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Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

Oncogene volume 27, pages 4024–4033 (2008)Cite this article

Abstract

From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.

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Acknowledgements

In the memory of Hélène Fontayne-Devaud (TR INSERM) who passed away on 15 April 2007. We thank Dominique Demeyer, Marie-José Dejonghe and Georges Grard for technical assistance, Sabine Quief and Céline Villenet for performing microarrays (Genomic Platform), Marie-Hélène Gevaert and Rosemary Siminsky (Department of Histology, Faculty of Medicine, University of Lille II) and the technicians of the Laboratory of Immunohistochemistry (Center of Biology-Pathology, CHRU-Lille). This work was supported by Cancéropôle Nord-Ouest, La Ligue Contre le Cancer, La Région Nord-Pas de Calais, INSERM and ARC No. 3765.

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Author notes

  1. C Gespach and J-L Desseyn: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche Jean-Pierre Aubert, U837, Faculté de Médecine, Lille, France

    V Gouyer, D Fontaine, H Fontayne-Devaud, E Leteurtre, S Truant, J-P Kerckaert, J-L Desseyn & G Huet

  2. Northwest canceropole, Lille, France

    V Gouyer, D Fontaine, P Dumont, H Fontayne-Devaud, E Leteurtre, S Truant, H Drobecq, J-P Kerckaert, Y de Launoit, J-L Desseyn & G Huet

  3. CHRU, Lille, France

    V Gouyer, E Leteurtre, S Truant & G Huet

  4. UMR 8161, Institut de Biologie de Lille, Lille, France

    P Dumont, H Drobecq & Y de Launoit

  5. Laboratory of Experimental Cancerology, Gent University Hospital, Gent, Belgium

    O de Wever & M Bracke

  6. Department of Cell Biology and Cell Pathology, Philipps-Universität Marburg, Marburg, Germany

    D Delacour

  7. INSERM, U673, Paris, France

    C Gespach

  8. Laboratory of Molecular and Clinical Oncology of Solid Tumors, Faculté de Médecine, Hôpital Saint-Antoine, Université Pierre et Marie Curie-Paris 6, Paris Cedex, France

    C Gespach

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  1. V Gouyer
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Gouyer, V., Fontaine, D., Dumont, P. et al. Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells. Oncogene 27, 4024–4033 (2008). https://doi.org/10.1038/onc.2008.42

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