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A causal role for E-cadherin in the transition from adenoma to carcinoma

Nature volume 392, pages 190–193 (1998)Cite this article

Abstract

Development of malignant tumours is in part characterized by the ability of a tumour cell to overcome cell–cell adhesion and to invade surrounding tissue. E-cadherin is the main adhesion molecule of epithelia1,2,3 and it has been implicated in carcinogenesis because it is frequently lost in human epithelial cancers4,5,6. Re-establishing the functional cadherin complex in tumour cell lines results in a reversion from an invasive to a benign epithelial phenotype7. However, it remained unresolved whether the loss of E-cadherin-mediated cell adhesion was a cause or a consequence of tumour progression in vivo. Here we report that the loss of E-cadherin expression coincides with the transition from well differentiated adenoma to invasive carcinoma in a transgenic mouse model of pancreatic β-cell carcinogenesis (Rip1Tag2)8. Intercrossing Rip1Tag2 mice with transgenic mice that maintain E-cadherin expression in β-tumour cells results in arrest of tumour development at the adenoma stage, whereas expression of a dominant-negative form of E-cadherin induces early invasion and metastasis. The results demonstrate that loss of E-cadherin-mediated cell adhesion is one rate-limiting step in the progression from adenoma to carcinoma.

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Figure 1: Histopathological and immunohistochemical analyses of tumorigenesis.
Figure 2: Expression of epithelial markers during the transition from β-cell adenoma to carcinoma in Rip1Tag2 transgenic mice.
Figure 3: Forced expression of E-cadherin blocks the transition from adenoma to carcinoma.
Figure 4: Forced expression of dominant-negative E-cadherin induces tumour-cell invasion and metastasis.

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Acknowledgements

We thank D. Hanahan and R. Kelly for support and discussions. We are grateful to W. Jochum for expertise in histopathology and M. Herzig and S. Luef for technical assistance. We thank M. Cotten, E. F. Wagner, H. Beug, K. Nasmyth and G. M. Lamm for critical comments on the manuscript. Animal care was in accordance with institutional guidelines. Supported in part by the Austrian Industrial Research Promotion Fund (A.-K.P., P. W., G.C.) and by the Swedish Cancer Society, Lion's Cancer Research Foundation, Umeå University and M. Gergvalls Stiftelse (U.D., H.S.)

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Authors and Affiliations

  1. Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030, Vienna, Austria

    Anne-Karina Perl, Petra Wilgenbus & Gerhard Christofori

  2. Department of Microbiology, Ume University, S-90187, Ume, Sweden

    Ulf Dahl & Henrik Semb

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  1. Anne-Karina Perl
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  2. Petra Wilgenbus
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  3. Ulf Dahl
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  5. Gerhard Christofori
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Correspondence to Gerhard Christofori.

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Perl, AK., Wilgenbus, P., Dahl, U. et al. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998). https://doi.org/10.1038/32433

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