B-cells and IL-4 promote methylcholanthrene-induced carcinogenesis but there is no evidence for a role of T/NKT-cells and their effector molecules (Fas-ligand, TNF-α, perforin)
Thomas Kammertoens
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
T.K. and Z.Q. contributed equally to this work
Search for more papers by this authorZhihai Qin
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
T.K. and Z.Q. contributed equally to this work
Search for more papers by this authorDana Briesemeister
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
Search for more papers by this authorAlbert Bendelac
Department of Pathology, University of Chicago, Chicago, IL
Search for more papers by this authorCorresponding Author
Thomas Blankenstein
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany
Tel.: +49-30-94062310, Fax: +49-30-94062453
Max-Delbrück Centrum für Molekulare Medizin, Robert-Rössle Strasse 10, 13122 Berlin, GermanySearch for more papers by this authorThomas Kammertoens
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
T.K. and Z.Q. contributed equally to this work
Search for more papers by this authorZhihai Qin
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
T.K. and Z.Q. contributed equally to this work
Search for more papers by this authorDana Briesemeister
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
Search for more papers by this authorAlbert Bendelac
Department of Pathology, University of Chicago, Chicago, IL
Search for more papers by this authorCorresponding Author
Thomas Blankenstein
Institut für Immunologie, Charité, Campus Benjamin-Franklin, Berlin, Germany
Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany
Tel.: +49-30-94062310, Fax: +49-30-94062453
Max-Delbrück Centrum für Molekulare Medizin, Robert-Rössle Strasse 10, 13122 Berlin, GermanySearch for more papers by this authorAbstract
Mice deficient either in subtypes of immune cells, cytokines or lytic pathways have been subjected to chemical carcinogenesis by methylcholanthrene to evaluate whether these components of the immune system affect tumor development. Inbred mice of the same genotype but from different sources differed in tumor development in magnitude comparable to that previously attributed to differences in immunocompetence. This suggested that genetic drift between separate inbred colonies of mice and/or environmental factors (e.g., transport of the animals) influenced carcinogenesis. Therefore, littermates were used as control in subsequent experiments. Although deficiency of T-cells, NKT-cells, perforin, Fas-ligand, TNF-α-receptor failed to reveal significant differences in tumor development, the presence of B-cells and IL-4 enhanced tumor development under similar experimental conditions.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
Filename | Description |
---|---|
IJC_27411_sm_SuppFigs.pdf83.7 KB | Supporting Information Figure 1. BALB/c nude and non-littermates as indicated were injected with MCA and tumor development was observed. Amount and injection route of MCA, number of mice per experimental group (in parenthesis) and sex of the mice are indicated. A), B) 800 μg, C), D) 400 μg MCA. E) C57 BL/6 nude (nu/nu), heterozygous (nu/wt) and homozygous (wt/wt) control littermates. Figure 2. B-cell deficiency increases latency after MCA-carcinogenesis. B-cell-deficient μMT mice (??) and control littermates (WT) as indicated were injected with 800μg MCA and tumor development was observed. Amount and injection route of MCA, number of mice per experimental group (in parenthesis) and sex of the mice are indicated. Figure 3. IL-6 or IL-10 deficiency does not affect MCA-carcinogenesis at high doses of MCA. IL-6 (A-B) or IL-10 (C-D)-deficient mice and control littermates (WT) as indicated were injected with MCA and tumor development was observed. Amount and injection route of MCA, number of mice per experimental group (in parenthesis) and sex of the mice are indicated. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther 1992; 54: 63–128.
- 2 Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140: 883–99.
- 3 Salerno RA, Whitmire CE, Garcia IM, Huebner RJ. Chemical carcinogenesis in mice inhibited by interferon. Nat New Biol 1972; 239: 31–2.
- 4 Rous P, Friedewald WF. The carcinogenic effect of methylcholanthrene and of tar on rabbit papillomas due to a virus. Science 1941; 94: 495–6.
- 5 Woodruff M, Speedy G. Inhibition of chemical carcinogenesis by Corynebacterium parvum. Proc R Soc Lond B Biol Sci 1978; 201: 209–15.
- 6 Takagi A, Matsuzaki T, Sato M, Nomoto K, Morotomi M, Yokokura T. Enhancement of natural killer cytotoxicity delayed murine carcinogenesis by a probiotic microorganism. Carcinogenesis 2001; 22: 599–605.
- 7 Creau-Goldberg N, Salomon JC. Immunotherapy of primary methylcholanthrene-induced mouse tumours by intratumoral BCG. Br J Cancer 1980; 41: 541–52.
- 8 Roe FJ, Grant GA. Inhibition by germ-free status of development of liver and lung tumours in mice exposed neonatally to 7,12-dimethylbenz(a)anthracene: implications in relation to tests for carcinogenicity. Int J Cancer 1970; 6: 133–44.
- 9 Marchant J. The effect of methylcholanthrene and different social conditions on the appearance of breast tumours in NZY mice. Br J Cancer 1966; 20: 210–5.
- 10 Molomut N, Lazere F, Smith LW. Effect of audiogenic stress upon methylcholanthrene-induced carcinogenesis in mice. Cancer Res 1963; 23: 1097–101.
- 11 Baker DG. Influence of a chronic environmental stress on the incidence of methylcholanthrene-induced tumors. Cancer Res 1977; 37: 3939–44.
- 12 Konno A, Hishinuma K, Hashimoto Y, Kimura S, Nishimura T. Dietary restriction reduces the incidence of 3-methylcholanthrene-induced tumors in mice: close correlation with its potentiating effect on host T cell functions. Cancer Immunol Immunother 1991; 33: 293–8.
- 13 Rashkis HA. Systemic stress as an inhibitor of experimental tumors in Swiss mice. Science 1952; 116: 169–71.
- 14 Welsch CW. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 1985; 45: 3415–43.
- 15 Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107–11.
- 16 Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 2001; 13: 459–63.
- 17 Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 2000; 191: 661–8.
- 18 van den Broek ME, Kagi D, Ossendorp F, Toes R, Vamvakas S, Lutz WK, Melief CJ, Zinkernagel RM, Hengartner H. Decreased tumor surveillance in perforin-deficient mice. J Exp Med 1996; 184: 1781–90.
- 19 Qin Z, Blankenstein T. A cancer immunosurveillance controversy. Nat Immunol 2004; 5: 3–4; author reply -5.
- 20 Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD, Smyth MJ. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA 2008; 105: 652–6.
- 21 Schreiber TH, Podack ER. A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas. Br J Cancer 2009; 101: 381–6.
- 22 Stutman O. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science 1974; 183: 534–6.
- 23 Stutman O. Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous matings and heterozygous matings and effect of age and carcinogen dose. J Natl Cancer Inst 1979; 62: 353–8.
- 24 Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y. NKG2D function protects the host from tumor initiation. J Exp Med 2005; 202: 583–8.
- 25 Smyth MJ. Clarification of data used in three studies on MCA-induction of sarcoma in mice. Blood 2008; 111: 4419.
- 26 Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH, Fox JG. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol 2003; 162: 691–702.
- 27 Enzler T, Gillessen S, Manis JP, Ferguson D, Fleming J, Alt FW, Mihm M, Dranoff G. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med 2003; 197: 1213–9.
- 28 Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331: 1565–70.
- 29 Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970; 13: 1–27.
- 30 Prehn RT, Main JM. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957; 18: 769–78.
- 31 Klein G, Sjogren HO, Klein E, Hellstrom KE. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 1960; 20: 1561–72.
- 32 Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450: 903–7.
- 33 Grant GA, Roe FJ. Effect of germ-free status and antilymphocyte serum on induction of various tumours in mice by a chemical carcinogen given at birth. Nature 1969; 223: 1060.
- 34 Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008; 28: 571–80.
- 35 Prehn RT, Bartlett GL. Surveillance, latency and the two levels of MCA-induced tumor immunogenicity. Int J Cancer 1987; 39: 106–10.
- 36 Qin Z, Kim HJ, Hemme J, Blankenstein T. Inhibition of methylcholanthrene-induced carcinogenesis by an interferon gamma receptor-dependent foreign body reaction. J Exp Med 2002; 195: 1479–90.
- 37 de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 2005; 7: 411–23.
- 38
Hasan M,
Polic B,
Bralic M,
Jonjic S,
Rajewsky K.
Incomplete block of B cell development and immunoglobulin production in mice carrying the muMT mutation on the BALB/c background.
Eur J Immunol
2002;
32:
3463–71.
10.1002/1521-4141(200212)32:12<3463::AID-IMMU3463>3.0.CO;2-B CAS PubMed Web of Science® Google Scholar
- 39 Klein G, Klein E. Immune surveillance against virus-induced tumors and nonrejectability of spontaneous tumors: contrasting consequences of host versus tumor evolution. Proc Natl Acad Sci USA 1977; 74: 2121–5.
- 40 Bailey DW. How pure are inbred strains of mice? Immunol Today 1982; 3: 210–14.
- 41 Prehn RT. Immunostimulation of chemical oncogenesis in the mouse. Int J Cancer 1977; 20: 918–22.
- 42 DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 2009; 16: 91–102.
- 43 Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 1989; 169: 59–72.
- 44 Rondini EA, Walters DM, Bauer AK. Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner. Part Fibre Toxicol 2010; 7: 9.
- 45 Blankenstein T, Qin Z. Chemical carcinogens as foreign bodies and some pitfalls regarding cancer immune surveillance. Adv Cancer Res 2003; 90: 179–207.
- 46 Krelin Y, Voronov E, Dotan S, Elkabets M, Reich E, Fogel M, Huszar M, Iwakura Y, Segal S, Dinarello CA, Apte RN. Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res 2007; 67: 1062–71.
- 47 Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M, Kollias G, Balkwill F. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5: 828–31.
- 48 Roberts SJ, Ng BY, Filler RB, Lewis J, Glusac EJ, Hayday AC, Tigelaar RE, Girardi M. Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis. Proc Natl Acad Sci USA 2007; 104: 6770–5.
- 49 Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437: 141–6.
- 50 DuPage M, Cheung AF, Mazumdar C, Winslow MM, Bronson R, Schmidt LM, Crowley D, Chen J, Jacks T. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 2011; 19: 72–85.