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Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour–host interactions

  • Ron N. Apte
    Correspondence
    Corresponding author: Tel.: +972 8 647 7270; fax: +972 8 647 7626.
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Yakov Krelin
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Xiaoping Song
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Shahar Dotan
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Eli Recih
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Moshe Elkabets
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Yaron Carmi
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Tatyana Dvorkin
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Roslayn M. White
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Lubov Gayvoronsky
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Shraga Segal
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • Elena Voronov
    Affiliations
    Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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      Abstract

      Interleukin-1 (IL-1) comprises a family of closely related genes; the two major agonistic proteins, IL-1α and IL-1β, are pleiotropic and affect mainly inflammation, immunity and haemopoiesis. IL-1β is active solely in its secreted form, whereas IL-1α is active mainly as an intracellular precursor. IL-1 is abundant at tumour sites, where it may affect the process of carcinogenesis, tumour growth and invasiveness and the patterns of tumour–host interactions. Here, we review the effects of micro-environment- and tumour cell-derived IL-1 on malignant processes in experimental tumour models. We propose that membrane-associated IL-1α expressed on malignant cells stimulates anti-tumour immunity, while secretable IL-1β derived from the micro-environment or the malignant cells, activates inflammation that promotes invasiveness and induces tumour-mediated suppression. Inhibition of the function of IL-1 by the inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra), reduces tumour invasiveness and alleviates tumour-mediated suppression, pointing to its feasible use in cancer therapy. Differential manipulation of IL-1α and IL-1β in malignant cells or in the tumour’s micro-environment may open new possibilities for using IL-1 in cancer immunotherapy.

      Keywords

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      References

        • Nathan C.
        Points of control in inflammation.
        Nature. 2002; 420: 846-852
        • Clevers H.
        At the crossroads of inflammation and cancer.
        Cell. 2004; 118: 671-674
        • Balkwill F.
        • Mantovani A.
        Inflammation and cancer: back to Virchow?.
        Lancet. 2001; 357: 539-545
        • Coussens L.M.
        • Werb Z.
        Inflammatory cells and cancer: think different!.
        J Exp Med. 2001; 193: F23-F26
        • Coussens L.M.
        • Werb Z.
        Inflammation and cancer.
        Nature. 2002; 420: 860-867
        • Cordon-Cardo C.
        • Prives C.
        At the crossroads of inflammation and tumorigenesis.
        J Exp Med. 1999; 190: 1367-1370
        • Vakkila J.
        • Lotze M.T.
        Inflammation and necrosis promote tumour growth.
        Nat Rev Immunol. 2004; 4: 641-648
        • Balkwill F.
        • Charles K.A.
        • Mantovani A.
        Smoldering and polarized inflammation in the initiation and promotion of malignant disease.
        Cancer Cell. 2005; 7: 211-217
        • Pollard J.W.
        Tumour-educated macrophages promote tumour progression and metastasis.
        Nat Rev Cancer. 2004; 4: 71-78
        • Philip M.
        • Rowley D.A.
        • Schreiber H.
        Inflammation as a tumor promoter in cancer induction.
        Semin Cancer Biol. 2004; 14: 433-439
        • Arend W.P.
        The balance between IL-1 and IL-1Ra in disease.
        Cytokine Growth Factor Rev. 2002; 13: 323-340
        • Apte R.N.
        • Voronov E.
        Interleukin-1-a major pleiotropic cytokine in tumor–host interactions.
        Semin Cancer Biol. 2002; 12: 277-290
        • Dinarello C.A.
        Biologic basis for interleukin-1 in disease.
        Blood. 1996; 87: 2095-2147
        • Dinarello C.A.
        The IL-1 family and inflammatory diseases.
        Clin Exp Rheumatol. 2002; 20: S1-S13
        • Braddock M.
        • Quinn A.
        Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention.
        Nat Rev Drug Discov. 2004; 3: 330-339
        • Mantovani A.
        • Muzio M.
        • Ghezzi P.
        • Colotta C.
        • Introna M.
        Regulation of inhibitory pathways of the interleukin-1 system.
        Ann NY Acad Sci. 1998; 840: 338-351
        • Stylianou E.
        • Saklatvala J.
        Interleukin-1.
        Int J Biochem Cell Biol. 1998; 30: 1075-1079
        • Sims J.E.
        IL-1 and IL-18 receptors, and their extended family.
        Curr Opin Immunol. 2002; 14: 117-122
        • O’Neill L.A.
        Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily.
        Curr Top Microbiol Immunol. 2002; 270: 47-61
        • Mantovani A.
        • Locati M.
        • Polentarutti N.
        • Vecchi A.
        • Garlanda C.
        Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR.
        J Leukoc Biol. 2004; 75: 738-742
        • Douvdevani A.
        • Huleihel M.
        • Zoller M.
        • Segal S.
        • Apte R.N.
        Reduced tumorigenicity of fibrosarcomas which constitutively generate IL-1 alpha either spontaneously or following IL-1 alpha gene transfer.
        Int J Cancer. 1992; 51: 822-830
        • Zoller M.
        • Douvdevani A.
        • Segal S.
        • Apte R.N.
        Interleukin-1 production by transformed fibroblasts. II. Influence on antigen presentation and T-cell-mediated anti-tumor response.
        Int J Cancer. 1992; 50: 450-457
        • Zoller M.
        • Douvdevani A.
        • Segal S.
        • Apte R.N.
        Interleukin-1 produced by tumorigenic fibroblasts influences tumor rejection.
        Int J Cancer. 1992; 50: 443-449
        • Apte R.N.
        • Douvdevani A.
        • Zoller M.
        • et al.
        Cytokine-induced tumor immunogenicity: endogenous interleukin-1 alpha expressed by fibrosarcoma cells confers reduced tumorigenicity.
        Immunol Lett. 1993; 39: 45-52
        • Apte R.N.
        • Dvorkin T.
        • Song X.
        • et al.
        Opposing effects of IL-1 alpha and IL-1 beta on malignancy patterns. Tumor cell-associated IL-1 alpha potentiates anti-tumor immune responses and tumor regression, whereas IL-1 beta potentiates invasiveness.
        Adv Exp Med Biol. 2000; 479: 277-288
        • Voronov E.
        • Weinstein Y.
        • Benharroch D.
        • et al.
        Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression.
        Cancer Res. 1999; 59: 1029-1035
        • Song X.
        • Voronov E.
        • Dvorkin T.
        • et al.
        Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness.
        J Immunol. 2003; 171: 6448-6456
        • Werman A.
        • Werman-Venkert R.
        • White R.
        • et al.
        The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription.
        Proc Natl Acad Sci USA. 2004; 101: 2434-2439
        • Hacham M.
        • Argov S.
        • White R.M.
        • Segal S.
        • Apte R.N.
        Different patterns of interleukin-1alpha and interleukin-1beta expression in organs of normal young and old mice.
        Eur Cytokine Netw. 2002; 13: 55-65
        • Hacham M.
        • Argov S.
        • White R.M.
        • Segal S.
        • Apte R.N.
        Distinct patterns of IL-1 alpha and IL-1 beta organ distribution–a possible basis for organ mechanisms of innate immunity.
        Adv Exp Med Biol. 2000; 479: 185-202
        • Horai R.
        • Asano M.
        • Sudo K.
        • et al.
        Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion.
        J Exp Med. 1998; 187: 1463-1475
        • Horai R.
        • Saijo S.
        • Tanioka H.
        • et al.
        Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice.
        J Exp Med. 2000; 191: 313-320
        • Iwakura Y.
        Roles of IL-1 in the development of rheumatoid arthritis: consideration from mouse models.
        Cytokine Growth Factor Rev. 2002; 13: 341-355
        • Nicklin M.J.
        • Hughes D.E.
        • Barton J.L.
        • Ure J.M.
        • Duff G.W.
        Arterial inflammation in mice lacking the interleukin1 receptor antagonist gene.
        J Exp Med. 2000; 191: 303-312
        • Nakae S.
        • Asano M.
        • Horai R.
        • Iwakura Y.
        Interleukin-1 beta, but not interleukin-1 alpha, is required for T-cell-dependent antibody production.
        Immunology. 2001; 104: 402-409
        • Nakae S.
        • Asano M.
        • Horai R.
        • Sakaguchi N.
        • Iwakura Y.
        IL-1 enhances T cell-dependent antibody production through induction of CD40 ligand and OX40 on T cells.
        J Immunol. 2001; 167: 90-97
        • Nakae S.
        • Naruse-Nakajima C.
        • Sudo K.
        • Horai R.
        • Asano M.
        • Iwakura Y.
        IL-1 alpha, but not IL-1 beta, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity.
        Int Immunol. 2001; 13: 1471-1478
        • Qin Z.
        • Kim H.J.
        • Hemme J.
        • Blankenstein T.
        Inhibition of methylcholanthrene-induced carcinogenesis by an interferon gamma receptor-dependent foreign body reaction.
        J Exp Med. 2002; 195: 1479-1490
        • Blankenstein T.
        • Qin Z.
        Chemical carcinogens as foreign bodies and some pitfalls regarding cancer immune surveillance.
        Adv Cancer Res. 2003; 90: 179-207
        • Blankenstein T.
        • Qin Z.
        The role of IFN-gamma in tumor transplantation immunity and inhibition of chemical carcinogenesis.
        Curr Opin Immunol. 2003; 15: 148-154
        • Scott K.A.
        • Arnott C.H.
        • Robinson S.C.
        • et al.
        TNF-alpha regulates epithelial expression of MMP-9 and integrin alphavbeta6 during tumour promotion. A role for TNF-alpha in keratinocyte migration?.
        Oncogene. 2004; 23: 6954-6966
        • Scott K.A.
        • Moore R.J.
        • Arnott C.H.
        • et al.
        An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors.
        Mol Cancer Ther. 2003; 2: 445-451
        • Arnott C.H.
        • Scott K.A.
        • Moore R.J.
        • et al.
        Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway.
        Oncogene. 2002; 21: 4728-4738
        • Suganuma M.
        • Okabe S.
        • Marino M.W.
        • Sakai A.
        • Sueoka E.
        • Fujiki H.
        Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice.
        Cancer Res. 1999; 59: 4516-4518
        • Balkwill F.
        Tumor necrosis factor or tumor promoting factor?.
        Cytokine Growth Factor Rev. 2002; 13: 135-141
        • Szlosarek P.W.
        • Balkwill F.R.
        Tumour necrosis factor alpha: a potential target for the therapy of solid tumours.
        Lancet Oncol. 2003; 4: 565-573
        • Knight B.
        • Yeoh G.C.
        • Husk K.L.
        • et al.
        Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice.
        J Exp Med. 2000; 192: 1809-1818
        • Li X.
        • Eckard J.
        • Shah R.
        • Malluck C.
        • Frenkel K.
        Interleukin-1alpha up-regulation in vivo by a potent carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and control of DMBA-induced inflammatory responses.
        Cancer Res. 2002; 62: 417-423
        • Murphy J.E.
        • Morales R.E.
        • Scott J.
        • Kupper T.S.
        IL-1 alpha, innate immunity, and skin carcinogenesis: the effect of constitutive expression of IL-1 alpha in epidermis on chemical carcinogenesis.
        J Immunol. 2003; 170: 5697-5703
        • Pikarsky E.
        • Porat R.M.
        • Stein I.
        • et al.
        NF-kappaB functions as a tumour promoter in inflammation-associated cancer.
        Nature. 2004; 431: 461-466
        • Greten F.R.
        • Eckmann L.
        • Greten T.F.
        • et al.
        IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
        Cell. 2004; 118: 285-296
        • Lin A.
        • Karin M.
        NF-kappaB in cancer: a marked target.
        Semin Cancer Biol. 2003; 13: 107-114
        • Amit S.
        • Ben-Neriah Y.
        NF-kappaB activation in cancer: a challenge for ubiquitination- and proteasome-based therapeutic approach.
        Semin Cancer Biol. 2003; 13: 15-28
        • Dunn G.P.
        • Bruce A.T.
        • Ikeda H.
        • Old L.J.
        • Schreiber R.D.
        Cancer immunoediting: from immunosurveillance to tumor escape.
        Nat Immunol. 2002; 3: 991-998
        • Ikeda H.
        • Old L.J.
        • Schreiber R.D.
        The roles of IFN gamma in protection against tumor development and cancer immunoediting.
        Cytokine Growth Factor Rev. 2002; 13: 95-109
        • Dunn G.P.
        • Old L.J.
        • Schreiber R.D.
        The immunobiology of cancer immunosurveillance and immunoediting.
        Immunity. 2004; 21: 137-148
        • Dunn G.P.
        • Old L.J.
        • Schreiber R.D.
        The three Es of cancer immunoediting.
        Annu Rev Immunol. 2004; 22: 329-360
        • Douvdevani A.
        • Huleihel M.
        • Segal S.
        • Apte R.N.
        Aberrations in interleukin-1 expression in oncogene-transformed fibrosarcoma lines: constitutive interleukin-1 alpha transcription and manifestation of biological activity.
        Eur Cytokine Netw. 1991; 2: 257-264
        • Gabrilovich D.
        Mechanisms and functional significance of tumour-induced dendritic-cell defects.
        Nat Rev Immunol. 2004; 4: 941-952
        • Kusmartsev S.
        • Gabrilovich D.I.
        Immature myeloid cells and cancer-associated immune suppression.
        Cancer Immunol Immunother. 2002; 51: 293-298
        • Serafini P.
        • De Santo C.
        • Marigo I.
        • et al.
        Derangement of immune responses by myeloid suppressor cells.
        Cancer Immunol Immunother. 2004; 53: 64-72
        • Voronov E.
        • Shouval D.S.
        • Krelin Y.
        • et al.
        IL-1 is required for tumor invasiveness and angiogenesis.
        Proc Natl Acad Sci USA. 2003;
        • Bar D.
        • Apte R.N.
        • Voronov E.
        • Dinarello C.A.
        • Cohen S.
        A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development.
        FASEB J. 2004; 18: 161-163