Journal of Mammary Gland Biology and Neoplasia

, Volume 12, Issue 2–3, pp 127–133 | Cite as

Differential Cadherin Expression: Potential Markers for Epithelial to Mesenchymal Transformation During Tumor Progression

  • Georgia Agiostratidou
  • James Hulit
  • Greg R. Phillips
  • Rachel B. Hazan
Article

Abstract

The cadherin family of adhesion molecules regulates cell–cell interactions during development and in tissues. The prototypical cadherin, E-cadherin, is responsible for maintaining interactions of epithelial cells and is frequently downregulated during tumor progression. N-cadherin, normally found in fibroblasts and neural cells, can be upregulated during tumor progression and can increase the invasiveness of tumor cells. The proinvasive effects of N-cadherin expression in tumor cells result from two possible mechanisms: promotion of tumor cell interactions with the N-cadherin-expressing microenvironment, or enhancement of signaling via the fibroblast growth factor receptor. The downregulation of E-cadherin and the upregulation of N-cadherin in tumors may be a result of an epithelial to mesenchymal transformation (EMT) of tumor cells, which is notoriously difficult to detect in vivo. Double labeling of individual tumors with specific E- and N-cadherin antibodies suggests that EMT can occur heterogeneously and/or transiently within an invasive tumor.

Keywords

Adhesion Metastasis Breast cancer Signaling Invasion 

Abbreviations

EMT

epithelial to mesenchymal transition

MMP

matrix metalloprotease

EGF

epidermal growth factor

IGF

insulin growth factor

FGF

fibroblast growth factor

HGF

hepatocyte growth factor

TGFβ

transforming growth factor beta

References

  1. 1.
    Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Hay ED. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 2005;233:706–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E, et al. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 2004;64:8585–94.PubMedCrossRefGoogle Scholar
  4. 4.
    Hirano S, Suzuki ST, Redies C. The cadherin superfamily in neural development: diversity, function and interaction with other molecules. Front Biosci 2003;8:d306–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548–58.PubMedCrossRefGoogle Scholar
  6. 6.
    Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005;436:123–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Halbleib JM, Nelson WJ. Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev 2006;20:3199–214.PubMedCrossRefGoogle Scholar
  8. 8.
    Blaschuk OW, Sullivan R, David S, Pouliot Y. Identification of a cadherin cell adhesion recognition sequence. Dev Biol 1990;139:227–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Patel SD, Ciatto C, Chen CP, Bahna F, Rajebhosale M, Arkus N, et al. Type II cadherin ectodomain structures: implications for classical cadherin specificity. Cell 2006;124:1255–68.PubMedCrossRefGoogle Scholar
  10. 10.
    Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, et al. Structural basis of cell–cell adhesion by cadherins. Nature 1995;374:327–37.PubMedCrossRefGoogle Scholar
  11. 11.
    Shan WS, Tanaka H, Phillips GR, Arndt K, Yoshida M, Colman DR, et al. Functional cis-heterodimers of N- and R-cadherins. J Cell Biol 2000;148:579–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Shimoyama Y, Tsujimoto G, Kitajima M, Natori M. Identification of three human type-II classic cadherins and frequent heterophilic interactions between different subclasses of type-II classic cadherins. Biochem J 2000;349:159–67.PubMedCrossRefGoogle Scholar
  13. 13.
    Shan W, Yagita Y, Wang Z, Koch A, Svenningsen AF, Gruzglin E, et al. The minimal essential unit for cadherin-mediated intercellular adhesion comprises extracellular domains 1 and 2. J Biol Chem 2004;279:55914–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim JB, Islam S, Kim YJ, Prudoff RS, Sass KM, Wheelock MJ, et al. N-Cadherin extracellular repeat 4 mediates epithelial to mesenchymal transition and increased motility. J Cell Biol 2000;151:1193–206.PubMedCrossRefGoogle Scholar
  15. 15.
    Suyama K, Shapiro I, Guttman M, Hazan RB. A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2002;2:301–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Anastasiadis PZ, Reynolds AB. Regulation of Rho GTPases by p120-catenin. Curr Opin Cell Biol 2001;13:604–10.PubMedCrossRefGoogle Scholar
  17. 17.
    Noren NK, Liu BP, Burridge K, Kreft B. p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol 2000;150:567–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Davis MA, Ireton RC, Reynolds AB. A core function for p120-catenin in cadherin turnover. J Cell Biol 2003;163:525–34.PubMedCrossRefGoogle Scholar
  19. 19.
    Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev 2006;16:51–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H. Assembly of the cadherin-catenin complex in vitro with recombinant proteins. J Cell Sci 1994;107(Pt 12):3655–63.PubMedGoogle Scholar
  21. 21.
    Kobielak A, Fuchs E. Alpha-catenin: at the junction of intercellular adhesion and actin dynamics. Nat Rev Mol Cell Biol 2004;5:614–25.PubMedCrossRefGoogle Scholar
  22. 22.
    Weis WI, Nelson WJ. Re-solving the cadherin-catenin-actin conundrum. J Biol Chem 2006;281:35593–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Parks AL, Curtis D. Presenilin diversifies its portfolio. Trends Genet 2007;23:140–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, et al. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003;114:635–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 1998;153:333–9.PubMedGoogle Scholar
  26. 26.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis. Cancer Sci 2003;94:575–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol 2004;48:365–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002;3:155–66.PubMedCrossRefGoogle Scholar
  30. 30.
    Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 2005;24:2375–85.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004;6:931–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol 2005;168:29–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Castanon I, Baylies MK. A Twist in fate: evolutionary comparison of Twist structure and function. Gene 2002;287:11–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004;117:927–39.PubMedCrossRefGoogle Scholar
  35. 35.
    Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem 2001;276:27424–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 1997;139:1861–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Liwosz A, Lei T, Kukuruzinska MA. N-glycosylation affects the molecular organization and stability of E-cadherin junctions. J Biol Chem 2006;281:23138–49.PubMedCrossRefGoogle Scholar
  38. 38.
    Hazan RB, Kang L, Whooley BP, Borgen PI. N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes Commun 1997;4:399–411.PubMedGoogle Scholar
  39. 39.
    Nieman MT, Prudoff RS, Johnson KR, Wheelock MJ. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 1999;147:631–44.PubMedCrossRefGoogle Scholar
  40. 40.
    Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 2000;148:779–90.PubMedCrossRefGoogle Scholar
  41. 41.
    Rosivatz E, Becker I, Bamba M, Schott C, Diebold J, Mayr D, et al. Neoexpression of N-cadherin in E-cadherin positive colon cancers. Int J Cancer 2004;111:711–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Shintani Y, Hollingsworth MA, Wheelock MJ, Johnson KR. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res 2006;66:11745–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Tanaka H, Shan W, Phillips GR, Arndt K, Bozdagi O, Shapiro L, et al. Molecular modification of N-cadherin in response to synaptic activity. Neuron 2000;25:93–107.PubMedCrossRefGoogle Scholar
  44. 44.
    Nagi C, Guttman M, Jaffer S, Qiao R, Keren R, Triana A, et al. N-cadherin expression in breast cancer: correlation with an aggressive histologic variant-invasive micropapillary carcinoma. Breast Cancer Res Treat 2005;94:225–35.PubMedCrossRefGoogle Scholar
  45. 45.
    Voura EB, Sandig M, Siu CH. Cell–cell interactions during transendothelial migration of tumor cells. Microsc Res Tech 1998;43:265–75.PubMedCrossRefGoogle Scholar
  46. 46.
    Debruyne P, Vermeulen S, Mareel M. The role of the E-cadherin/catenin complex in gastrointestinal cancer. Acta Gastroenterol Belg 1999;62:393–402.PubMedGoogle Scholar
  47. 47.
    Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol 2003;14:1705–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshinaga K, Inoue H, Utsunomiya T, Sonoda H, Masuda T, Mimori K, et al. N-cadherin is regulated by activin A and associated with tumor aggressiveness in esophageal carcinoma. Clin Cancer Res 2004;10:5702–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res 2004;10:4125–33.PubMedCrossRefGoogle Scholar
  50. 50.
    Tran NL, Nagle RB, Cress AE, Heimark RL. N-Cadherin expression in human prostate carcinoma cell lines. An epithelial-mesenchymal transformation mediating adhesion with stromal cells. Am J Pathol 1999;155:787–98.PubMedGoogle Scholar
  51. 51.
    Sandig M, Voura EB, Kalnins VI, Siu CH. Role of cadherins in the transendothelial migration of melanoma cells in culture. Cell Motil Cytoskelet 1997;38:351–64.CrossRefGoogle Scholar
  52. 52.
    Williams EJ, Furness J, Walsh FS, Doherty P. Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron 1994;13:583–94.PubMedCrossRefGoogle Scholar
  53. 53.
    Hulit J, Suyama K, Chung S, Keren R, Agiostratido G, Qiao S, et al. N-cadherin signaling potentiates mammary tumor metastasis via enhanced ERK activation. Cancer Res 2007;67:3106–16.PubMedCrossRefGoogle Scholar
  54. 54.
    Knudsen KA, Sauer C, Johnson KR, Wheelock MJ. Effect of N-cadherin misexpression by the mammary epithelium in mice. J Cell Biochem 2005;95:1093–107.PubMedCrossRefGoogle Scholar
  55. 55.
    Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 1992;12:954–61.PubMedGoogle Scholar
  56. 56.
    Maglione JE, Moghanaki D, Young LJ, Manner CK, Ellies LG, Joseph SO, et al. Transgenic polyoma middle-T mice model premalignant mammary disease. Cancer Res 2001;61:8298–305.PubMedGoogle Scholar
  57. 57.
    Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 2003;163:2113–26.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Georgia Agiostratidou
    • 1
  • James Hulit
    • 1
  • Greg R. Phillips
    • 2
  • Rachel B. Hazan
    • 1
    • 3
  1. 1.Department of PathologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Fishberg Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA
  3. 3.Albert Einstein College of MedicineBronxUSA

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