Neural Cell Adhesion Molecule in Cancer: Expression and Mechanisms

  • Silvia Zecchini
  • Ugo CavallaroEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 663)


Neural cell adhesion molecule (NCAM) was initially characterized in cells of the nervous system, where its role in various neural processes is well established. However, NCAM is also expressed in a wide variety of non-neuronal cell types, where its function has been remained largely elusive. Importantly, the expression of NCAM appears to be deregulated in many different cancer types, pointing to a possible role in tumor development. Expression studies in cancer and functional studies in various experimental settings indicate that NCAM can exert both a positive and a negative regulation on cancer progression, depending on the tumor context.

This review will provide an overview of tumor-associated alterations in NCAM expression, discussing a subset of cellular and molecular mechanisms that likely underlie the heterogeneous function of NCAM in human cancer.


NCAM Tumor progression Metastasis Angiogenesis Fibroblast growth factor receptor Signaling 



We apologize to all colleagues whose important work could not be cited. The work in the authors’ laboratory is supported by the Italian Association for Cancer Research, the Association for International Cancer Research, the Telethon Foundation, and the Cariplo Foundation. We thank C. Francavilla and G. Pajè for the help in preparing the figures.


  1. 1.
    Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4:118-132PubMedCrossRefGoogle Scholar
  2. 2.
    Bruses JL, Rutishauser U (2001) Roles, regulation, and mechanism of polysialic acid function during neural development. Biochimie 83:635-643PubMedCrossRefGoogle Scholar
  3. 3.
    Jimbo T, Nakayama J, Akahane K, Fukuda M (2001) Effect of polysialic acid on the tumor xenografts implanted into nude mice. Int J Cancer 94:192-199PubMedCrossRefGoogle Scholar
  4. 4.
    Gluer S, Zense M, Radtke E, von Schweinitz D (1998) Polysialylated neural cell adhesion molecule in childhood ganglioneuroma and neuroblastoma of different histological grade and clinical stage. Langenbecks Arch Surg 383:340-344PubMedCrossRefGoogle Scholar
  5. 5.
    Seidenfaden R, Krauter A, Schertzinger F, Gerardy-Schahn R, Hildebrandt H (2003) Polysialic acid directs tumor cell growth by controlling heterophilic neural cell adhesion molecule interactions. Mol Cell Biol 23:5908-5918PubMedCrossRefGoogle Scholar
  6. 6.
    Sasaki H, Yoshida K, Ikeda E et al (1998) Expression of the neural cell adhesion molecule in astrocytic tumors: an inverse correlation with malignancy. Cancer 82:1921-1931PubMedCrossRefGoogle Scholar
  7. 7.
    Krushel LA, Tai MH, Cunningham BA, Edelman GM, Crossin KL (1998) Neural cell adhesion molecule (N-CAM) domains and intracellular signaling pathways involved in the inhibition of astrocyte proliferation. Proc Natl Acad Sci USA 95:2592-2596PubMedCrossRefGoogle Scholar
  8. 8.
    Komminoth P, Roth J, Saremaslani P, Matias-Guiu X, Wolfe HJ, Heitz PU (1994) Polysialic acid of the neural cell adhesion molecule in the human thyroid: a marker for medullary thyroid carcinoma and primary C-cell hyperplasia. An immunohistochemical study on 79 thyroid lesions. Am J Surg Pathol 18:399-411PubMedCrossRefGoogle Scholar
  9. 9.
    Lantuejoul S, Moro D, Michalides RJ, Brambilla C, Brambilla E (1998) Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am J Surg Pathol 22:1267-1276PubMedCrossRefGoogle Scholar
  10. 10.
    Trouillas J, Daniel L, Guigard MP et al (2003) Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion. J Neurosurg 98:1084-1093PubMedCrossRefGoogle Scholar
  11. 11.
    Blaheta RA, Hundemer M, Mayer G et al (2002) Expression level of neural cell adhesion molecule (NCAM) inversely correlates with the ability of neuroblastoma cells to adhere to endothelium in vitro. Cell Commun Adhes 9:131-147PubMedCrossRefGoogle Scholar
  12. 12.
    Blaheta RA, Daher FH, Michaelis M et al (2006) Chemoresistance induces enhanced adhesion and transendothelial penetration of neuroblastoma cells by down-regulating NCAM surface expression. BMC Cancer 6:294PubMedCrossRefGoogle Scholar
  13. 13.
    Lynch DF Jr, Hassen W, Clements MA, Schellhammer PF, Wright GL Jr (1997) Serum levels of endothelial and neural cell adhesion molecules in prostate cancer. Prostate 32:214-220PubMedCrossRefGoogle Scholar
  14. 14.
    Gluer S, Schelp C, Madry N, von Schweinitz D, Eckhardt M, Gerardy-Schahn R (1998) Serum polysialylated neural cell adhesion molecule in childhood neuroblastoma. Br J Cancer 78:106-110PubMedCrossRefGoogle Scholar
  15. 15.
    Todaro L, Christiansen S, Varela M et al (2007) Alteration of serum and tumoral neural cell adhesion molecule (NCAM) isoforms in patients with brain tumors. J Neurooncol 83:135-144PubMedCrossRefGoogle Scholar
  16. 16.
    Bataille R, Jego G, Robillard N et al (2006) The phenotype of normal, reactive and malignant plasma cells. Identification of “many and multiple myelomas” and of new targets for myeloma therapy. Haematologica 91:1234-1240PubMedGoogle Scholar
  17. 17.
    Ely SA, Knowles DM (2002) Expression of CD56/neural cell adhesion molecule correlates with the presence of lytic bone lesions in multiple myeloma and distinguishes myeloma from monoclonal gammopathy of undetermined significance and lymphomas with plasmacytoid differentiation. Am J Pathol 160:1293-1299PubMedCrossRefGoogle Scholar
  18. 18.
    Martin P, Santon A, Bellas C (2004) Neural cell adhesion molecule expression in plasma cells in bone marrow biopsies and aspirates allows discrimination between multiple myeloma, monoclonal gammopathy of uncertain significance and polyclonal plasmacytosis. Histopathology 44:375-380PubMedCrossRefGoogle Scholar
  19. 19.
    Rawstron A, Barrans S, Blythe D et al (1999) Distribution of myeloma plasma cells in peripheral blood and bone marrow correlates with CD56 expression. Br J Haematol 104:138-143PubMedCrossRefGoogle Scholar
  20. 20.
    Sahara N, Takeshita A (2004) Prognostic significance of surface markers expressed in multiple myeloma: CD56 and other antigens. Leuk Lymphoma 45:61-65PubMedCrossRefGoogle Scholar
  21. 21.
    Novotny JR, Nuckel H, Duhrsen U (2006) Correlation between expression of CD56/NCAM and severe leukostasis in hyperleukocytic acute myelomonocytic leukaemia. Eur J Haematol 76:299-308PubMedCrossRefGoogle Scholar
  22. 22.
    Raspadori D, Damiani D, Lenoci M et al (2001) CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia 15:1161-1164PubMedCrossRefGoogle Scholar
  23. 23.
    Yang DH, Lee JJ, Mun YC et al (2007) Predictable prognostic factor of CD56 expression in patients with acute myeloid leukemia with t(8:21) after high dose cytarabine or allogeneic hematopoietic stem cell transplantation. Am J Hematol 82:1-5PubMedCrossRefGoogle Scholar
  24. 24.
    Gattenloehner S, Chuvpilo S, Langebrake C et al (2007) Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression. Blood 110:2027-2033PubMedCrossRefGoogle Scholar
  25. 25.
    Yamagata T, Maki K, Mitani K (2005) Runx1/AML1 in normal and abnormal hematopoiesis. Int J Hematol 82:1-8PubMedCrossRefGoogle Scholar
  26. 26.
    Roesler J, Srivatsan E, Moatamed F, Peters J, Livingston EH (1997) Tumor suppressor activity of neural cell adhesion molecule in colon carcinoma. Am J Surg 174:251-257PubMedCrossRefGoogle Scholar
  27. 27.
    Huerta S, Srivatsan ES, Venkatesan N et al (2001) Alternative mRNA splicing in colon cancer causes loss of expression of neural cell adhesion molecule. Surgery 130:834-843PubMedCrossRefGoogle Scholar
  28. 28.
    Kameda K, Shimada H, Ishikawa T et al (1999) Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion. Cancer Lett 137:201-207PubMedCrossRefGoogle Scholar
  29. 29.
    Tezel E, Kawase Y, Takeda S, Oshima K, Nakao A (2001) Expression of neural cell adhesion molecule in pancreatic cancer. Pancreas 22:122-125PubMedCrossRefGoogle Scholar
  30. 30.
    Naito Y, Kinoshita H, Okabe Y et al (2006) CD56 (NCAM) expression in pancreatic carcinoma and the surrounding pancreatic tissue. Kurume Med J 53:59-62PubMedCrossRefGoogle Scholar
  31. 31.
    Deramaudt TB, Takaoka M, Upadhyay R et al (2006) N-cadherin and keratinocyte growth factor receptor mediate the functional interplay between Ki-RASG12V and p53V143A in promoting pancreatic cell migration, invasion, and tissue architecture disruption. Mol Cell Biol 26:4185-4200PubMedCrossRefGoogle Scholar
  32. 32.
    Vargas F, Tolosa E, Sospedra M et al (1994) Characterization of neural cell adhesion molecule (NCAM) expression in thyroid follicular cells: induction by cytokines and over-expression in autoimmune glands. Clin Exp Immunol 98:478-488PubMedCrossRefGoogle Scholar
  33. 33.
    Zeromski J, Bagnasco M, Paolieri F, Dworacki G (1992) Expression of CD56 (NKH-1) differentiation antigen in human thyroid epithelium. Clin Exp Immunol 89:474-478PubMedCrossRefGoogle Scholar
  34. 34.
    Satoh F, Umemura S, Yasuda M, Osamura RY (2001) Neuroendocrine marker expression in thyroid epithelial tumors. Endocr Pathol 12:291-299PubMedCrossRefGoogle Scholar
  35. 35.
    Scarpino S, Di Napoli A, Melotti F, Talerico C, Cancrini A, Ruco L (2007) Papillary carcinoma of the thyroid: low expression of NCAM (CD56) is associated with downregulation of VEGF-D production by tumour cells. J Pathol 212:411-419PubMedCrossRefGoogle Scholar
  36. 36.
    Onganer PU, Seckl MJ, Djamgoz MB (2005) Neuronal characteristics of small-cell lung cancer. Br J Cancer 93:1197-1201PubMedCrossRefGoogle Scholar
  37. 37.
    Niklinski J, Furman M (1995) Clinical tumour markers in lung cancer. Eur J Cancer Prev 4:129-138PubMedCrossRefGoogle Scholar
  38. 38.
    Miyahara R, Tanaka F, Nakagawa T, Matsuoka K, Isii K, Wada H (2001) Expression of neural cell adhesion molecules (polysialylated form of neural cell adhesion molecule and L1-cell adhesion molecule) on resected small cell lung cancer specimens: in relation to proliferation state. J Surg Oncol 77:49-54PubMedCrossRefGoogle Scholar
  39. 39.
    Ornadel D, Ledermann JA, Eagle K et al (1998) Biodistribution of a radiolabelled monoclonal antibody NY3D11 recognizing the neural cell adhesion molecule in tumour xenografts and patients with small-cell lung cancer. Br J Cancer 77:103-109PubMedCrossRefGoogle Scholar
  40. 40.
    Hosono MN, Hosono M, Mishra AK et al (2000) Rhenium-188-labeled anti-neural cell adhesion molecule antibodies with 2-iminothiolane modification for targeting small-cell lung cancer. Ann Nucl Med 14:173-179PubMedCrossRefGoogle Scholar
  41. 41.
    Michalides R, Kwa B, Springall D et al (1994) NCAM and lung cancer. Int J Cancer Suppl 8:34-37PubMedCrossRefGoogle Scholar
  42. 42.
    Johnson BE, Kelley MJ (1998) Autocrine growth factors and neuroendocrine markers in the development of small-cell lung cancer. Oncology (Williston Park) 12:11-14Google Scholar
  43. 43.
    Murray N, Salgia R, Fossella FV (2004) Targeted molecules in small cell lung cancer. Semin Oncol 31:106-111PubMedCrossRefGoogle Scholar
  44. 44.
    Yu A, Choi J, Ohno K, Levin B, Rom WN, Meruelo D (2000) Specific cell targeting for delivery of toxins into small-cell lung cancer using a streptavidin fusion protein complex. DNA Cell Biol 19:383-388PubMedCrossRefGoogle Scholar
  45. 45.
    Zangemeister-Wittke U, Collinson AR, Frosch B, Waibel R, Schenker T, Stahel RA (1994) Immunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer. Br J Cancer 69:32-39PubMedCrossRefGoogle Scholar
  46. 46.
    Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115-122PubMedCrossRefGoogle Scholar
  47. 47.
    Lahr G, Mayerhofer A, Bucher S, Barthels D, Wille W, Gratzl M (1993) Neural cell adhesion molecules in rat endocrine tissues and tumor cells: distribution and molecular analysis. Endocrinology 132:1207-1217PubMedCrossRefGoogle Scholar
  48. 48.
    Moller CJ, Christgau S, Williamson MR et al (1992) Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas. Mol Endocrinol 6:1332-1342PubMedCrossRefGoogle Scholar
  49. 49.
    Cavallaro U, Niedermeyer J, Fuxa M, Christofori G (2001) N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 3:650-657PubMedCrossRefGoogle Scholar
  50. 50.
    Perl AK, Dahl U, Wilgenbus P, Cremer H, Semb H, Christofori G (1999) Reduced expression of neural cell adhesion molecule induces metastatic dissemination of pancreatic beta tumor cells. Nat Med 5:286-291PubMedCrossRefGoogle Scholar
  51. 51.
    Crnic I, Strittmatter K, Cavallaro U et al (2004) Loss of neural cell adhesion molecule induces tumor metastasis by up-regulating lymphangiogenesis. Cancer Res 64:8630-8638PubMedCrossRefGoogle Scholar
  52. 52.
    Cavallaro U, Christofori G (2001) Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim Biophys Acta 1552:39-45PubMedGoogle Scholar
  53. 53.
    Alpaugh ML, Tomlinson JS, Ye Y, Barsky SH (2002) Relationship of sialyl-Lewis(x/a) underexpression and E-cadherin overexpression in the lymphovascular embolus of inflammatory breast carcinoma. Am J Pathol 161:619-628PubMedCrossRefGoogle Scholar
  54. 54.
    Xian X, Hakansson J, Stahlberg A et al (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642-651PubMedCrossRefGoogle Scholar
  55. 55.
    Mayerhofer A, Spanel-Borowski K, Watkins S, Gratzl M (1992) Cultured microvascular endothelial cells derived from the bovine corpus luteum possess NCAM-140. Exp Cell Res 201:545-548PubMedCrossRefGoogle Scholar
  56. 56.
    Foets BJ, van den Oord JJ, Volpes R, Missotten L (1992) In situ immunohistochemical analysis of cell adhesion molecules on human corneal endothelial cells. Br J Ophthalmol 76:205-209PubMedCrossRefGoogle Scholar
  57. 57.
    Mizutani H, Roswit W, Hemperly J et al (1994) Human dermal microvascular endothelial cells express the 140-kD isoform of neural cell adhesion molecule. Biochem Biophys Res Commun 203:686-693PubMedCrossRefGoogle Scholar
  58. 58.
    Gingras MC, Roussel E, Bruner JM, Branch CD, Moser RP (1995) Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain tissue. J Neuroimmunol 57:143-153PubMedCrossRefGoogle Scholar
  59. 59.
    Bekker MN, Arkesteijn JB, van den Akker NM et al (2005) Increased NCAM expression and vascular development in trisomy 16 mouse embryos: relationship with nuchal translucency. Pediatr Res 58:1222-1227PubMedCrossRefGoogle Scholar
  60. 60.
    Bussolati B, Deambrosis I, Russo S, Deregibus MC, Camussi G (2003) Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J 17:1159-1161PubMedGoogle Scholar
  61. 61.
    Geninatti Crich S, Bussolati B, Tei L et al (2006) Magnetic resonance visualization of tumor angiogenesis by targeting neural cell adhesion molecules with the highly sensitive gadolinium-loaded apoferritin probe. Cancer Res 66:9196-9201PubMedCrossRefGoogle Scholar
  62. 62.
    Bussolati B, Grange C, Bruno S et al (2006) Neural-cell adhesion molecule (NCAM) expression by immature and tumor-derived endothelial cells favors cell organization into capillary-like structures. Exp Cell Res 312:913-924PubMedCrossRefGoogle Scholar
  63. 63.
    Williams EJ, Furness J, Walsh FS, Doherty P (1994) Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron 13:583-594PubMedCrossRefGoogle Scholar
  64. 64.
    Francavilla C, Loeffler S, Piccini D, Kren A, Christofori G, Cavallaro U (2007) Neural cell adhesion molecule regulates the cellular response to fibroblast growth factor. J Cell Sci 120:4388-4394PubMedCrossRefGoogle Scholar
  65. 65.
    Kiselyov VV, Skladchikova G, Hinsby AM et al (2003) Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure (Camb) 11:691-701CrossRefGoogle Scholar
  66. 66.
    Grose R, Dickson C (2005) Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 16:179-186PubMedCrossRefGoogle Scholar
  67. 67.
    Jensen M, Berthold F (2007) Targeting the neural cell adhesion molecule in cancer. Cancer Lett 258:9-21PubMedCrossRefGoogle Scholar
  68. 68.
    Gluer S, Schelp C, Gerardy-Schahn R, von Schweinitz D (1998) Polysialylated neural cell adhesion molecule as a marker for differential diagnosis in pediatric tumors. J Pediatr Surg 33:1516-1520PubMedCrossRefGoogle Scholar
  69. 69.
    Zeromski J, Biczysko M, Stajgis P, Lawniczak M, Biczysko W (1999) CD56(NCAM) antigen in glandular epithelium of human thyroid: light microscopic and ultrastructural study. Folia Histochem Cytobiol 37:11-17PubMedGoogle Scholar
  70. 70.
    Zeromski J, Dworacki G, Jenek J et al (1999) Protein and mRNA expression of CD56/N-CAM on follicular epithelial cells of the human thyroid. Int J Immunopathol Pharmacol 12:23-30PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.IFOM - The FIRC Institute of Molecular Oncology, IFOM-IEO CampusMilanoItaly

Personalised recommendations