Abstract
The aim of this book chapter is to present the latest basic research developments on the role of inflammation in bladder cancer and provide insights into their future clinical significance in preventing bladder carcinogenesis and progression. Bladder cancer is a highly immunogenic malignancy. Urothelial cancer cells aim to manipulate the immune system by inhibiting its cytotoxic function while stimulating the secretion of growth promoting factors. Cytokine-induced imbalances in the distribution and differentiation of tumor-infiltrating cytotoxic cells can boost bladder cancer cell proliferation. Tumor-induced release of excessive amount of cytokines causes an “inflammatory storm” which drives metastasis formation via degradation of extracellular matrix proteins. Tumor-related selective cyclooxygenase-2 (COX-2) upregulation suppresses the cell-mediated immune response via aberrant prostaglandin metabolism resulting in failure of differentiation of myeloid cell progenitors into mature antigen-presenting cells. T cells are capable of increasing the oxidative stress on bladder cancer cells via induction of COX-2 and STEAP expression. Some evidence also suggests that COX-2 activation may be also involved in inflammation-mediated cancer stem cell proliferation. Antibodies against the VEGF-co-receptor neuropilin decrease the angiogenetic potential of bladder cancer cells. Inflammation-based predictive bladder cancer models have demonstrated to accurately predict response to treatment both in the curative and palliative setting. While randomized trials do not support a clinical benefit for the use of anti-inflammatory drugs (i.e., celecoxib, atorvastatin) in preventing recurrence of low-grade bladder cancer, further investigations are warranted in the setting of high-grade tumors since the immune response to cancer stimuli is most probably more pronounced in advanced stages.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Abdollah F, Gandaglia G, Thuret R, Schmitges J, Tian Z, Jeldres C, Passoni NM, Briganti A, Shariat SF, Perrotte P, Montorsi F, Karakiewicz PI, Sun M (2013) Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. doi:10.1016/j.canep.2013.02.002
Ajili F, Kourda N, Darouiche A, Chebil M, Boubaker S (2013) Prognostic value of tumor-associated macrophages count in human non-muscle-invasive bladder cancer treated by BCG immunotherapy. Ultrastruct Pathol 37(1):56–61
Azumi M, Kobayashi H, Aoki N, Sato K, Kimura S, Kakizaki H, Tateno M (2010) Six-transmembrane epithelial antigen of the prostate as an immunotherapeutic target for renal cell and bladder cancer. J Urol 183(5):2036–2044
Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J, Rouprêt M (2011) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 59(6):997–1008
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545
Boström PJ, Aaltonen V, Söderström KO, Uotila P, Laato M (2001a) Expression of cyclooxygenase-1 and -2 in urinary bladder carcinomas in vivo and in vitro and prostaglandin E2 synthesis in cultured bladder cancer cells. Pathology 33(4):469–474
Boström PJ, Uotila P, Rajala P, Nurmi M, Huhtaniemi I, Laato M (2001b) Interferon-alpha inhibits cyclooxygenase-1 and stimulates cyclooxygenase-2 expression in bladder cancer cells in vitro. Urol Res 29(1):20–24
Cekic C, Sag D, Li Y, Theodorescu D, Strieter RM, Linden J (2012) Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J Immunol 188(1):198–205
Chi LJ, Lu HT, Li GL, Wang XM, Su Y, Xu WH, Shen BZ (2010) Involvement of T helper type 17 and regulatory T cell activity in tumour immunology of bladder carcinoma. Clin Exp Immunol 161(3):480–489
Cholesterol Treatment Trialists’ (CTT) Collaboration (2012) Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 7(1):e29849
Dufresne M, Dumas G, Asselin E, Carrier C, Pouliot M, Reyes-Moreno C (2011) Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells. Mol Immunol 48(12–13):1556–1567
Edin S, Wikberg M, Dahlin AM, Rutegård J, Öberg Å, Oldenborg PA, Palmqvist R (2012) The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS ONE 7(10):e47045
Eruslanov E, Daurkin I, Vieweg J, Daaka Y, Kusmartsev S (2011) Aberrant PGE2 metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells. Int Immunopharmacol 11(7):848–855
Eruslanov E, Neuberger M, Daurkin I, Perrin GQ, Algood C, Dahm P, Rosser C, Vieweg J, Gilbert SM, Kusmartsev S (2012) Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. Int J Cancer 130(5):1109–1119
Gakis G, Kruck S, Stenzl A (2010) Can the burden of follow-up in low-grade noninvasive bladder cancer be reduced by photodynamic diagnosis, perioperative instillations, imaging, and urine markers? Curr Opin Urol 20(5):388–392
Gakis G, Todenhöfer T, Stenzl A (2011a) The prognostic value of hematological and systemic inflammatory disorders in invasive bladder cancer. Curr Opin Urol 21(5):428–433
Gakis G, Todenhöfer T, Renninger M, Schilling D, Sievert KD, Schwentner C, Stenzl A (2011b) Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score. BJU Int 108(11):1800–1805
Gakis G, Efstathiou JA, Lerner SP, Cookson MS, Keegan KA, Guru KA, Shipley WU, Heidenreich A, Schoenberg MP, Sagaloswky AI, Soloway MS, Stenzl A (2013) ICUD-EAU International Consultation on bladder cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 63(1):45–57
Gildea JJ, Seraj MJ, Oxford G, Harding MA, Hampton GM, Moskaluk CA, Frierson HF, Conaway MR, Theodorescu D (2002) RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res 62(22):6418–6423
Grunewald TG, Bach H, Cossarizza A, Matsumoto I (2012) The STEAP protein family: versatile oxidoreductases and targets for cancer immunotherapy with overlapping and distinct cellular functions. Biol Cell 104(11):641–657
Ishioka J, Saito K, Sakura M, Yokoyama M, Matsuoka Y, Numao N, Koga F, Masuda H, Fujii Y, Kawakami S, Kihara K (2012) Development of a nomogram incorporating serum C-reactive protein level to predict overall survival of patients with advanced urothelial carcinoma and its evaluation by decision curve analysis. Br J Cancer 107(7):1031–1036
Kawai K, Miyazaki J, Joraku A, Nishiyama H, Akaza H (2013) Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: current understanding and perspectives on engineered BCG vaccine. Cancer Sci 104(1):22–27
Khwaja F, Allen J, Lynch J, Andrews P, Djakiew D (2004) Ibuprofen inhibits survival of bladder cancer cells by induced expression of the p75NTR tumor suppressor protein. Cancer Res 64(17):6207–6213
Ledue TB, Weiner DL, Sipe JD, Poulin SE, Collins MF, Rifai N (1998) Analytical evaluation of particle-enhanced immunonephelometric assays for C-reactive protein, serum amyloid A and mannose-binding protein in human serum. Ann Clin Biochem 35(Pt 6):745–753
Liang PY, Li HY, Zhou ZY, Jin YX, Wang SX, Peng XH, Ou SJ (2013) Overexpression of immunoglobulin G prompts cell proliferation and inhibits cell apoptosis in human urothelial carcinoma. Tumour Biol. doi:10.1007/s13277-013-0717-z
Liu W, O’Donnell MA, Chen X, Han R, Luo Y (2009) Recombinant bacillus Calmette-Guérin (BCG) expressing interferon-alpha 2B enhances human mononuclear cell cytotoxicity against bladder cancer cell lines in vitro. Cancer Immunol Immunother 58(10):1647–1655
Meyer-Siegler KL, Cox J, Leng L, Bucala R, Vera PL (2010) Macrophage migration inhibitory factor anti-thrombin III complexes are decreased in bladder cancer patient serum: complex formation as a mechanism of inactivation. Cancer Lett 290(1):49–57
Okamoto M, Oyasu R (1997) Transformation in vitro of a nontumorigenic rat urothelial cell line by tumor necrosis factor-alpha. Lab Invest 77(2):139–144
Okamoto M, Kawai K, Reznikoff CA, Oyasu R (1996) Transformation in vitro of a nontumorigenic rat urothelial cell line by hydrogen peroxide. Cancer Res 56(20):4649–4653
Parada B, Sereno J, Reis F, Teixeira-Lemos E, Garrido P, Pinto AF, Cunha MF, Pinto R, Mota A, Figueiredo A, Teixeira F (2009) Anti-inflammatory, anti-proliferative and antioxidant profiles of selective cyclooxygenase-2 inhibition as chemoprevention for rat bladder carcinogenesis. Cancer Biol Ther 8(17):1615–1622
Robert-Koch-Institut (2010) Krebs in Deutschland. Berlin, pp 84–88
Saban MR, Sferra TJ, Davis CA, Simpson C, Allen A, Maier J, Fowler B, Knowlton N, Birder L, Wu XR, Saban R (2010) Neuropilin-VEGF signaling pathway acts as a key modulator of vascular, lymphatic, and inflammatory cell responses of the bladder to intravesical BCG treatment. Am J Physiol Renal Physiol 299(6):F1245–F1256
Sabichi AL, Lee JJ, Grossman HB, Liu S, Richmond E, Czerniak BA, De la Cerda J, Eagle C, Viner JL, Palmer JL, Lerner SP (2011) A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer. Cancer Prev Res (Phila) 4(10):1580–1589
Said N, Theodorescu D (2012) RhoGDI2 suppresses bladder cancer metastasis via reduction of inflammation in the tumor microenvironment. Oncoimmunology 1(7):1175–1177
Said N, Sanchez-Carbayo M, Smith SC, Theodorescu D (2012) RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration. J Clin Invest 122(4):1503–1518
Said N, Frierson HF, Sanchez-Carbayo M, Brekken RA, Theodorescu D (2013) Loss of SPARC in bladder cancer enhances carcinogenesis and progression. J Clin Invest. doi:10.1172/JCI64782
Saito K, Urakami S, Komai Y, Yasuda Y, Kubo Y, Kitsukawa S, Okubo Y, Yamamoto S, Yonese J, Fukui I (2012) Impact of C-reactive protein kinetics on survival of patients with advanced urothelial carcinoma treated by second-line chemotherapy with gemcitabine, etoposide and cisplatin. BJU Int 110(10):1478–1484
Siemes C, Vissser LE, Coebergh JW, Splinter TA, Witteman JC, Uitterlinden AG, Hofman A, Pols HA, Stricker BH (2006) C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam study. J Clin Oncol 24(33):5216–5222
St Hill CA (2011) Interactions between endothelial selectins and cancer cells regulate metastasis. Front Biosci 16:3233–3251
Stenzl A, Hennenlotter J, Schilling D (2008) Can we still afford bladder cancer? Curr Opin Urol 18(5):488–492
Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, Ribal MJ, Sherif A, Witjes JA (2011) Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol 59(6):1009–1018
Thanan R, Murata M, Ma N, Hammam O, Wishahi M, El Leithy T, Hiraku Y, Oikawa S, Kawanishi S (2012) Nuclear localization of COX-2 in relation to the expression of stemness markers in urinary bladder cancer. Mediators Inflamm 2012:165879. doi:10.1155/2012/165879
Theodorescu D, Sapisono LM, Conaway MR, Oxford G, Hampton GM, Frierson HF Jr (2004) Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer. Clin Cancer Res 10(11):3800–3806
Trichopoulos D, Psaltopoulou T, Orfanos P, Trichopoulou A, Boffetta P (2006) Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiol Biomarkers Prev 15(2):381–384
Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9(13):4653–4665
van der Horst G, Bost L, van der Pluijm G (2012) Epithelial plasticity, cancer stem cells, and the tumor-supportive stroma in bladder carcinoma. Mol Cancer Res 10(8):995–1009
Wight TN (2002) Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol 14(5):617–623
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Basel
About this chapter
Cite this chapter
Gakis, G. (2014). The Role of Inflammation in Bladder Cancer. In: Aggarwal, B., Sung, B., Gupta, S. (eds) Inflammation and Cancer. Advances in Experimental Medicine and Biology, vol 816. Springer, Basel. https://doi.org/10.1007/978-3-0348-0837-8_8
Download citation
DOI: https://doi.org/10.1007/978-3-0348-0837-8_8
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0348-0836-1
Online ISBN: 978-3-0348-0837-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)