Urologic Oncology: Seminars and Original Investigations
Original articleHuman TLR gene family members are differentially expressed in patients with urothelial carcinoma of the bladder☆,☆☆
Introduction
Urothelial carcinoma (UC) comprise 95% of malignant tumors of the bladder and is the second cause of death among urogenital tumors. According to the Turkish Ministry of Health, UC is the third most common cancer type in males but is not in top 10 of cancer types in female patients [1].
Certain risk factors such as smoking and occupational factors are responsible for the development of UCs although the etiology of the disease is still unclear. Abnormal molecular events such as mutations in certain tumor supressor genes in normal urothelial cells are involved in the conventional carcinogenesis model of UC [2], [3].
UCs are classified morphologically and clinically into noninvasive tumors and muscle-invasive tumors. Studies have shown that there are 2 different molecular pathways involved in the subtypes of UC. The most important genomic alterations in low-grade noninvasive UCs have been found in the genes involved in FGFR3, HRAS, and mTOR pathways [4], [5]. In contrast, the genetically altered genes in high-grade noninvasive tumors and invasive tumors are specific tumor supressor genes such as TP53 and RBL1 [2], [4]. The tumor microenvironment also plays a critical role in multiple stages of tumor progression, especially immune-escaping, distant metastasis, and chemotherapy resistance. There is increasing evidence that there are alterations in the expression profiles of Toll-like receptors (TLRs) which recognize danger-associated molecular patterns derived from cancer cells in the tumor microenvironment [6], [7]. Taken together, these studies demonstrate that it may be important to investigate TLR expression in normal urothelium and in their malignant counterparts in tumor tissue.
TLRs are type I transmembrane receptors composed of the extracellular leukine-rich repeat domain and the cytoplasmic Toll/IL-1 receptor domain. Different TLRs recognize various pathogen-associated molecular patterns such as lipopolysaccharide, single-stranded RNA, DNA contained CpG motif, and danger-associated molecular patterns. TLR3, 7, 8, and 9 are localized in the endosomal compartment, whereas the remainder are localized on the plasma membrane of the cell. TLRs are also expressed in cancer cells and may stimulate important molecules such as the antiapoptotic proteins that are involved in cancer cell proliferation [6], [7], [8], [9]. In addition, the ligands derived from cancer cells may increase TLRs expression, and then the cells start to release certain chemokines and cytokines as important components of the tumor microenvironment. Immune cells activated by these cytokines can release other cytokines that cause immune tolerance, limiting antitumor immunity [6], [7], [10]. Therefore, it has been suggested that alterations to the expression pattern of TLR could be a novel potential therapeutic target in cancer.
TLRs have been extensively studied in different cell types and tissues but very limited information is available on urothelial tissue. The aim of this study was to examine TLR expression in nonmalignant urothelium and UC. It was also aimed to determine whether urine-based TLR expression analysis might reflect the TLR expression status in corresponding tumor tissues.
Section snippets
Urothelial tissue and urine samples
The study included 24 consecutive patients who underwent transurethral resection (TUR) of bladder tumors at our instution between 2012 and 2014. All primary tumor samples from the patients were histologically verified as UC and were classified according to WHO and WHO/ISUP [11]. Patients with hematuria who underwent TUR were also studied and a group of 46 patients with no cellular events of inflammatory reaction and no tumor cells during histopathological evaluation of the urothelium were
Patient and tumor characteristics
The mean age of the UC group (1 female and 23 males) and the noncancerous group (34 females and 12 males) was 64.91 ± 12.36 years (range: 45–90 years) and 52.21 ± 17.35 years (range: 24–81 years), respectively. Of the 24 UC patients, 13 (54.2%) were smokers and there was only 1 patient with a positive family history of UC.
The tumor characteristics are summarized in Table 1. None of the patients were found to have lymph node involvement. In the pathological examination of the pT1 tumors,
Discussion
TLRs are expressed in a variety of immune cells, including macrophages, natural killer cells, B cells, and dendritic cells. Recent studies have reported that TLRs are also expressed in both normal epithelial cells and tumor cells [6], [12], [13]. TLR family members exhibit distinct patterns of distribution in tissues [14], [15]. At present, only limited information is available related to the expression of TLRs in urothelial tissue. One clear result of all these studies are that TLR4 and TLR5
Conclusions
In summary, the TLR gene expression profiles reflect the heterogeneity within UC and the expression patterns of specific TLRs might be involved in the pathogenesis of UC. However, our study shows that the TLR family members cannot be used as biomarkers in UC. Further studies are needed to determine reliable biomarkers which could be used for the management of UC in routine clinical practice.
Acknowledgments
The authors want to acknowledge the support of Caroline Jane Walker for language editing. We also thank M. Rasid Bakir, MSc, for statistical analysis.
References (42)
- et al.
Molecular genetics of bladder cancer: emerging mechanisms of tumor initiation and progression
Urol Oncol
(2010) - et al.
TLR-mediated immune responses in the urinary tract
Curr Opin Microbiol
(2008) - et al.
Toll-like receptors in normal and malignant human bladders
J Urol
(2011) - et al.
Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression
Eur J Cancer
(2010) - et al.
TLR9 expression is associated with prognosis in patients with glioblastoma multiforme
J Clin Neurosci
(2012) - et al.
Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer
Eur Urol
(2011) - Republic of Turkey, Ministry of Health, Cancer Statistics Yearbook,...
- et al.
Origins of bladder cancer
Annu Rev Pathol
(2016) Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet?
Nat Rev Urol
(2012)- et al.
Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification
J Clin Oncol
(2006)
Cancer cells expressing toll-like receptors and the tumor microenvironment
Cancer Microenviron
The yin and yang of toll-like receptors in cancer
Oncogene
Toll-like receptors and cancer
Nat Rev Cancer
Toll-like receptor stimulation in cancer: a pro- and anti-tumor double-edged sword
Immunobiology
Innate and adaptive immune cells in the tumor microenvironment
Nat Immunol
Tumours of the urinary system
Targeting pattern recognition receptors in cancer immunotherapy
Targ Oncol
Toll-like receptors: the swiss army knife of immunity and vaccine development.
Clin Transl Immunology
Toll-like receptor expression in normal ovary and ovarian tumors
Cancer Immunol Immunother
Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria
Immunology
Toll-like receptor that prevents infection by uropathogenic bacteria
Science
Cited by (5)
Implications of Toll-like receptors (TLRs) and their signaling mechanisms in human cancers
2023, Pathology Research and PracticeHost defense peptides as innate immunomodulators in the pathogenesis of colitis
2018, Antimicrobial Peptides in Gastrointestinal DiseasesToll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis
2021, Frontiers in Cell and Developmental Biology
- ☆
This work was supported by Pamukkale University Scientific Research Unit (Grant no. 2012SBE015).
- ☆☆
This work was partly presented during the V. International Congress of Molecular Medicine, 20–22 May 2015, Izmir, Turkey.