMed  Google Scholar 

  141. Acharya, P. S. et al. Fibroblast migration is mediated by CD44-dependent TGF beta activation. J. Cell Sci. 121, 1393–1402 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Allouche, M., Charrad, R. S., Bettaieb, A., Greenland, C., Grignon, C. & Smadja-Joffe, F. Ligation of the CD44 adhesion molecule inhibits drug-induced apoptosis in human myeloid leukemia cells. Blood 96, 1187–1190 (2000).

    CAS  PubMed  Google Scholar 

  143. Bates, R. C., Edwards, N. S., Burns, G. F. & Fisher, D. E. A CD44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/Akt in colon carcinoma cells. Cancer Res. 61, 5275–5283 (2001).

    CAS  PubMed  Google Scholar 

  144. Fujita, Y. et al. CD44 signaling through focal adhesion kinase and its anti-apoptotic effect. FEBS Lett. 528, 101–108 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Yu, Q., Toole, B. P. & Stamenkovic, I. Induction of apoptosis of metastatic mammary carcinoma cells in vivo by disruption of tumor cell surface CD44 function. J. Exp. Med. 186, 1985–1996 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Marhaba, R., Klingbeil, P., Nuebel, T., Nazarenko, I., Buechler, M. W. & Zöller, M. CD44 and EpCAM: cancer-initiating cell markers. Curr. Mol. Med. 8, 784–804 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Wang, S. J. & Bourguignon, L. Y. Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 132, 771–778 (2006).

    Article  PubMed  Google Scholar 

  148. Sherman, L. S., Rizvi, T. A., Karyala, S. & Ratner, N. CD44 enhances neuregulin signaling by Schwann cells. J. Cell Biol. 150, 1071–1084 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ghatak, S., Misra, S. & Toole, B. P. Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells. J. Biol. Chem. 280, 8875–8883 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Misra, S., Hascall, V. C., Berger, F. G., Markwald, R. R. & Ghatak, S. Hyaluronan, CD44, and cyclooxygenase-2 in colon cancer. Connect. Tissue Res. 49, 219–224 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. Orian-Rousseau, V. et al. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. Mol. Biol. Cell 18, 76–83 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Matzke, A. et al. Haploinsufficiency of c-Met in cd44-/- mice identifies a collaboration of CD44 and c-Met in vivo. Mol. Cell Biol. 27, 8797–8806 (2007). Demonstrates in a model of CD44-deficient mice the functional importance of the crosstalk between CD44 and RTKs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Krause, D. S. & Van Etten, R. A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 353, 172–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Misra, S., Toole, B. P. & Ghatak, S. Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells. J. Biol. Chem. 281, 34936–34941 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Lynch, C. C., Vargo-Gogola, T., Martin, M. D., Fingleton, B., Crawford, H. C. & Matrisian, L. M. Matrix metalloproteinase 7 mediates mammary epithelial cell tumorigenesis through the ErbB4 receptor. Cancer Res. 67, 6760–6767 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Yu, Q. & Stamenkovic, I. Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. Clin. Exp. Metastasis 21, 235–242 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Cooper, J. A. & Qian, H. A mechanism for SRC kinase-dependent signaling by noncatalytic receptors. Biochemistry 47, 5681–5688 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Ingley, E. Src family kinases: Regulation of their activities, levels and identification of new pathways. Biochim. Biophys. Acta 1784, 56–65 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Bates, R. C., Elith, C. A., Thorne, R. F. & Burns, G. F. Engagement of variant CD44 confers resistance to anti-integrin antibody-mediated apoptosis in a colon carcinoma cell line. Cell Adhes. Commun. 6, 21–38 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Katagiri, Y. U. et al. CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine- glycine-aspartic acid, thereby stimulating cell motility and chemotaxis. Cancer Res. 59, 219–226 (1999).

    CAS  PubMed  Google Scholar 

  161. Miletti-González, K. E. et al. The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res. 65, 6660–6667 (2005).

    Article  PubMed  Google Scholar 

  162. Misra, S., Ghatak, S. & Toole, B. P. Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2. J. Biol. Chem. 280, 20310–20315 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Dean, M., Fojo, T. & Bates, S. Tumour stem cells anddrug resistance. Nature Rev. Cancer 5, 275–284 (2005).

    Article  CAS  Google Scholar 

  164. Baumgartner, G., Gomar-Höss, C., Sakr, L., Ulsperger, E. & Wogritsch, C. The impact of extracellular matrix on the chemoresistance of solid tumors--experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy. Cancer Lett. 131, 85–99 (1998).

    Article  CAS  PubMed  Google Scholar 

  165. Slomiany, M. G. et al. Abrogating drug resistance in malignant peripheral nerve sheath tumors by disrupting hyaluronan-CD44 interactions with small hyaluronan oligosaccharides. Cancer Res. 69, 4992–4998 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Liu, C. M., Chang, C. H., Yu, C. H., Hsu, C. C. & Huang, L. L. Hyaluronan substratum induces multidrug resistance in human mesenchymal stem cells via CD44 signaling. Cell Tissue Res. 336, 465–475 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Xu, Y., Stamenkovic, I. & Yu, Q. CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma. Cancer Res. 70, 2455–2464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  169. Mimeault, M. & Batra, S. K. New advances on critical implications of tumor- and metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence. Histol. Histopathol. 25, 1057–1073 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Guise, T. Examining the metastatic niche: targeting the microenvironment. Semin. Oncol. 37 Suppl 2, S2–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  171. Blum, B. & Benvenisty, N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8, 3822–3830 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Schatton, T., Frank, N. Y. & Frank, M. H. Identification and targeting of cancer stem cells. Bioessays 31, 1038–1049 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Godar, S. et al. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62–73 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Akisik, E., Bavbek, S. & Dalay, N. CD44 variant exons in leukemia and lymphoma. Pathol. Oncol. Res. 8, 36–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  175. Liebisch, P. et al. CD44v6, a target for novel antibody treatment approaches, is frequently expressed in multiple myeloma and associated with deletion of chromosome arm 13q. Haematologica 90, 489–493 (2005).

    CAS  PubMed  Google Scholar 

  176. Avin, E., Haimovich, J. & Hollander, N. Anti-idiotype x anti-CD44 bispecific antibodies inhibit invasion of lymphoid organs by B cell lymphoma. J. Immunol. 173, 4736–4743 (2004). One of few reports describing efficacy, selectivity and avoidance of side effects of bispecific antibodies that target with both arms, one directed towards CD44, the tumour cell.

    Article  CAS  PubMed  Google Scholar 

  177. Yang, Z. F. et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13, 153–166 (2008).

    Article  CAS  PubMed  Google Scholar 

  178. Seiter, S. et al. Prevention of tumor metastasis formation by anti-variant CD44. J. Exp. Med. 177, 443–455 (1993).

    Article  CAS  PubMed  Google Scholar 

  179. Rupp, U. et al. Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6- positive metastatic breast cancer: final results of a phase I study. Anticancer Drugs 18, 477–485 (2007).

    Article  CAS  PubMed  Google Scholar 

  180. Tijink, B. M. et al. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin. Cancer Res. 12, 6064–6072 (2006).

    Article  CAS  PubMed  Google Scholar 

  181. Somasundaram, C., Arch., R., Matzku, S. & Zöller, M. Development of a bispecific F(ab')2 conjugate against the complement receptor CR3 of macrophages and a variant CD44 antigen of rat pancreatic adenocarcinoma for redirecting macrophage-mediated tumor cytotoxicity. Cancer Immunol. Immunother. 42, 343–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  182. Hibino, S., Shibuya, M., Engbring, J. A., Mochizuki, M., Nomizu, M. & Kleinman, H. K. Identification of an active site on the laminin alpha5 chain globular domain that binds to CD44 and inhibits malignancy. Cancer Res. 64, 4810–4816 (2004).

    Article  CAS  PubMed  Google Scholar 

  183. Hibino, S. et al. Laminin alpha5 chain metastasis- and angiogenesis-inhibiting peptide blocks fibroblast growth factor 2 activity by binding to the heparan sulfate chains of CD44. Cancer Res. 65, 10494–10501 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Slomiany, M. G., Dai, L., Tolliver, L. B., Grass, G. D., Zeng, Y. & Toole, B. P. Inhibition of Functional Hyaluronan-CD44 Interactions in CD133-positive Primary Human Ovarian Carcinoma Cells by Small Hyaluronan Oligosaccharides. Clin. Cancer Res. 15, 7593–7601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Ween, M. P., Hummitzsch, K., Rodgers, R. J., Oehler, M. K. & Ricciardelli, C. Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides. Clin. Exp. Metastasis 28, 113–125 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Golshani, R., Lopez, L., Estrella, V., Kramer, M., Iida, N. & Lokeshwar, V. B. Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44. Cancer Res. 68, 483–491 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. De Stefano, I. et al. Hyaluronic acid-paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts. Cancer Chemother. Pharmacol. 2010 Sep 17. [Epub ahead of print].

  188. Rivkin, I., Cohen, K., Koffler, J., Melikhov, D., Peer, D. & Margalit, R. Paclitaxel-clusters coated with hyaluronan as selective tumor-targeted nanovectors. Biomaterials 31, 7106–7114 (2010).

    Article  CAS  PubMed  Google Scholar 

  189. Dhillon, J., Astanehe, A., Lee, C., Fotovati, A., Hu, K. & Dunn, S. E. The expression of activated Y-box binding protein-1 serine 102 mediates trastuzumab resistance in breast cancer cells by increasing CD44+ cells. Oncogene 29, 6294–6300 (2010).

    Article  CAS  PubMed  Google Scholar 

  190. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. So, J. Y. et al. A novel Gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. Mol. Pharmacol. 79, 360–367 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Anido, J. et al. TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 18, 655–668 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author would like to cordially thank (former) people of her laboratory for cited work, and R. Marhaba and K. Malinowska for helpful comments. The author's laboratory is supported by the German Research Foundation, The German Cancer Research Foundation and the National Cancer Centre, Heidelberg/Mannheim.

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Supplementary information

Supplementary information S1 (table)

CD44 expression on CIC and LIC (PDF 221 kb)

Supplementary information S2 (table)

List of markers with frequently used synonyms (PDF 158 kb)

Supplementary information S3 (figure)

CD44 as a therapeutic target for CIC (PDF 481 kb)

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Glossary

Alternative splicing

A key mechanism that accounts for gene expression diversity. Splicing is tightly regulated by a range of RNA and protein factors and RNA sequence elements that function in a cooperative manner.

Link domain

Named according to considerable homologies with the cartilage link protein and the proteoglycan core protein.

SRC family

Cytoplasmic tyrosine kinases, which are controlled by multiple membrane receptors and which signal to various downstream effectors.

ERM proteins

Mediate actin–membrane linkage and regulate signalling molecules.

Bmi1

Member of the Polycomb group of transcriptional repressors that epigenetically modify chromatin and participate in the establishment and maintenance of cell fates. These proteins have important roles in both stem cell self-renewal and cancer development.

ATP-binding cassette (ABC) transporters

Can pump a wide variety of endogenous and exogenous compounds out of cells. They are widely expressed in stem cells and CICs and confer the side population phenotype.

Protein kinase Cε (PKCε)

Several isoforms of this enzyme mediate serine and threonine phosphorylation in many different protein substrates thus propagating various signal transduction pathways leading to transcription factor activation.

MicroRNA (miRNA)

A class of small non-coding RNA molecules that regulate gene expression at the post-transcriptional level.

Epithelial–mesenchymal transition (EMT)

An evolutionary conserved developmental programme adopted by tumour cells, in which cells change from an epithelial to a mesenchymal phenotype.

Extracellular matrix (ECM)

Well-ordered complex network of glycoproteins and proteoglycans surrounding cells and organizing tissue. It is essential for cell survival, migration and proliferation.

Endosteal niche

Arrangement of osteoblasts, osteoclasts, mesenchymal stem cells, reticular cells and probably endothelial cells at the inner site of the bone that serves for homing and activity of HSCs.

Focal adhesion kinase (FAK)

A non-receptor protein tyrosine kinase. FAK is a scaffold for organizing a network of signalling and cytoskeletal proteins. It is implicated in signalling pathways involved in cell motility, proliferation and apoptosis.

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Zöller, M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?. Nat Rev Cancer 11, 254–267 (2011). https://doi.org/10.1038/nrc3023

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