Expression of TLR4 and major inflammatory cytokines in patients with bladder cancer of different grade and stage
DOI:
https://doi.org/10.32471/exp-oncology.2312-8852.vol-43-no-2.16102Keywords:
gene expression, INF-γ, TGF-β1, TLR4, TNF, urinary bladder cancerAbstract
Summary. Background: The bladder cancer is immunogenic, and neoantigens generated by tumor cells trigger a notable immune response in the host. On the other hand, multiple immune escape mechanisms allow for avoiding the recognition by the host immune system. Toll-like receptor type 4 and inflammatory cytokines play major role in the immune response to bladder cancer. Aim: To assess the expression of TLR4 and the genes of major inflammatory cytokines in tumor cells and in unaffected tissue of the bladder. Materials and Methods: The pairs of samples from the urinary bladder tumor and unaffected adjacent tissue were obtained from 50 surgically treated patients with bladder cancer. The level of expression of TLR4, TGF-β1, INF-γ, TNF-α genes was evaluated by real-time polymerase chain reaction. Results: Bladder cancer cells are characterized by lower expression levels of TLR4, TGF-β1, INF-γ, TNF-α as compared to unaffected tissue. In patients with recurrent cancer, expression of TLR-4 and cytokines does not change both in tumor and in unaffected tissue of the bladder. Expression of TLR4 is identically low both in low- and high-grade cancer. Expression levels of the INF-γ and TNF-α are remarkably low in muscle-invasive cancer compared to the unaffected bladder tissue. The level of TGF-β1 in bladder cancer is comparable to the unaffected tissue of the bladder, while in the intact and metastatic lymph nodes it is significantly upregulated. Conclusion: Bladder cancer tissue differs from the unaffected part of the bladder wall in the level of TLR4, TGF-β1, INF-γ, TNF-α expression.
References
Sjödahl G, Lauss M, Lövgren K, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 2012; 18: 3377–86.
Lindgren D, Frigyesi A, Gudjonsson S, et al. Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res 2010; 70: 3463–72.
Park JC, Citrin DE, Agarwal PK, Apolo AB. Multimodal management of muscle-invasive bladder cancer. Curr Probl Cancer 2014; 38: 80–108.
Network CGAR. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315–22.
Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502: 333–9.
Smith SG, Zaharoff DA. Future directions in bladder cancer immunotherapy: towards adaptive immunity. Immunotherapy 2016; 8: 351–65.
Basith S, Manavalan B, Yoo TH, et al. Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res 2012; 35: 1297–316.
Botos I, Segal DM, Davies DR. The structural biology of Toll-like receptors. Structure 2011; 19: 447–59.
Kusuhara Y, Daizumoto K, Kawai K, et al. Low expression of toll-like receptor 4 is associated with poor prognosis in bladder cancer. Anticancer Res 2019; 39: 703–11.
Shcheblyakov DV, Logunov DY, Tukhvatulin AI, et al. Toll-like receptors (TLRs): the role in tumor progression. Acta Naturae 2010; 2: 21–9.
Ohadian Moghadam S, Nowroozi MR. Toll-like receptors: The role in bladder cancer development, progression and immunotherapy. Scand J Immunol 2019; 90: e12818.
Li J, Yang F, Wei F, Ren X. The role of toll-like receptor 4 in tumor microenvironment. Oncotarget 2017; 8: 66656–67.
Yakovlev PG, Gorbach OI, Khranovska NM, et al. Changes in expression of TLR-4, TGF-β, INF-γ, TNF-α in cultured T24/83 cells of invasive bladder cancer treated with cisplatin and/or polyphenolic adjuvant melanin. Exp Oncol 2021;43: 7–14.
Hemmi H, Akira S. TLR signalling and the function of dendritic cells. Chem Immunol Allergy 2005; 86: 120–35.
Zhang Z, Schluesener HJ. Mammalian toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 2006; 63: 2901–7.
Obermajer N, Urban J, Wieckowski E, et al. Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents. Nat Protoc 2018; 13: 335–57.
Sato Y, Goto Y, Narita N, Hoon DS. Cancer cells expressing Toll-like receptors and the tumor microenvironment. Cancer Microenviron 2009; 2: 205–14.
Loskog A, Ninalga C, Paul-Wetterberg G, et al. Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. J Urol 2007; 177: 353–8.
Mantovani A, Locati M. Tumor-associated macrophages as a paradigm of macrophage plasticity, diversity, and polarization: lessons and open questions. Arterioscler Thromb Vasc Biol 2013; 33: 1478–83.
Qian Y, Deng J, Xie H, et al. Regulation of TLR4-induced IL-6 response in bladder cancer cells by opposing actions of MAPK and PI3K signaling. J Cancer Res Clin Oncol 2009; 135: 379–86.
Qian Y, Deng J, Geng L, et al. TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells. Cancer Invest 2008; 26: 816–21.
Houghton BB, Chalasani V, Hayne D, et al. Intravesical chemotherapy plus bacille Calmette-Guérin in non-muscle invasive bladder cancer: a systematic review with meta-analysis. BJU Int 2013; 111: 977–83.
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