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Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment

Oncogene volume 24, pages 8240–8251 (2005)Cite this article

Abstract

We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT–PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA–ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.

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Abbreviations

ECM:

extracellular matrix

HIF-1α:

hypoxia-inducible factor 1α

PAR-1:

proteinase-activated receptors type I

PKG:

protein kinase G

ROK:

Rho-associated coiled-coil-containing protein kinase

TN-C:

tenascin-C

SPARC:

secreted protein acidic rich in cysteine

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Acknowledgements

This work was aided by INSERM, IPSEN (PhD grant to Q-DN), and the FORTIS Verzekeringen (Brussels, Belgium). We thank Dr Rudolph for the characterization of malignant effusions-derived cancer cells, Miss C Boissard and Mr M Clark for valuable technical assistance, and Dr K Kaibuchi, Dr L Zardi, Dr G Flatau, Dr WJ Nelson, Dr J-P Stasch, Dr B Westley, and Yoshitomi Pharmaceutical Industries Ltd (Osaka, Japan) for sharing materials.

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Author notes

  1. Quang-Dé Nguyen and Olivier De Wever: These two authors contributed equally to this work

Authors and Affiliations

  1. INSERM U673, Molecular and Clinical Oncology of Human Solid Tumors, Hôpital Saint-Antoine, 184 Rue du faubourg Saint-Antoine, Paris, Cedex 12, 75571, France

    Quang-Dé Nguyen, Olivier De Wever & Christian Gespach

  2. The Laboratory of Experimental Cancerology, Ghent University Hospital, B-9000 Ghent, Belgium

    Erik Bruyneel, An Hendrix, Marc Mareel & Marc Bracke

  3. Department of Internal Medicine, University of Kiel, Schittenhelmstr. 12, Kiel, 24105, Germany

    Wan-Zhuo Xie, Martin Leibl & Frank Gieseler

  4. First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China

    Wan-Zhuo Xie

  5. CNRS UMR8078, Hôpital Marie Lannelongue, Le Plessis-Robinson, 92350, France

    Alain Lombet

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  1. Quang-Dé Nguyen
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Correspondence to Christian Gespach.

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Nguyen, QD., De Wever, O., Bruyneel, E. et al. Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment. Oncogene 24, 8240–8251 (2005). https://doi.org/10.1038/sj.onc.1208990

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