Abstract
Introduction: During bladder tumorigenesis, thymopoiesis is usually downregulated. Considering that the thymus is the site of most T-cell development, this phenomenon may be related to thymic involution. However, the mechanisms involved in this phenomenon remain to be elucidated. Materials and Methods: An MB 49 murine bladder tumor model was used to identify mechanisms that might underlie this process. Results: The thymuses of tumor-bearing mice showed less cellularity than those of healthy mice. Involution was found to be associated with less proliferation and more apoptosis of thymic epithelial cells (TEC). Foxn1, KGF, and IL-7, three factors known to be involved in thymic development, were also downregulated in the thymuses of tumor bearers. When these mice were intravenously injected with KGF, the thymic microenvironment, thymopoiesis, and T-cell differentiation all returned to near normal status. Conclusions: The decreases in thymopoiesis and impaired T-cell differentiation may be attributable to changes in the thymic microenvironment. Improving the function of TEC, rather than T-cell progenitors, should be the focus of therapy.
References
1.
Shiku H: Importance of CD4+ helper T-cells in antitumor immunity. Int J Hematol 2003;77:435-438.
2.
Suttmann H, Riemensberger J, Bentien G, Schmaltz D, Stöckle M, Jocham D, Böhle A, Brandau S: Neutrophil granulocytes are required for effective bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res 2006;66:8250-8257.
3.
Agarwal A, Verma S, Burra U, Murthy NS, Mohanty NK, Saxena S: Flow cytometric analysis of Th1 and Th2 cytokines in PBMCs as a parameter of immunological dysfunction in patients of superficial transitional cell carcinoma of bladder. Cancer Immunol Immunother 2006;55:734-743.
4.
Can B, Baseskioglu M, Yılmaz E, Colak A, Ozen A, Yenilmez A: Pretreatment parameters obtained from peripheral blood sample predicts invasiveness of bladder carcinoma. Urol Int 2012;89:468-472.
5.
Andaloussi AE, Han Y, Lesniak MS: Progression of intracranial glioma disrupts thymic homeostasis and induces T-cell apoptosis in vivo. Cancer Immunol Immunother 2008;57:1807-1816.
6.
Mandal D, Lahiry L, Bhattacharyya A, Bhattacharyya S, Sa G, Das T: Tumor-induced thymic involution via inhibition of IL-7Ra and its JAK-STAT signaling pathway: protection by black tea. Int Immunopharmacol 2006;6:433-444.
7.
Roberto C, Norman H, Altman DM: Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice. Cancer Immunol Immunother 2009;58:2059-2072.
8.
Koch U, Radtke F: Mechanisms of T cell development and transformation. Annu Rev Cell Dev Biol 2011;27:539-562.
9.
Mandal D, Bhattacharyya A, Lahiry L, Choudhuri T, Sa G, Das T: Failure in peripheral immuno-surveillance due to thymic atrophy: importance of thymocyte maturation and apoptosis in adult tumor-bearer. Life Sci 2005;77:2703-2716.
10.
Ladi E, Yin X, Chtanova T, Robey EA: Thymic microenvironments for T cell differentiation and selection. Nat Immunol 2006;7:338-343.
11.
Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, Gray DH, Feinman J, Kochman AA, Eng JM, Suh D, Muriglan SJ, Boyd RL, van den Brink MR: Keratinocyte growth factor (KGF) is required for post-natal thymic regeneration. Blood 2006;107:2453-2460.
12.
Min D, Panoskaltsis-Mortari A, Kuro-O M, Holländer GA, Blazar BR, Weinberg KI: Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007;109:2529-2537.
13.
Summerhayes IC, Franks LM: Effects of donor age on neoplastic transformation of adult mouse bladder epithelium in vitro. J Natl Cancer Inst 1979;62:1017-1023.
14.
Mori K, Itoi M, Tsukamoto N, Amagai T: Foxn1 is essential for vascularization of the murine thymus anlage. Cell Immunol 2010;260:66-69.
15.
Lu N, Wang YH, Wang YH, Arima K, Hanabuchi S, Liu YJ: TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis. J Exp Med 2009;206:2111-2119.
16.
Recchia F, Sica G, Candeloro G, Necozione S, Bisegna R, Bratta M, Rea S: Maintenance immunotherapy in metastatic breast cancer. Oncol Rep 2008;20:1173-1179.
17.
Peng P, Yan Y, Keng S: Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. Oncol Rep 2011;25:749-762.
18.
Hu J, August A: Naive and innate memory phenotype CD4+ T-cells have different requirements for active Itk for their development. J Immunol 2008;180:6544-6552.
19.
Nitta T, Ohigashi I, Nakagawa Y, Takahama Y: Cytokine crosstalk for thymic medulla formation. Curr Opin Immunol 2011;23:190-197.
20.
Shanker A: Is thymus redundant after adulthood? Immunol Lett 2004;91:79-86.
21.
Sun QL, Charyulu V, Lobo D, Lopez DM: Role of thymic stromal cell dysfunction in the thymic involution of mammary tumor-bearing mice. Anticancer Res 2002;22:91-96.
22.
Carrio R, Lopez DM: Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1. Int J Mol Med 2009;23:89-98.
23.
Carrio R, Torroella-Kouri M, Iragavarapu-Charyulu V, Lopez DM: Tumor-induced thymic atrophy: alteration in interferons and Jak/Stats signaling pathways. Int J Oncol 2011;38:547-553.
24.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960-1964.
25.
Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL: Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10:55-62.
26.
Giovannetti A, Pierdominici M, Di Iorio A: Apoptosis in the homeostasis of the immune system and in human immune mediated diseases. Curr Pharm Des 2008;14:253-268.
27.
Heng TS, Chidgey AP, Boyd RL: Getting back at nature: understanding thymic development and overcoming its atrophy. Curr Opin Pharmacol 2010;10:425-433.
28.
Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI, Krenger W, Holländer GA: Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 2002;100:682-691.
29.
Kelly RM, Goren EM, Taylor PA, Mueller SN, Stefanski HE, Osborn MJ, Scott HS, Komarova EA, Gudkov AV, Holländer GA, Blazar BR: Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation. Blood 2010;115:1088-1097.
30.
Panoskaltsis-Mortari A, Taylor PA, Rubin JS, Uren A, Welniak LA, Murphy WJ, Farrell CL, Lacey DL, Blazar BR: Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury. Blood 2000;96:4350-4356.
31.
Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Holländer GA: Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 2007;109:3803-3811.
32.
Danzl NM, Donlin LT, Alexandropoulos K: Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin. J Exp Med 2010;207:999-1013.
33.
Berent-Maoz B, Montecino-Rodriguez E, Signer RA, Dorshkind K: Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a. Blood 2012;119:5715-5721.
34.
Wang KX, Shi YF, Ron Y, Kazanecki CC, Denhardt DT: Plasma osteopontin modulates chronic restraint stress-induced thymus atrophy by regulating stress hormones: inhibition by an anti-osteopontin monoclonal antibody. J Immunol 2009;182:2485-2491.
35.
Wyllie AH: Glucocorticoid-induced thymocyte apoptosis is associated with endogenous nuclease activation. Nature 1980;284:555-556.
36.
Pearse G: Histopathology of the thymus. Toxicol Pathol 2006;34:515-547.
37.
Talaber G, Kvell K, Varecza Z, Boldizsar F, Parnell SM, Jenkinson EJ, Anderson G, Berki T, Pongracz JE: Wnt-4 protects thymic epithelial cells against dexamethasone-induced senescence. Rejuvenation Res 2011;14:241-248.
38.
Rasmuson T, Ljungberg B, Grankvist K, Jacobsen J, Olsson T: Increased serum cortisol levels are associated with high tumour grade in patients with renal cell carcinoma. Acta Oncol 2001;40:83-87.
39.
Bernabé DG, Tamae AC, Miyahara GI, Sundefeld ML, Oliveira SP, Biasoli ÉR: Increased plasma and salivary cortisol levels in patients with oral cancer and their association with clinical stage. Clin Pathol 2012;65:934-939.
40.
Rubin B: Natural immunity has significant impact on immune responses against cancer. Scand J Immunol 2009;69:275-290.
41.
Legrand N, Dontje W, van Lent AU, Spits H, Blom B: Human thymus regeneration and T cell reconstitution. Semin Immunology 2007;19:280-288.
42.
Chidgey AP, Boyd RL: Stemming the tide of thymic aging. Nat Immunol 2006;7:1013-1016.
© 2013 S. Karger AG, Basel
2013
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