Clinical & Experimental Metastasis

, Volume 36, Issue 2, pp 87–95 | Cite as

Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166

  • Ariana von Lersner
  • Lenny Droesen
  • Andries ZijlstraEmail author
Molecules in Metastasis


In epithelial-derived cancers, altered regulation of cell–cell adhesion facilitates the disruption of tissue cohesion that is central to the progression to malignant disease. Although numerous intercellular adhesion molecules participate in epithelial adhesion, the immunoglobulin superfamily (IgSF) member activated leukocyte cell adhesion molecule (ALCAM), has emerged from multiple independent studies as a central contributor to tumor progression. ALCAM is an archetypal member of the IgSF with conventional organization of five Ig-like domains involved in homo- and heterotypic adhesions. Like many IgSF members, ALCAM is broadly expressed and involved in cellular adhesion across many cellular processes. While the redundancy of intercellular adhesion molecules (CAMs) could diminish the impact of any single CAM, consistent correlation between ALCAM expression and patient outcome for multiple cancers underscores its role in tumor progression. Unlike most oncogenes and tumor suppressors, ALCAM is neither mutated nor amplified or deleted. Experimental disruption of ALCAM-mediated adhesions implies that this IgSF member contributes to tumor progression through dynamic turnover of the protein at the cell surface. Since ALCAM is not frequently altered at the gene level, it appears to promote malignant behavior through regulation of its availability rather than its specific activity. These observations help explain its heterogeneous expression within malignant disease and the drastic changes in protein levels across tumor progression. To reveal how ALCAM contributes to tumor progression, we review regulation of its gene expression, alternative splicing, targeted proteolysis, binding partners, and surface shedding within the context of cancer. Studying ALCAM regulation has led to a novel understanding of the fine-tuning of cell adhesive state through the utilization of otherwise normal regulatory processes, which thereby enable tumor cell invasion and metastasis.


ALCAM/CD166 regulation ALCAM/CD166 alternative splicing Cell adhesion Dynamic cell adhesion CAM regulation 



This study was supported by National Cancer Institute (Grant Nos. 5T32CA009592-30, R01 CA218526).


  1. 1.
    Ivanov DB, Philippova MP, Tkachuk VA (2001) Structure and functions of classical cadherins. Biochem Mosc 66:1174–1186CrossRefGoogle Scholar
  2. 2.
    Yates B, Braschi B, Gray KA et al (2017) the HGNC and VGNC resources in 2017. Nucleic Acids Res 45:D619–D625. CrossRefGoogle Scholar
  3. 3.
    Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6:622–634. CrossRefGoogle Scholar
  4. 4.
    Harris TJC, Tepass U (2010) Adherens junctions: from molecules to morphogenesis. Nat Rev Mol Cell Biol 11:502–514. CrossRefGoogle Scholar
  5. 5.
    Barczyk M, Carracedo S, Gullberg D (2010) Integrins. Cell Tissue Res 339:269–280. CrossRefGoogle Scholar
  6. 6.
    Bökel C, Brown NH (2002) Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell 3:311–321CrossRefGoogle Scholar
  7. 7.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687CrossRefGoogle Scholar
  8. 8.
    McEver RP (2015) Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res 107:331–339. CrossRefGoogle Scholar
  9. 9.
    Vestweber D (2015) How leukocytes cross the vascular endothelium. Nat Rev Immunol 15:692–704. CrossRefGoogle Scholar
  10. 10.
    Ley K, Kansas GS (2004) Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat Rev Immunol 4:325–335CrossRefGoogle Scholar
  11. 11.
    Wai Wong C, Dye DE, Coombe DR (2012) The role of immunoglobulin superfamily cell adhesion molecules in cancer metastasis. Int J Cell Biol 2012:340296. CrossRefGoogle Scholar
  12. 12.
    Williams AF, Barclay AN (1988) The immunoglobulin superfamily—domains for cell surface recognition. Annu Rev Immunol 6:381–405. CrossRefGoogle Scholar
  13. 13.
    Minner S, Kraetzig F, Tachezy M et al (2011) Low activated leukocyte cell adhesion molecule expression is associated with advanced tumor stage and early prostate-specific antigen relapse in prostate cancer. Hum Pathol 42:1946–1952. CrossRefGoogle Scholar
  14. 14.
    Burandt E, Bari Noubar T, Lebeau A et al (2014) Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: a TMA-based immunohistochemical study on 2,197 breast cancer patients. Oncol Rep 32:2628–2634. CrossRefGoogle Scholar
  15. 15.
    Lugli A, Iezzi G, Hostettler I et al (2010) Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer. Br J Cancer 103:382–390. CrossRefGoogle Scholar
  16. 16.
    Arnold Egloff SA, Du L, Loomans HA et al (2017) Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer. Oncotarget 8:722–741. Google Scholar
  17. 17.
    Ihnen M, Kress K, Kersten JF et al (2012) Relevance of activated leukocyte cell adhesion molecule (ALCAM) in tumor tissue and sera of cervical cancer patients. BMC Cancer 12:140. CrossRefGoogle Scholar
  18. 18.
    Fujiwara K, Ohuchida K, Sada M et al (2014) CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells. PLoS ONE 9:e107247. CrossRefGoogle Scholar
  19. 19.
    Donizy P, Zietek M, Halon A et al (2015) Prognostic significance of ALCAM (CD166/MEMD) expression in cutaneous melanoma patients. Diagn Pathol 10:86. CrossRefGoogle Scholar
  20. 20.
    Clauditz TS, Rheinbaben von K, Lebok P et al (2014) Activated leukocyte cell adhesion molecule (ALCAM/CD166) expression in head and neck squamous cell carcinoma (HNSSC). Pathol Res Pract 210:649–655. CrossRefGoogle Scholar
  21. 21.
    Ofori-Acquah SF, King JA (2008) Activated leukocyte cell adhesion molecule: a new paradox in cancer. Transl Res 151:122–128. CrossRefGoogle Scholar
  22. 22.
    van Kempen LC, Nelissen JM, Degen WG et al (2001) Molecular basis for the homophilic activated leukocyte cell adhesion molecule (ALCAM)–ALCAM interaction. J Biol Chem 276:25783–25790. CrossRefGoogle Scholar
  23. 23.
    Jeannet R, Cai Q, Liu H et al (2013) Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal. Stem Cells 31:560–571. CrossRefGoogle Scholar
  24. 24.
    Manhas J, Bhattacharya A, Agrawal SK et al (2016) Characterization of cancer stem cells from different grades of human colorectal cancer. Tumour Biol 37:14069–14081. CrossRefGoogle Scholar
  25. 25.
    Wang F, Scoville D, He XC et al (2013) Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 145:383–395.e1-21. CrossRefGoogle Scholar
  26. 26.
    Smith NR, Davies PS, Levin TG et al (2017) Cell adhesion molecule CD166/ALCAM functions within the crypt to orchestrate murine intestinal stem cell homeostasis. Cell Mol Gastroenterol Hepatol 3:389–409. CrossRefGoogle Scholar
  27. 27.
    Cayrol R, Wosik K, Berard JL et al (2008) Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol 9:137–145. CrossRefGoogle Scholar
  28. 28.
    Smith JR, Chipps TJ, Ilias H et al (2012) Expression and regulation of activated leukocyte cell adhesion molecule in human retinal vascular endothelial cells. Exp Eye Res 104:89–93. CrossRefGoogle Scholar
  29. 29.
    Karagogeos D, Pourquie C, Kyriakopoulou K, et al (1997) Expression of the cell adhesion proteins BEN/SC1/DM-GRASP and TAG-1 defines early steps of axonogenesis in the human spinal cord. J Comp Neurol 379:415–427.;2-6 CrossRefGoogle Scholar
  30. 30.
    Bowen MA, Patel DD, Li X et al (1995) Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand. J Exp Med 181:2213–2220CrossRefGoogle Scholar
  31. 31.
    King JA, Tan F, Mbeunkui F et al (2010) Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer. Mol Cancer 9:266. CrossRefGoogle Scholar
  32. 32.
    Tan F, Mbunkui F, Ofori-Acquah SF (2012) Cloning of the human activated leukocyte cell adhesion molecule promoter and identification of its tissue-independent transcriptional activation by Sp1. Cell Mol Biol Lett 17:571–585. CrossRefGoogle Scholar
  33. 33.
    Kavurma MM, Bobryshev Y, Khachigian LM (2002) Ets-1 positively regulates Fas ligand transcription via cooperative interactions with Sp1. J Biol Chem 277:36244–36252CrossRefGoogle Scholar
  34. 34.
    Shirasaki F, Makhluf HA, LeRoy C et al (1999) Ets transcription factors cooperate with Sp1 to activate the human tenascin-C promoter. Oncogene 18:7755–7764. CrossRefGoogle Scholar
  35. 35.
    Zhao Y, Zhang W, Guo Z et al (2013) Inhibition of the transcription factor Sp1 suppresses colon cancer stem cell growth and induces apoptosis in vitro and in nude mouse xenografts. Oncol Rep 30:1782–1792. CrossRefGoogle Scholar
  36. 36.
    Wang J, Gu Z, Ni P et al (2011) NF-kappaB P50/P65 hetero-dimer mediates differential regulation of CD166/ALCAM expression via interaction with micoRNA-9 after serum deprivation, providing evidence for a novel negative auto-regulatory loop. Nucleic Acids Res 39:6440–6455. CrossRefGoogle Scholar
  37. 37.
    Nelissen JM, Peters IM, de Grooth BG et al (2000) Dynamic regulation of activated leukocyte cell adhesion molecule-mediated homotypic cell adhesion through the actin cytoskeleton. Mol Biol Cell 11:2057–2068CrossRefGoogle Scholar
  38. 38.
    Gilsanz A, Sanchez-Martin L, Gutierrez-Lopez MD et al (2013) ALCAM/CD166 adhesive function is regulated by the tetraspanin CD9. Cell Mol Life Sci 70:475–493. CrossRefGoogle Scholar
  39. 39.
    Weidle UH, Eggle D, Klostermann S, Swart GWM (2010) ALCAM/CD166: cancer-related issues. Cancer Genomics Proteomics 7:231–243Google Scholar
  40. 40.
    Ochwat D, Hoja-Lukowicz D, Litynska A (2004) N-glycoproteins bearing beta1–6 branched oligosaccharides from the A375 human melanoma cell line analysed by tandem mass spectrometry. Melanoma Res 14:479–485CrossRefGoogle Scholar
  41. 41.
    Yu M-J, Pisitkun T, Wang G et al (2006) LC–MS/MS analysis of apical and basolateral plasma membranes of rat renal collecting duct cells. Mol Cell Proteomics 5:2131–2145. CrossRefGoogle Scholar
  42. 42.
    Kovalenko OV, Metcalf DG, DeGrado WF, Hemler ME (2005) Structural organization and interactions of transmembrane domains in tetraspanin proteins. BMC Struct Biol 5:11. CrossRefGoogle Scholar
  43. 43.
    Hemler ME (2003) Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 19:397–422. CrossRefGoogle Scholar
  44. 44.
    Tudor C, Riet te J, Eich C et al (2014) Syntenin-1 and ezrin proteins link activated leukocyte cell adhesion molecule to the actin cytoskeleton. J Biol Chem 289:13445–13460. CrossRefGoogle Scholar
  45. 45.
    Xiao M, Yan M, Zhang J et al (2017) Cancer stem-like cell related protein CD166 degrades through E3 ubiquitin ligase CHIP in head and neck cancer. Exp Cell Res 353:46–53. CrossRefGoogle Scholar
  46. 46.
    Hebron KE, Li EY, Arnold Egloff SA et al (2018) Alternative splicing of ALCAM enables tunable regulation of cell–cell adhesion through differential proteolysis. Sci Rep 8:3208. CrossRefGoogle Scholar
  47. 47.
    Rosso O, Piazza T, Bongarzone I et al (2007) The ALCAM shedding by the metalloprotease ADAM17/TACE is involved in motility of ovarian carcinoma cells. Mol Cancer Res 5:1246–1253. CrossRefGoogle Scholar
  48. 48.
    Hansen AG, Arnold SA, Jiang M et al (2014) ALCAM/CD166 is a TGF-beta-responsive marker and functional regulator of prostate cancer metastasis to bone. Cancer Res 74:1404–1415. CrossRefGoogle Scholar
  49. 49.
    Hinkle CL, Sunnarborg SW, Loiselle D et al (2004) Selective roles for tumor necrosis factor alpha-converting enzyme/ADAM17 in the shedding of the epidermal growth factor receptor ligand family: the juxtamembrane stalk determines cleavage efficiency. J Biol Chem 279:24179–24188CrossRefGoogle Scholar
  50. 50.
    Carbotti G, Orengo AM, Mezzanzanica D et al (2013) Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors. Int J Cancer 132:2597–2605. CrossRefGoogle Scholar
  51. 51.
    Hansen AG, Freeman TJ, Arnold SA et al (2013) Elevated ALCAM shedding in colorectal cancer correlates with poor patient outcome. Cancer Res 73:2955–2964. CrossRefGoogle Scholar
  52. 52.
    Tachezy M, Zander H, Marx AH et al (2012) ALCAM (CD166) expression and serum levels in pancreatic cancer. PLoS ONE 7:e39018. CrossRefGoogle Scholar
  53. 53.
    Wierzbicki A, Gil M, Ciesielski M et al (2008) Immunization with a mimotope of GD2 ganglioside induces CD8+ T cells that recognize cell adhesion molecules on tumor cells. J Immunol 181:6644–6653CrossRefGoogle Scholar
  54. 54.
    Soto MS, Serres S, Anthony DC, Sibson NR (2013) Functional role of endothelial adhesion molecules in the early stages of brain metastasis. Neurooncology 16:540–551. Google Scholar
  55. 55.
    Bughani U, Saha A, Kuriakose A et al (2017) T cell activation and differentiation is modulated by a CD6 domain 1 antibody itolizumab. PLoS ONE 12:e0180088. CrossRefGoogle Scholar
  56. 56.
    Hassan NJ, Barclay AN, Brown MH (2004) Frontline: optimal T cell activation requires the engagement of CD6 and CD166. Eur J Immunol 34:930–940. CrossRefGoogle Scholar
  57. 57.
    Zimmerman AW, Joosten B, Torensma R et al (2006) Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells. Blood 107:3212–3220. CrossRefGoogle Scholar
  58. 58.
    Oliveira MI, Goncalves CM, Pinto M et al (2012) CD6 attenuates early and late signaling events, setting thresholds for T-cell activation. Eur J Immunol 42:195–205. CrossRefGoogle Scholar
  59. 59.
    Orta-Mascaro M, Consuegra-Fernandez M, Carreras E et al (2016) CD6 modulates thymocyte selection and peripheral T cell homeostasis. J Exp Med 213:1387–1397. CrossRefGoogle Scholar
  60. 60.
    Patel DD, Wee SF, Whichard LP et al (1995) Identification and characterization of a 100-kD ligand for CD6 on human thymic epithelial cells. J Exp Med 181:1563–1568CrossRefGoogle Scholar
  61. 61.
    Li Y, Singer NG, Whitbred J et al (2017) CD6 as a potential target for treating multiple sclerosis. Proc Natl Acad Sci USA 114:2687–2692. CrossRefGoogle Scholar
  62. 62.
    Rodriguez PC, Torres-Moya R, Reyes G et al (2012) A clinical exploratory study with itolizumab, an anti-CD6 monoclonal antibody, in patients with rheumatoid arthritis. Results Immunol 2:204–211CrossRefGoogle Scholar
  63. 63.
    Consuegra-Fernandez M, Julia M, Martinez-Florensa M et al (2018) Genetic and experimental evidence for the involvement of the CD6 lymphocyte receptor in psoriasis. Cell Mol Immunol 15:898–906. CrossRefGoogle Scholar
  64. 64.
    Tormo BR, García CA, Chong A, Ochoa C, Faxas ME, Sagaró B et al (1994) Immunohistopathology of cutaneous T-cell lymphomas treated with topic ior t1 (anti CD6) monoclonal antibody Biotecnol Apl 11:20–23Google Scholar
  65. 65.
    Izquierdo-Cano L, Espinosa-Estrada E, Hernández-Padrón C et al (2014) Anticuerpo monoclonal humanizado itolizumab (anti-cd6) en síndromes linfoproliferativos cd6+. Experiencia preliminar. [Humanized monoclonal antibody itolizumab (anti-cd6) in patients with lymphoproliferative disorders cd6+. Preliminary experience]. Rev Cuba Hematol Inmunol Hemoter 30(3) (Spanish)Google Scholar
  66. 66.
    Samaha H, Pignata A, Fousek K et al (2018) A homing system targets therapeutic T cells to brain cancer. Nature 561:331–337CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Program in Cancer BiologyVanderbilt UniversityNashvilleUSA
  2. 2.Vanderbilt University Medical CenterNashvilleUSA
  3. 3.Institute of Applied Biosciences and ChemistryHogeschool Arnhem en Nijmegen University of Applied SciencesNijmegenNetherlands
  4. 4.Department of Pathology, Microbiology and ImmunologyVanderbilt University Medical CenterNashvilleUSA
  5. 5.Vanderbilt Ingram Cancer CenterNashvilleUSA

Personalised recommendations