All Title Author
Keywords Abstract

PLOS ONE  2013 

Tumor-Produced Versican V1 Enhances hCAP18/LL-37 Expression in Macrophages through Activation of TLR2 and Vitamin D3 Signaling to Promote Ovarian Cancer Progression In Vitro

DOI: 10.1371/journal.pone.0056616

Full-Text   Cite this paper   Add to My Lib

Abstract:

Tumor-associated macrophages have been shown to promote tumor growth. They may have an obligatory function in angiogenesis, invasion, and metastasis through release of inflammatory mediators. Their presence in ovarian cancer has been correlated with poor prognosis in these patients. The human cationic antimicrobial protein-18 (hCAP18)/LL-37 was originally identified as an effector molecule of the innate immune system. It is released by innate immune cells, such as macrophages, to combat microorganisms. Previous studies have characterized the hCAP18/LL-37 as a growth factor that has been shown to promote ovarian tumor progression. However, the role hCAP18/LL-37 has in macrophage-promoted ovarian tumor development and how its expression is controlled in this context remains poorly understood. Here, we demonstrate in co-culture experiments of macrophages and ovarian cancer cells a significant increase in the in vitro proliferation and invasiveness of the tumor cells is observed. These enhanced growth and invasion properties correlated with hCAP18/LL-37 induction. HCAP18/LL-37 expression was diminished by addition of two neutralizing antibodies, TLR2 or TLR6, as well as Cyp27B1 or VDR inhibitors. Furthermore, either the TLR2 or TLR6 antibody reduced vitamin D3 signaling and tumor cell progression in vitro. Addition of Cyp27B1 or VDR inhibitors abrogated TLR2/6 activation-induced expression of hCAP18/LL-37 in macrophages. Knockdown of tumor-produced versican V1 by RNAi in these tumor cells led to a decreased induction of hCAP18/LL-37 in macrophages. Versican V1 knockdown also inhibited TLR2 and vitamin D3 signaling, as well as growth and invasiveness of these tumor cells in the in vitro co-culture. In summary, we have found that versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and subsequent vitamin D-dependent mechanisms which promote ovarian tumor progression in vitro.

References

[1]  Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140: 883–899.
[2]  Yoshimura A (2006) Signal transduction of inflammatory cytokines and tumor development. Cancer Sci 97: 439–447.
[3]  Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420: 860–867.
[4]  Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454: 436–444.
[5]  Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4: 71–78.
[6]  Koukourakis MI, Giatromanolaki A, Kakolyris S, O'Byrne KJ, Apostolikas N, et al. (1998) Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on tumour neoangiogenesis and survival. Br J Cancer 77: 1696–1703.
[7]  Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196: 254–265.
[8]  Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE (2009) Regulation of macrophage function in tumors: the multifaceted role of NF-{kappa}B. Blood 113: 3139–3146.
[9]  Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8: 618–631.
[10]  Wu WK, Wang G, Coffelt SB, Betancourt AM, Lee CW, et al. (2010) Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. Int J Cancer 127: 1741–1747.
[11]  Shaykhiev R, Beisswenger C, Kandler K, Senske J, Puchner A, et al. (2005) Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am J Physiol Lung Cell Mol Physiol 289: L842–L848.
[12]  Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, et al. (2006) The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 12: 636–641.
[13]  Coffelt SB, Scandurro AB (2008) Tumors sound the alarmin(s). Cancer Res 68: 6482–6485.
[14]  Coffelt SB, Waterman RS, Florez L, H?ner zu Bentrup K, Zwezdaryk KJ, et al. (2008) Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion. Int J Cancer 122: 1030–1039.
[15]  Beisswenger C, Bals R (2005) Antimicrobial peptides in lung inflammation. Chem Immunol Allergy 86: 55–71.
[16]  Bucki R, Leszczynska K, Namiot A, Sokolowski W (2010) Cathelicidin LL-37: a multitask antimicrobial peptide. Arch Immunol Ther Exp (Warsz.) 58: 15–25.
[17]  Hensel JA, Chanda D, Kumar S, Sawant A, Grizzle WE, et al. (2011) LL-37 as a therapeutic target for late stage prostate cancer. Prostate 71: 659–670.
[18]  Coffelt SB, Marini FC, Watson K, Zwezdaryk KJ, Dembinski JL, et al. (2009) The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci U.S.A 106: 3806–3811.
[19]  Coffelt SB, Tomchuck SL, Zwezdaryk KJ, Danka ES, Scandurro AB (2009) Leucine leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells. Mol Cancer Res 7: 907–915.
[20]  von HJ, Koczulla R, Shaykhiev R, Herr C, Pinkenburg O, et al. (2008) The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer 59: 12–23.
[21]  Heilborn JD, Nilsson MF, Jimenez CI, Sandstedt B, Borregaard N, et al. (2005) Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer 114: 713–719.
[22]  Kim JE, Kim HJ, Choi JM, Lee KH, Kim TY, et al. (2010) The antimicrobial peptide human cationic antimicrobial protein-18/cathelicidin LL-37 as a putative growth factor for malignant melanoma. Br J Dermatol 163: 959–967.
[23]  Gombart AF, Borregaard N, Koeffler HP (2005) 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 19: 1067–1077.
[24]  Liu PT, Stenger S, Li H, Wenzel L, Tan BH, et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773.
[25]  Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, et al. (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457: 102–106.
[26]  Grivennikov SI, Karin M (2011) Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis 70: Suppl 1: i104–i108.
[27]  Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, et al. (2008) ‘Re-educating’ tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205: 1261–1268.
[28]  Hess C, Herr C, Beisswenger C, Zakharkina T, Schmid RM, et al. (2010) Myeloid RelA regulates pulmonary host defense networks. Eur Respir J 35: 343–352.
[29]  Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, et al. (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175: 1197–1205.
[30]  Xiao S, Li D, Zhu HQ, Song MG, Pan XR, et al. (2006) RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins. Proc Natl Acad Sci U.S.A 103: 16448–16453.
[31]  Standiford TJ, Kuick R, Bhan U, Chen J, Newstead M, et al. (2011) TGF-β-induced IRAK-M expression in tumor associated macrophages regulates lung tumor growth. Oncogene. 30: 2475–2484.
[32]  Krutzik SR, Hewison M, Liu PT, Robles JA, Stenger S, et al. (2008) IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway. J Immunol 181: 7115–7120.
[33]  Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, et al. (2007) Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J.Clin.Invest 117: 803–811.
[34]  Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M (2010) Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 17: 89–97.
[35]  Grivennikov SI, Karin M (2010) Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20: 65–71.
[36]  Hagemann T, Robinson SC, Schulz M, Trumper L, Balkwill FR, et al. (2004) Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis 25: 1543–1549.
[37]  Erdag G, Morgan JR (2002) Interleukin-1alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts. Ann Surg 235: 113–124.
[38]  Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, et al. (2003) Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol 170: 5583–5589.
[39]  Voutilainen K, Anttila M, Sillanpaa S, Tammi R, Tammi M, et al. (2003) Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis. Int J Cancer 107: 359–364.
[40]  Ricciardelli C, Rodgers RJ (2006) Extracellular matrix of ovarian tumors. Semin Reprod Med 24: 270–282.

Full-Text

comments powered by Disqus

Contact Us

service@oalib.com

QQ:3279437679

微信:OALib Journal