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FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor

Oncogene volume 23, pages 5435–5446 (2004)Cite this article

Abstract

Fibroblast activation protein-α (FAP) is a cell surface serine protease expressed at sites of tissue remodeling in embryonic development. FAP is not expressed by mature somatic tissues except activated melanocytes and fibroblasts in wound healing or tumor stroma. FAP expression is specifically silenced in proliferating melanocytic cells during malignant transformation. To study the role of FAP as a tumor suppressor, the gene for mouse fap was cloned and mutated at the catalytic domain (FAP serine mutant, FSM). We found that expression of FAP or FSM at physiologic levels in mouse melanoma cells abrogated tumorigenicity. Remarkably, the mutant form FSM lacking specific serine protease activity was a more potent tumor suppressor. Tumor rejection was not due to adaptive immune responses because RAG1−/− mice challenged with melanoma cells expressing either FAP or FSM were not tumorigenic. In in vitro assays, FAP or FSM expression restored contact inhibition, led to cell cycle arrest at G0/G1 phase, and increased susceptibility to stress-induced apoptosis. Cell death in FAP+ or FSM+ melanoma cells was readily triggered by depletion of survival factors from the media, leading to subsequent activation of caspases via the intrinsic pathway. These results show that expression of FAP is a tumor suppressor that abrogates tumorigenicity through regulation of cell growth and survival.

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Acknowledgements

TR-M was a recipient of a CRI grant and EVS was supported by Wellcome Trust Grant 064583/KS/JH. This work was supported by the Quentin J Kennedy Foundation, Swim Across America and the Peter J Sharp/Breast Cancer Research Foundation. We would like to acknowledge Rodica Stan, PhD and Kathy Panageas, PhD for their help in the elaboration of this manuscript.

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Authors and Affiliations

  1. Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center and Weill Graduate School of Medical Sciences of Cornell University, 1275 York Avenue, New York, 10021, NY, USA

    Teresa Ramirez-Montagut & Alan N Houghton

  2. Laboratory of Molecular Neurooncology, The Rockefeller University and Howard Hughes Medical Institute, New York, 10021, NY, USA

    Nathalie E Blachere

  3. Basic Medical Sciences, St George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK

    Elena V Sviderskaya & Dorothy C Bennett

  4. Division of Research and Development, Boehringer Ingelheim Austria GmbH, Vienna, Austria

    Wolfgang J Rettig

  5. Department of Clinical Pathology, University of Vienna General Hospital, Vienna, Austria

    Pilar Garin-Chesa

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  1. Teresa Ramirez-Montagut
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  2. Nathalie E Blachere
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  7. Alan N Houghton
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Correspondence to Alan N Houghton.

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Ramirez-Montagut, T., Blachere, N., Sviderskaya, E. et al. FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor. Oncogene 23, 5435–5446 (2004). https://doi.org/10.1038/sj.onc.1207730

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