Abstract
Mast cells may have either antitumor or tumor-promoting potential. Nevertheless, mast cells in tumor microenvironment have been found to promote tumor growth. So far the mechanisms underlying the modulation of mast cell function in tumor microenvironment remains to be fully elucidated. Here, we report that tumor-promoting potential of mast cells could be augmented by molecules released from damaged tumor cells through cooperative stimulation of stem cell factor (SCF) and ligand for Toll-like receptor 4 (TLR4). Co-simulation with SCF and TLR4 ligand inhibited mast cell degranulation, but efficiently induced the production and secretion of VEGF, PDGF, and IL-10. Although TLR4 ligand alone may induce IL-12 expression in mast cells, co-stimulation with SCF and TLR4 ligand induced the expression of IL-10, but not IL-12, in mast cells. The phosphorylation of GSK3β was crucial for the effect of SCF and TLR4 ligand. In addition to inducing phosphorylation of GSK3β at Ser9 through PI3K pathway, SCF and TLR4 ligand cooperated to induce phosphorylation of GSK3β at Tyr216 by simultaneous activation of ERK and p38MAPK pathways. Both phospho-Ser9 and phospho-Tyr216 of GSK3β were required for IL-10 expression induced by SCF/TLR4 ligand, whereas suppressive effect of SCF/TLR4 ligand on mast cell degranulation was related to phospho-Tyr216. Importantly, the effect of SCF and TLR4 ligand on mast cells could be abrogated by inhibiting phosphorylation of GSK3β at Tyr216. These findings disclose the mechanisms underlying the modulation of mast cell function in tumor microenvironment, and suggest that inhibiting GSK3β in mast cells will be beneficial to the treatment of cancer.
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Abbreviations
- DTC-Ms:
-
Molecules from damaged tumor cells
- T-sMs:
-
Soluble molecules from tumor
- SCF:
-
Stem cell factor
- BMMC:
-
Bone marrow-derived mast cell
- sTLR4:
-
Soluble form of TLR4
References
Conti P, Castellani ML, Kempuraj D, Salini V, Vecchiet J, Tetè S et al (2007) Role of mast cells in tumor growth. Ann Clin Lab Sci 37:315–322
Maltby S, Khazaie K, McNagny KM (2009) Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 1796:19–26
Sinnamon MJ, Carter KJ, Sims LP, Lafleur B, Fingleton B, Matrisian LM (2008) A protective role of mast cells in intestinal tumorigenesis. Carcinogenesis 29:880–886
Henderson WR, Chi EY, Jong EC, Klebanoff SJ (1981) Mast cell-mediated tumor-cell cytotoxicity. Role of the peroxidase system. J Exp Med 153:520–533
Kormelink TG, Abudukelimu A, Redegeld FA (2009) Mast cells as target in cancer therapy. Curr Pharm Des 15:1868–1878
Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13:1211–1218
Ribatti D, Ennas MG, Vacca A, Ferreli F, Nico B, Orru S, Sirigu P (2003) Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest 33:420–425
Ribatti D, Crivellato E (2009) The controversial role of mast cells in tumor growth. Int Rev Cell Mol Biol 275:89–131
Ullrich SE, Nghiem DX, Khaskina P (2007) Suppression of an established immune response by UVA—a critical role for mast cells. Photochem Photobiol 83:1095–1100
Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ (2007) Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat Immunol 8:1095–1104
Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002
Nakano N, Nishiyama C, Kanada S, Niwa Y, Shimokawa N, Ushio H, Nishiyama M, Okumura K, Ogawa H (2007) Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections. Blood 109:4846–4855
Huang B, Lei Z, Zhang GM, Li D, Song C, Li B, Liu Y, Yuan Y, Unkeless J, Xiong H, Feng ZH (2008) SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood 112:1269–1279
Liu YY, Sun LC, Wei JJ, Li D, Yuan Y, Yan B et al (2010) Tumor cell-Released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells. J Immunol 185:2773–2782
Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C et al (2004) Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 431:1007–1011
Geng H, Zhang GM, Xiao H, Yuan Y, Li D, Zhang H, Qiu H, He YF, Feng ZH (2006) HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma. Int J Cancer 118:2657–2664
Walsh SK, Kane KA, Wainwright CL (2009) Mast cell degranulation—a mechanism for the anti-arrhythmic effect of endothelin-1? Br J Pharmacol 157:716–723
Tsan MF, Gao B (2004) Endogenous ligands of Toll-like receptors. J Leukoc Biol 76:514–519
Qiao H, Andrade MV, Lisboa FA, Morgan K, Beaven MA (2006) FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107:610–618
Youn HS, Lee JY, Fitzgerald KA, Young HA, Akira S, Hwang DH (2005) Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: molecular targets are TBK1 and RIP1 in TRIF complex. J Immunol 175:3339–3346
Theoharides TC, Conti P (2004) Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol 25:235–241
Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78
Martin M, Rehani K, Jope RS, Michalek SM (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6:777–784
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3 beta in cellular signaling. Prog Neurobiol 65:391–426
Miyashita K, Kawakami K, Nakada M, Mai W, Shakoori A, Fujisawa H, Hayashi Y, Hamada J, Minamoto T (2009) Potential therapeutic effect of glycogen synthase kinase 3 beta inhibition against human glioblastoma. Clin Cancer Res 15:887–897
Ott VL, Cambier JC, Kappler J, Marrack P, Swanson BJ (2003) Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat Immunol 4:974–981
Szczepanski MJ, Czystowska M, Szajnik M, Harasymczuk M, Boyiadzis M, Kruk-Zagajewska A, Szyfter W, Zeromski J, Whiteside TL (2009) Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res 69:3105–3113
Yasuda A, Sawai H, Takahashi H, Ochi N, Matsuo Y, Funahashi H, Sato M, Okada Y, Takeyama H, Manabe T (2007) Stem cell factor/c-kit receptor signaling enhances the proliferation and invasion of colorectal cancer cells through the PI3K/Akt pathway. Dig Dis Sci 52:2292–2300
Metcalfe DD, Peavy RD, Gilfillan AM (2009) Mechanisms of mast cell signaling in anaphylaxis. J Allergy Clin Immunol 124:639–646
Kim MS, Rådinger M, Gilfillan AM (2008) The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends Immunol 29:493–501
Kalesnikoff J, Rios EJ, Chen CC, Nakae S, Zabel BA, Butcher EC, Tsai M, Tam SY, Galli SJ (2006) RabGEF1 regulates stem cell factor/c-Kit-mediated signaling events and biological responses in mast cells. Proc Natl Acad Sci USA 103:2659–2664
Arrighi JF, Rebsamen M, Rousset F, Kindler V, Hauser C (2001) A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J Immunol 166:3837–3845
Ardeshna KM, Pizzey AR, Devereux S, Khwaja A (2000) The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells. Blood 96:1039–1046
Lawrence T (2007) Inflammation and cancer: a failure of resolution? Trends Pharmacol Sci 28:162–165
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867
Lin WW, Karin MA (2007) Cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183
Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, Mayer L, Unkeless JC, Xiong H (2005) Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65:5009–5014
Huang B, Lei Z, Zhao J, Gong W, Liu J, Chen Z, Liu Y, Li D, Yuan Y, Zhang GM, Feng ZH (2007) CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett 252:86–92
Shin HY, Kim JS, An NH, Park RK, Kim HM (2004) Effect of disodium cromoglycate on mast cell-mediated immediate-type allergic reactions. Life Sci 74:2877–2887
Acknowledgments
This work was supported by National Science Foundation of China (No. 30830095, 30771974, 30772589), Science Foundation of Ministry of Education of China (No. 20070487004), and National Development Program (973) For Key Basic Research of China (No. 2009CB521806).
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Wei, JJ., Song, CW., Sun, LC. et al. SCF and TLR4 ligand cooperate to augment the tumor-promoting potential of mast cells. Cancer Immunol Immunother 61, 303–312 (2012). https://doi.org/10.1007/s00262-011-1098-z
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DOI: https://doi.org/10.1007/s00262-011-1098-z