Abstract
Coexistence of pulmonary tuberculosis (TB) and lung cancer in clinic poses significant challenges for the diagnostic and treatment of both diseases. Although association of chronic inflammation and cancer is well-documented, causal relationship between TB infection and lung cancer are not understood. We present experimental evidence that chronic TB infection induces cell dysplasia and squamous cell carcinoma (SCC) in a lung-specific manner. First, squamous cell aggregates consistently appeared within the lung tissue associated with chronic TB lesions, and in some cases resembled SCCs. A transplantable tumor was established after the transfer of cells isolated from TB lung lesions into syngeneic recipients. Second, the (Mycobacterium tuberculosis) MTB-infected macrophages play a pivotal role in TB-induced carcinogenesis by inducing DNA damage in their vicinity and by the production of a potent epidermal growth factor epiregulin, which may serve as a paracrine survival and growth factor responsible for squamous metaplasia and tumorigenesis. Third, lung carcinogenesis during the course of chronic TB infection was more pronounced in animals with severe lung tissue damage mediated by TB-susceptibility locus sst1. Together, our experimental findings showed a causal link between pulmonary TB and lung tumorigenesis and established a genetic model for further analysis of carcinogenic mechanisms activated by TB infection.
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References
Ardies CM . (2003). Inflammation as cause for scar cancers of the lung. Integr Cancer Ther 2: 238–246.
Azad N, Rojanasakul Y, Vallyathan V . (2008). Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Health B Crit Rev 11: 1–15.
Baba I, Shirasawa S, Iwamoto R, Okumura K, Tsunoda T, Nishioka M et al. (2000). Involvement of deregulated epiregulin expression in tumorigenesis in vivo through activated Ki-Ras signaling pathway in human colon cancer cells. Cancer Res 60: 6886–6889.
Bewersdorf J, Bennett BT, Knight KL . (2006). H2AX chromatin structures and their response to DNA damage revealed by 4Pi microscopy. Proc Natl Acad Sci USA 103: 18137–18142.
Cagle PT, Cohle SD, Greenberg SD . (1985). Natural history of pulmonary scar cancers. Clinical and pathologic implications. Cancer 56: 2031–2035.
Coussens LM, Werb Z . (2002). Inflammation and cancer. Nature 420: 860–867.
Dacosta NA, Kinare SG . (1991). Association of lung carcinoma and tuberculosis. J Postgrad Med 37: 185–189.
Dalgleish AG, O'Byrne KJ . (2002). Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. Adv Cancer Res 84: 231–276.
Fujiwara N, Kobayashi K . (2005). Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 4: 281–286.
Gopalakrishnan P, Miller JE, McLaughlin JS . (1975). Pulmonary tuberculosis and coexisting carcinoma: a 10-year experience and review of the literature. Am Surg 41: 405–408.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Harris RC, Chung E, Coffey RJ . (2003). EGF receptor ligands. Exp Cell Res 284: 2–13.
Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR et al. (1997). Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106: 348–360.
Inagaki N, Goto H, Ogawara M, Nishi Y, Ando S, Inagaki M . (1997). Spatial patterns of Ca2+ signals define intracellular distribution of a signaling by Ca2+/Calmodulin-dependent protein kinase II. J Biol Chem 272: 25195–25199.
Jin DY . (2007). Molecular pathogenesis of hepatitis C virus-associated hepatocellular carcinoma. Front Biosci 12: 222–233.
Karin M, Lawrence T, Nizet V . (2006). Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124: 823–835.
Klein G, Klein E . (2005). Surveillance against tumors–is it mainly immunological? Immunol Lett 100: 29–33.
Komarova EA, Krivokrysenko V, Wang K, Neznanov N, Chernov MV, Komarov PG et al. (2005). p53 is a suppressor of inflammatory response in mice. FASEB J 19: 1030–1032.
Kramnik I, Dietrich WF, Demant P, Bloom BR . (2000). Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc Natl Acad Sci USA 97: 8560–8565.
Kurasawa T . (1998). The coexistence of pulmonary tuberculosis and lung cancer. Nippon Rinsho 56: 3167–3170.
Lawrence T . (2007). Inflammation and cancer: a failure of resolution? Trends Pharmacol Sci 28: 162–165.
Lawrence T, Gilroy DW . (2007). Chronic inflammation: a failure of resolution? Int J Exp Pathol 88: 85–94.
Lee D, Pearsall RS, Das S, Dey SK, Godfrey VL, Threadgill DW . (2004). Epiregulin is not essential for development of intestinal tumors but is required for protection from intestinal damage. Mol Cell Biol 24: 8907–8916.
Melnikova VO, Ananthaswamy HN . (2005). Cellular and molecular events leading to the development of skin cancer. Mutat Res 571: 91–106.
Mohan VP, Scanga CA, Yu K, Scott HM, Tanaka KE, Tsang E et al. (2001). Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infect Immun 69: 1847–1855.
Moutsopoulos NM, Wen J, Wahl SM . (2008). TGF-beta and tumors–an ill-fated alliance. Curr Opin Immunol 20: 234–240.
Naito Y, Yoshikawa T . (2002). Molecular and cellular mechanisms involved in Helicobacter pylori-induced inflammation and oxidative stress. Free Radic Biol Med 33: 323–336.
Nelson CM, Bissell MJ . (2006). Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 22: 287–309.
Nussenzweig A, Paull T . (2006). DNA repair: tails of histones lost. Nature 439: 406–407.
Oka K, Chan L . (2005). Inhibition and regression of atherosclerotic lesions. Acta Biochim Pol 52: 311–319.
Pastore S, Mascia F, Girolomoni G . (2006). The contribution of keratinocytes to the pathogenesis of atopic dermatitis. Eur J Dermatol 16: 125–131.
Preuss U, Landsberg G, Scheidtmann KH . (2003). Novel mitosis-specific phosphorylation of histone H3 at Thr11 mediated by Dlk/ZIP kinase. Nucleic Acids Res 31: 878–885.
Russell DG . (2007). Who puts the tubercle in tuberculosis? Nat Rev Microbiol 5: 39–47.
Sakuraba M, Hirama M, Hebisawa A, Sagara Y, Tamura A, Komatsu H . (2006). Coexistent lung carcinoma and active pulmonary tuberculosis in the same lobe. Ann Thorac Cardiovasc Surg 12: 53–55.
Sakurai R, Sasaki R, Yamaguchi M, Shibata A, Aoki K . (1989). Prognosis of female patients with pulmonary tuberculosis. Jpn J Med 28: 471–477.
Saunders BM, Britton WJ . (2007). Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol 85: 103–111.
Shelly M, Pinkas-Kramarski R, Guarino BC, Waterman H, Wang LM, Lyass L et al. (1998). Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes. J Biol Chem 273: 10496–10505.
Shirakata Y, Komurasaki T, Toyoda H, Hanakawa Y, Yamasaki K, Tokumaru S et al. (2000). Epiregulin, a novel member of the epidermal growth factor family, is an autocrine growth factor in normal human keratinocytes. J Biol Chem 275: 5748–5753.
Shirasawa S, Sugiyama S, Baba I, Inokuchi J, Sekine S, Ogino K et al. (2004). Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage. Proc Natl Acad Sci USA 101: 13921–13926.
Takahashi M, Hayashi K, Yoshida K, Ohkawa Y, Komurasaki T, Kitabatake A et al. (2003). Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells. Circulation 108: 2524–2529.
Tan TT, Coussens LM . (2007). Humoral immunity, inflammation and cancer. Curr Opin Immunol 19: 209–216.
Ting YM, Church WR, Ravikrishnan KP . (1976). Lung carcinoma superimposed on pulmonary tuberculosis. Radiology 119: 307–312.
Toyoda H, Komurasaki T, Uchida D, Morimoto S . (1997). Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family. Biochem J 326 (Part 1): 69–75.
Ulrichs T, Kaufmann SH . (2006). New insights into the function of granulomas in human tuberculosis. J Pathol 208: 261–269.
Ulrichs T, Kosmiadi GA, Trusov V, Jorg S, Pradl L, Titukhina M et al. (2004). Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol 204: 217–228.
van Kempen LC, de Visser KE, Coussens LM . (2006). Inflammation, proteases and cancer. Eur J Cancer 42: 728–734.
Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S et al. (2003). Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35: 238–245.
Wang Y, Zhang Z, Yan Y, Lemon WJ, LaRegina M, Morrison C et al. (2004). A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility. Cancer Res 64: 1647–1654.
Acknowledgements
We thank Drs Raju Kucherlapati, Steve Elledge, David Christiani and Barry Bloom for helpful discussions. The authors are grateful to Dr Mari Kuraguchi for technical advice.
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Nalbandian, A., Yan, BS., Pichugin, A. et al. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene 28, 1928–1938 (2009). https://doi.org/10.1038/onc.2009.32
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DOI: https://doi.org/10.1038/onc.2009.32
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