Abstract
Antimicrobial peptides, such as the cathelicidin LL-37/hCAP-18 and its mouse homolog cathelicidin-related antimicrobial peptide (CRAMP), are important effectors of the innate immune system with direct anti-bacterial activity. Cathelicidin is possibly involved in the regulation of tumor cell growth. The aim of this study was to characterize the role of cathelicidin expressed in non-tumorous cells in a preclinical mouse model of tumor growth. Wild-type and CRAMP-deficient animals were exposed to cigarette smoke (CS) and Lewis lung carcinoma cells were injected to initiate the growth of tumors in the lung. CS exposure significantly increased the proliferation of lung tumors in wild-type mice, but not in CRAMP-deficient mice. CS exposure induced the recruitment of myeloid cell into tumor tissue in a CRAMP-dependent manner. Mice lacking RelA/p65 specifically in myeloid cells showed impaired recruitment of CRAMP-positive cells into the lung. In vitro studies with human cells showed that LL-37/hCAP-18 in macrophages is induced by soluble factors derived from cancer cells. Taken together, these data indicate that cathelicidin expressed from myeloid cells promotes CS-induced lung tumor growth by further recruitment of inflammatory cells. The regulation of cathelicidin expression involves myeloid p65/RelA and soluble factor from tumor cells.
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References
Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG et al. Non-small-cell lung cancer. Lancet 2011; 378: 1727–1740.
Papi A, Casoni G, Caramori G, Guzzinati I, Boschetto P, Ravenna F et al. COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma. Thorax 2004; 59: 679–681.
Young RP, Hopkins RJ, Christmas T, Black PN, Metcalf P, Gamble GD . COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009; 34: 380–386.
Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M . Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 2010; 17: 89–97.
Grivennikov SI, Karin M . Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 2010; 20: 65–71.
Coussens LM, Werb Z . Inflammation and cancer. Nature 2002; 420: 860–867.
Bals R, Wilson JM . Cathelicidins—a family of multifunctional antimicrobial peptides. Cell Mol Life Sci 2003; 60: 711–720.
Bals R, Wang X, Zasloff M, Wilson JM . The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci USA 1998; 95: 9541–9546.
Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R . The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur J Biochem 1996; 238: 325–332.
Frohm M, Agerberth B, Ahangari G, Stahle-Backdahl M, Liden S, Wigzell H et al. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 1997; 272: 15258–15263.
Gallo RL, Kim KJ, Bernfield M, Kozak CA, Zanetti M, Merluzzi L et al. Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J Biol Chem 1997; 272: 13088–13093.
Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2001; 414: 454–457.
Bowdish DM, Davidson DJ, Hancock RE . A re-evaluation of the role of host defence peptides in mammalian immunity. Curr Protein Pept Sci 2005; 6: 35–51.
Bowdish DM, Davidson DJ, Scott MG, Hancock RE . Immunomodulatory activities of small host defense peptides. Antimicrob Agents Chemother 2005; 49: 1727–1732.
Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 2006; 12: 636–641.
Kovach MA, Ballinger MN, Newstead MW, Zeng X, Bhan U, Yu FS et al. Cathelicidin-related antimicrobial peptide is required for effective lung mucosal immunity in Gram-negative bacterial pneumonia. J Immunol 2012; 189: 304–311.
Koczulla R, von Degenfeld G, Kupatt C, Krotz F, Zahler S, Gloe T et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest 2003; 111: 1665–1672.
Coffelt SB, Waterman RS, Florez L, Honer zu Bentrup K, Zwezdaryk KJ, Tomchuck SL et al. Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion. Int J Cancer 2008; 122: 1030–1039.
Coffelt SB, Marini FC, Watson K, Zwezdaryk KJ, Dembinski JL, LaMarca HL et al. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci USA 2009; 106: 3806–3811.
Heilborn JD, Nilsson MF, Jimenez CI, Sandstedt B, Borregaard N, Tham E et al. Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. IntJ Cancer 2005; 114: 713–719.
Hensel JA, Chanda D, Kumar S, Sawant A, Grizzle WE, Siegal GP et al. LL-37 as a therapeutic target for late stage prostate cancer. Prostate 2011; 71: 659–670.
von Haussen J, Koczulla R, Shaykhiev R, Herr C, Pinkenburg O, Reimer D et al. The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer 2008; 59: 12–23.
Buchau AS, Morizane S, Trowbridge J, Schauber J, Kotol P, Bui JD et al. The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth. J Immunol 2010; 184: 369–378.
Kurosaka K, Chen Q, Yarovinsky F, Oppenheim JJ, Yang D . Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J Immunol 2005; 174: 6257–6265.
Yang D, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T-cells. J Exp Med 2000; 192: 1069–1074.
Li G, Domenico J, Jia Y, Lucas JJ, Gelfand EW . NF-kappaB-dependent induction of cathelicidin-related antimicrobial peptide in murine mast cells by lipopolysaccharide. Int Arch Allergy Immunol 2009; 150: 122–132.
Li D, Beisswenger C, Herr C, Hellberg J, Han G, Zakharkina T et al. Myeloid cell RelA/p65 promotes lung cancer proliferation through Wnt/β-catenin signaling in murine and human tumor cells. Oncogene 2014; 33: 1239–1248.
Tecle T, Tripathi S, Hartshorn KL . Review: defensins and cathelicidins in lung immunity. Innate Immun 2010; 16: 151–159.
Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311: 1770–1773.
Niyonsaba F, Hirata M, Ogawa H, Nagaoka I . Epithelial cell-derived antibacterial peptides human beta-defensins and cathelicidin: multifunctional activities on mast cells. Curr Drug Targets Inflamm Allergy 2003; 2: 224–231.
Tjabringa GS, Aarbiou J, Ninaber DK, Drijfhout JW, Sorensen OE, Borregaard N et al. The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor. J Immunol 2003; 171: 6690–6696.
Shaykhiev R, Beisswenger C, Kaendler K, Senske J, Puechner A, Damm T et al. The human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am J Physiol Lung Cell Mol Physiol 2005; 289: 842–848.
Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE . The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 2002; 169: 3883–3891.
Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K et al. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J Immunol 2006; 176: 2455–2464.
Heilborn JD, Nilsson MF, Kratz G, Weber G, Sorensen O, Borregaard N et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 2003; 120: 379–389.
Okumura K, Itoh A, Isogai E, Hirose K, Hosokawa Y, Abiko Y et al. C-terminal domain of human CAP18 antimicrobial peptide induces apoptosis in oral squamous cell carcinoma SAS-H1 cells. Cancer Lett 2004; 212: 185–194.
Steinstraesser L, Ring A, Bals R, Steinau HU, Langer S . The human host defense peptide LL37/hCAP accelerates angiogenesis in PEGT/PBT biopolymers. Ann Plastic Surg 2006; 56: 93–98.
Murdoch C, Muthana M, Coffelt SB, Lewis CE . The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008; 8: 618–631.
Gombart AF, Borregaard N, Koeffler HP . Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005; 19: 1067–1077.
Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjo A, Torma H, Stahle M . Vitamin D induces the antimicrobial protein hCAP18 in human skin. J Invest Dermatol 2005; 124: 1080–1082.
Heilborn JD, Weber G, Gronberg A, Dieterich C, Stahle M . Topical treatment with the vitamin D analogue calcipotriol enhances the upregulation of the antimicrobial protein hCAP18/LL-37 during wounding in human skin in vivo. Exp Dermatol 2010; 19: 332–338.
Liu PT, Modlin RL . Human macrophage host defense against Mycobacterium tuberculosis. Curr Opin Immunol 2008; 20: 371–376.
Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173: 2909–2912.
Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF . Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect Immunol 2002; 70: 953–963.
Muehleisen B, Bikle DD, Aguilera C, Burton DW, Sen GL, Deftos LJ et al. PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection. Sci Transl Med 2012; 4: 135–166.
Erdag G, Morgan JR . Interleukin-1alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts. Ann Surg 2002; 235: 113–124.
Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N . Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol 2003; 170: 5583–5589.
Pestonjamasp VK, Huttner KH, Gallo RL . Processing site and gene structure for the murine antimicrobial peptide CRAMP. Peptides 2001; 22: 1643–1650.
Barnes PJ . Chronic obstructive pulmonary disease. N Engl J Med 2000; 343: 269–280.
Golec M, Reichel C, Mackiewicz B, Skorska C, Curzytek K, Lemieszek M et al. Cathelicidin LL-37, granzymes, TGF-beta1 and cytokines levels in induced sputum from farmers with and without COPD. Ann Agric Environ Med 2009; 16: 289–297.
Hess C, Herr C, Beisswenger C, Zakharkina T, Schmid RM, Bals R . Myeloid RelA regulates pulmonary host defense networks. Eur Respir J 2010; 35: 343–352.
Buettner M, Meinken C, Bastian M, Bhat R, Stossel E, Faller G et al. Inverse correlation of maturity and antibacterial activity in human dendritic cells. J Immunol 2005; 174: 4203–4209.
Beisswenger C, Kandler K, Hess C, Garn H, Felgentreff K, Wegmann M et al. Allergic airway inflammation inhibits pulmonary antibacterial host defense. J Immunol 2006; 177: 1833–1837.
Beisswenger C, Platz J, Seifart C, Vogelmeier C, Bals R . Exposure of differentiated airway epithelial cells to volatile smoke in vitro. Respiration 2004; 71: 402–409.
Acknowledgements
This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG Ba 1641/12), the Federal Ministry of Education and Research (FKZ 01GI0881-0888) and the LOEWE-Schwerpunkt ‘Tumor and Inflammation’ of the state of Hesse (to RB). We thank Thomas Damm, Andreas Kamyschnikow and Anja Honecker for excellent technical support.
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Li, D., Beisswenger, C., Herr, C. et al. Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth. Oncogene 33, 2709–2716 (2014). https://doi.org/10.1038/onc.2013.248
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DOI: https://doi.org/10.1038/onc.2013.248
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