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Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

Oncogene volume 24, pages 1689–1697 (2005)Cite this article

Abstract

Overexpression of membrane-type-1 matrix metalloproteinase (MT1-MMP) in tumor cells has previously been shown to enhance tumor growth and metastasis. To establish if MT1-MMP is also able to confer tumorigenicity on nonmalignant epithelial cells, we transfected human MT1-MMP cDNA into Madin-Darby canine kidney (MDCK) cells expressing a tetracycline-repressible transactivator. Induction of MT1-MMP in the absence of doxycycline (Dox) was associated with activation of exogenous MMP-2 as well as with formation of large cysts and increased invasiveness in collagen matrices. Transfected cells were inoculated subcutaneously into two groups of nude mice, one of which received Dox to inhibit expression of MT1-MMP. Formation of tumor xenografts was observed in 11 of 17 mice maintained without Dox, but only in two of nine mice that received Dox (P<0.05). The xenografts were composed of tubular structures interspersed within a highly cellular stroma. The epithelial cells delimiting the lumen were polarized, as indicated by the basolateral distribution of Na,K-ATPase. Despite their differentiated appearance, the tumors lacked a well-defined boundary, and epithelial tubules invaded adjacent muscular layers. These results demonstrate that conditional expression of MT1-MMP in nonmalignant MDCK epithelial cells is by itself sufficient to drive formation of invasive tumors.

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Acknowledgements

We gratefully acknowledge the initial contribution of Dr J Soriano in setting up the MDCK Tet-Off expression system. We also thank Mrs P Couleru, J Rial-Robert and D Ben-Nasr for excellent technical assistance, Drs G Hosseini and A Wohlwend for helpful advice, N Dupont for secretarial work, Dr M Seiki for providing the human MT1-MMP probe and Dr L Orci for critical reading of the manuscript. This study was supported by Grants No. 31-61446.00 and 3100A0-101734 from the Swiss National Science Foundation (to RM) and NIH Grants CA83017 and CA77470 (to AYS).

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Authors and Affiliations

  1. Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Rue Michel-Servet 1, CH-1211, Geneva, 4, Switzerland

    Priscilla Soulié, Fabio Carrozzino, Michael S Pepper & Roberto Montesano

  2. Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Alex Y Strongin

  3. Institut Curie, Section de Recherche, Rue d'Ulm, 75248, Paris, France

    Marie-France Poupon

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  1. Priscilla Soulié
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Correspondence to Roberto Montesano.

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Soulié, P., Carrozzino, F., Pepper, M. et al. Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells. Oncogene 24, 1689–1697 (2005). https://doi.org/10.1038/sj.onc.1208360

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