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      Inhibition of Methylcholanthrene-induced Carcinogenesis by an Interferon γ Receptor–dependent Foreign Body Reaction

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          Abstract

          The foreign body reaction is one of the oldest host defense mechanisms against tissue damage which involves inflammation, scarring, and encapsulation. The chemical carcinogen methylcholanthrene (MCA) induces fibrosarcoma and tissue damage in parallel at the injection site. Tumor development induced by MCA but not due to p53-deficiency is increased in interferon-γ receptor (IFN-γR)–deficient mice. In the absence of IFN-γR, MCA diffusion and DNA damage of surrounding cells is increased. Locally produced IFN-γ induces the formation of a fibrotic capsule. Encapsulated MCA can persist virtually life-long in mice without inducing tumors. Together, the foreign body reaction against MCA prevents malignant transformation, probably by reducing DNA damage. This mechanism is more efficient in the presence of IFN-γR. Our results indicates that inflammation and scarring, both suspected to contribute to malignancy, prevent cancer in certain situations.

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          IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.

          V Shankaran, H. Ikeda, A. T. Bruce … (2001)
          Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice. However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response. Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals.
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            MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.

            Lisa Coussens, Christopher Tinkle, Douglas Hanahan … (2000)
            The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.
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              Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.

              D H Kaplan, V Shankaran, A. Dighe … (1998)
              This study demonstrates that endogenously produced interferon gamma (IFN-gamma) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. Compared with wild-type mice, mice lacking sensitivity to either IFN-gamma (i.e., IFN-gamma receptor-deficient mice) or all IFN family members (i.e., Stat1-deficient mice) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen methylcholanthrene. In addition, IFN-gamma-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene. IFN-gamma-insensitive p53(-/-) mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. Using tumor cells derived from methylcholanthrene-treated IFN-gamma-insensitive mice, we found IFN-gamma's actions to be mediated at least partly through its direct effects on the tumor cell leading to enhanced tumor cell immunogenicity. The importance and generality of this system is evidenced by the finding that certain types of human tumors become selectively unresponsive to IFN-gamma. Thus, IFN-gamma forms the basis of an extrinsic tumor-suppressor mechanism in immunocompetent hosts.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Exp Med
                Title: The Journal of Experimental Medicine
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date (Print): 3 June 2002
                Volume: 195
                Issue: 11
                Pages: 1479-1490
                Affiliations
                [1 ]Institute of Immunology, Free University, Berlin, 12200 Berlin, Germany
                [2 ]Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany
                Author notes

                Address correspondence to Zhihai Qin, Institute of Immunology, Free University, Berlin 12200, Germany. Phone: 49-30-8445-4607; Fax: 49-30-8445-4613; E-mail: zhihai@ 123456ukbf.fu-berlin.de

                Article
                Publisher ID: 011887
                DOI: 10.1084/jem.20011887
                PMC ID: 2193538
                PubMed ID: 12045246
                SO-VID: d1d4d882-3cdd-4553-8b62-8ca994468402
                Copyright © Copyright © 2002, The Rockefeller University Press
                History
                Date received : 13 November 2001
                Date revision received : 11 April 2002
                Date accepted : 29 April 2002
                Categories
                Subject: Article

                ScienceOpen disciplines: Medicine
                Keywords: tissue damage,immune surveillance,tissue repair,encapsulation,inflammation
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: tissue damage, immune surveillance, tissue repair, encapsulation, inflammation

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