Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_53_библиотеки_им_акад_М_И_Перельмана
.pdf
9.11.4 TLR4
9.11.4.1 Structure and Function
Among different TLRs, TLR4 is known as a particular TLR molecule because of its
bi-functional activity as extra- and intracellular TLR and application of two different
signaling pathways of MyD88-dependent and TRIF-dependent (Fig. 9.4). Moreover,
the activity of TLR4 depends on the co-receptor of MD-2 as an accessory protein
(Figs. 9.3 and 9.4). TLR belongs to TLR4 family and its gene is located on
chromosomal position of 9q32–33. The molecules of TLR4 are expressed by innate
immune cells of eosinophils, MΦs, mast cells, monocytes, myeloid and
plasmacytoid DCs and neutrophils and non-immune cells of endothelial-, epithe-
lial-, and smooth muscle cells (Table 9.2). The expression of TLR4 gene within the
urinary tract area occurs by urothelial cells in both of kidney and urinary bladder.
Formation of the hexameric structure of (TLR4-MD-2-LPS)
2
(Gram-negative bac-
terial lipopolysaccharide) triggers the TLR4 signaling pathway (Figs. 9.2 and 9.4).
The TLR4 ligand of LPS supports the tumor development and survival. Further-
more, XAMPs like cocaine, methamphetamine, and morphine (a common substance
for treating pain both in acute and chronic forms) trend to link to MD-2 which may
lead to TLR4 dimerization and neuro-immune signaling activation in central nervous
system (CNS). This property of TLR4 shows its importance in treatment of drug
addiction. TLR4 activation and upregulation may have correlation with tumor
relapse, chemo-resistance, and metastasis in colorectal, pancreatic, laryngeal, ovar-
ian, breast, prostate, esophageal squamous cell, adrenocortical, colon, head and neck
squamous cell, urinary bladder, and lung cancers (Basith et al. 2012; Behzadi and
Behzadi 2016; Behzadi et al. 2019; Boozari et al. 2019; Dajon et al. 2017; Huang
et al. 2018; Saghazadeh and Rezaei 2020; Wang et al. 2 020).
9.11.4.2 TLR4 SNPs and Their Role
In previous investigations, it was recognized that the SNPs of rs10759931 and
D299G (rs4986790) in exon region of TLR4 gene are in correlation with breast
cancer while the SNPs of rs2770150 and rs10759932 in promoter region of TLR4
gene have no associ ation with breast cancer; however, the C allele of this SNP has
protective effect on gastric canc er. Moreover, the SNP of T393I (rs4986791) in
TLR4 gene with CT genotype has higher relation with lung cancer rather than the
other genotypes of the mentioned SNP and also is associated with gastric cancer. The
+3725G/C polymorphism increases the susceptibility of individuals to breast cancer.
The SNPs of rs10759931 and rs11536898 in TLR4 gene have correlation with colon
cancer with no limitations among patients while the SNP of rs2770150 in TLR4 gene
is associated with colon cancer in women patients with >50 years old. The SNP of
rs1927911(C/T) TT genotype in TLR4 gene and the SNP of rs6973569 in IL-17 gene
have synergistic effect on each other regard ing colorectal cancer. It has been reported
that, the low incidence of the SNPs of D299G (rs4986790) and T393I (rs4986791) in
TLR4 gene is associated with ovarian cancer in female patients.
The AG genotype and G allele of T393I (rs4986791) in TLR4 gene is related to
gastric cancer. The C allele and CC genotype of rs11536889 in TLR4 gene is also
306 P. Behzadi
https://t.me/medicina_free
positively associated with gastric cancer. G allele a/w of D299G (rs4986790) in
TLR4 gene is associated with tumor development in distal part of stomach and the
GG and AG genotypes of this SNP are positively associated with colorectal cancer.
The polymorphisms of +896A A/G and +1196C/T in TLR4 gene are correlated with
gastric cancer. Moreover, the T399I polymorphisms in TLR4 gene are related to
occurrence of cervical, prostate, and nasopharyngeal cancers. The nasopharyngeal
carcinoma is the result of increase in expression of IL-1α, IL-10, and TNF-α and the
process of tumorigenesis. Another investigation has revealed that the 11381G/C
variant in 3’UTR region of TLR4 gene is in association with prostate cancer. The GG
genotype of rs1156858, G/A SNP and TC genotype of rs1927911 are positively
associated with developing prostate cancer (Gomaz et al. 2012; Medvedev 2013;
Pandey et al. 2018; Se mlali et al. 2018; Theodoropoulos et al. 2012).
9.11.4.3 TLR4 SNP in Urinary Bladder Cancer
The SNPs in the gene of TLR4 may lead to BCa. In this regard, C allele, GC and CC
genotypes of the 729G/C (rs11536865) and +3725G/C and GC and CC genotypes
and C allele of rs11536889 SNPs in TLR4 are significantly in association with BCa
(Table 9.2) (Pandey et al. 2018; Shen et al. 2013, 2015). In a meta-analysis study
done by Zhu et al. showed that there is no association between 196 to 174 del
polymorphism in TLR2 gene and BCa. Moreover, their results indicated that the
SNPs of rs11536889, rs1927911, rs1927 914, rs2149356, rs4986790, and rs4986791
in TLR4 gene increase the risk of different cancers (Zhu et al. 2013). Singh et al. in
their investigation indicated that there is no significant correl ation between the SNP
of T399I (rs4986791) in TLR4 gene and BCa (Singh et al. 2013).
9.11.5 TLR5
9.11.5.1 Structure and Function
TLR5 molecule belongs to TLR5 family and its locus is located on 1q33.3 position
on chromosome (Table 9.2). Bacterial flagellin is the inducer of TLR5 in urothelial
cells of urinary bladder and kidneys (Fig. 9.2). However, the expression of TLR5 is
high in urinary bladder and low in kidneys. The TLR5 molecules are expressed by
the innate immune cells of MΦs, monocytes, myeloid and plasmacytoid DCs,
neutrophils and NK cells, the adaptive immune cells of T, and the non-immune
cells of endothelial- and epithelial cells (Table 9.2). The TLR5 resembling TLR2
signaling pathway is able to increase the proliferation activity and survival of the
cancerous cells in gastric cancer which may lead to enhance the process of tumor
metastasis. In contrast, the report ed results from previous studies regarding breast
cancer show that, the signaling pathway of TLR5 downregulates the expression of
some cyclins of E2, B1, and D2 which may lead to prevent the proliferation of tumor
cells.
The expression of TLR5 increases in intestinal adenocarcinoma, ovarian, gastric,
cervical, breast, and colon cancers and reduces in esophageal adenocarcinoma
(Ayala-Cuellar et al. 2019; Basith et al. 2012; Behzadi and Behzadi 201 6 ; Behzadi
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 307
https://t.me/medicina_free
et al. 2019; Boozari et al. 2019; Dajon et al. 2017; Gomaz et al. 2012; Huang et al.
2018; Javaid and Choi 2020; Ohadian Moghadam and Nowroozi 2019; Saghazadeh
and Rezaei 2020; Wang et al. 2020).
9.11.5.2 TLR5 SNPs and Their Role
The SNP of rs5744168 T allele in TLR5 gene has correlation with sporadic breast
cancer. The SNPs of rs2072493 (A > G) and 5744174 (T > C) CC genotype are
associated with colorectal and colon cancers. In addition, the SNP of F616L
(rs5744174) (TC + CC) in TLR5 gene has significant correlation with H. pylori
and gastric cancer (Gomaz et al. 2012; Medvedev 2013; Ranjbar et al. 2017; Semlali
et al. 2018).
9.11.5.3 TLR5 SNP in Urinary Bladder Cancer
No meta-analysis was found regarding the association of TLR5 gene and BCa.
9.11.6 TLR6
9.11.6.1 Structure and Function
The TLR6 like TLR1, TLR2, and TLR10 belongs to TLR2 family and its gene is
located on chromosomal position of 4p14. The TLR6 gene together with TLR1 and
TLR10 genes forms a gene cluster of TLR10-TLR1-TLR6 on 4p14 position of
genomic chromosome. A functional TLR6 can only be recogni zed in the form of
heterodimers of TLR2/TLR6 and extracellular-TLR4/TLR6 (in Alzheimer’s dis-
ease). The TLR6 links to Diacyl lipoprotein as its specific ligand (Fig. 9.2). TLR6
molecules are expressed by innate immune cells of MΦs, mast cells, monocytes,
myeloid and plasmacytoid DCs, neutrophils and NK cells, adaptive immune cells
of B, and non-immune cells of endothelial- and epithelial cells (Table 9.2). The
extracellular heterodimer of TLR2/TLR6 resembling TLR1/TLR2 heterodimer has
m spatial configuration. It has been recognized that, the truncated transmembrane
peptide belonging to TLR2 as a novel antagonist against TLR2/TLR6 heterodimer is
able to interact with TLR6, specifically. Oxidized lipoproteins (with low density)
and fibers of amyloid-β peptides induce in flammatory signaling pathway throughout
the heterodimers of TLR4/TLR6 (TLR4/TLR6/CD36). The transmembrane domains
belonging to TLRs of 4 and 6 play vital role in formation of TLR4/TLR6
heterodimers. Interestingly, the truncated transmembrane domains pertaining to
TLRs of 4 and 6 and related derivatives are recognized as antagonists against
formation of TLR4 and TLR6 dimers (Behzadi and Behzadi 2016; Boozari et al.
2019; Dajon et al. 20 17; Godfroy III et al. 2012; Gomaz et al. 2012; Saghazadeh and
Rezaei 2020; Shmuel-Galia et al. 2017; Stewart et al. 2010; Wang et al. 2020; Zeng
et al. 2017).
Bioinformatic studies indicate that TLR2/TLR6 heterodimer in contrast to TLR1/
TLR2 heterodimer has no hydrophobic channel; because the TLR6 misses hydro-
phobic binding pocket. Due to this fact, the agonists of CU-T12-9 and Pam
3
CSK
4
and the antagonist of CU-CPT22 cannot be linked to TLR2/TLR6 to activate it. In
308 P. Behzadi
https://t.me/medicina_free
accordance with previous studies, the TLR2 plays an axial role in recognition of
PAMPs and DAMPs (e.g., high mobility group box 1 (HMGB 1)) in heterodimers of
TLR1/TLR2 and TLR2/TLR6. Interestingly, the TLRs of 1 and 6 have ~66%
similarity in their amino acid sequences; however, the similarity of the amino acid
sequences constructing the TLRs 1 and 6 active binding sites is low which may lead
to different configurations in the related active binding sites (Behzadi and Behzadi
2016; Behzadi et al. 2019 ; Wang et al. 2020).
9.11.6.2 TLR6 SNPs and Their Role
The people with homo-/heterozygotes for A1401G SNP in promoter of TLR6 gene
are susceptible to prostate cancer while those with SNP of C744T in their TLR6 gene
are protected against asthma. Moreover, the SNP of V427A, 1280 T > C
(rs5743815) in TLR6 gene is associated with NHL (Gomaz et al. 2012; Kutikhin
2011; Medvedev 2013; Ranjbar et al. 2017; Semlali et al. 2018; Vijay 2018).
9.11.6.3 TLR6 SNP in Urinary Bladder Cancer
No meta-analysis was found regarding the association of TLR6 gene and BCa.
9.11.7 TLR7
9.11.7.1 Structure and Function
TLR7, a TLR member belonging to TLR9 family with chromosomal position of
Xp22.3 which resembling TLR4 has two types of extra- and intracellular structures
(Table 9.2). TLR7 links to its ligand molecule of ssRNA (Fig. 9.2). The main cells
which express TLR7 molecules for the most are recognized as B cells (adaptive
immune cells) and the innate immune cells of eosinophils, MΦs, monocytes,
neutrophils and plasmacytoid DCs. The non-immune cells of endothelial cells
express the molecules of TLR7, too (Table 9.2). The molecule of TLR7 is very
close to TLR8 in both chromosomal location and function. TLRs 7 and 8 both
recognize intracellular microorganisms’ nucleosides and nucleotides (in the form of
single stranded RNA (ssRNA)) (Fig. 9.2) (e.g., viral ssRNAs of HIV) and possess
two active binding sites (Fig. 9.5). The first binding site in both TLRs of 7 and 8 is
conserved and links to small-molecule ligands. However, the second binding site of
TLR7 differs from the TLR8. The second active binding site in TLR7 links to
ssRNA and has synergistic effect on the first active binding site. The activation of
TLR7 results in inflammatory responses and type I IFN production (Fig. 9.4). Hence,
the activation of TLR7 signaling pathway participates in both of anti-tumor and anti-
viral therapeutics. Now, we know the anti-cancer positive effects of TLR7 antagonist
like imiquimod. The expression of TLR7 increases in multiple myeloma cells,
esophageal squamous cell, lung, and colorectal cancers (Basith et al. 2012; Behzadi
and Behzadi 2016; Behzadi et al. 2019; Boozari et al. 2019; Chi et al. 2017; Dajon
et al. 2017; Huang et al. 2018; Saghazadeh and Rezaei 2020; Wang et al. 2020).
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 309
https://t.me/medicina_free
9.11.7.2 TLR7 SNPs and Their Role
The SNP of rs3853839 (G/C) in TLR7 gene has correlation with metastatic colon
cancer chemotherapy via etuximab as a predictive biomarker (Okazaki et al. 2017;
Semlali et al. 2018).
9.11.7.3 TLR7 SNP in Urinary Bladder Cancer
No meta-analysis was found regarding the association of TLR7 gene and BCa.
9.11.8 TLR8
9.11.8.1 Structure and Function
TLR8 belongs to TLR9 family members which its locus is situated on genomic
chromosome with position of Xp22. TLR8, as an intracellular molecule is expressed
mostly by the innate immune cells of MΦs, mast cells, monocytes, myeloid and
plasmacytoid DCs and neutrophils, the adaptive immune cells of T and T
regs
, and
Fig. 9.5 The structure of hTLR8 heterodimer in combination of ssRNA. The two active binding
sites are shown. The first site which binds to small molecules like uridine and the second site binds
to short oligonucleotides like UG (4R08 PDB file) (Tanji et al. 2015)
310 P. Behzadi
https://t.me/medicina_free
non-immune cells of endothelial- and epithelial cells (Table 9.2). As mentioned
before, TLR8 encompasses two active binding sites including a conserved one
which links to small-molecule ligands (e.g., Uridine) and the other which connects
to short oligonucleotides (e.g., UG). The TLRs of 7 and 8 have high similarities in
their sequences and functions (Fig. 9.5). TLR8 recognizes microbial (bacterial and
viral) ssRNA molecules (Fig. 9.2) and in particular those ssRNAs enriched by
uridine and guanosine molecules. The hTLR8 signaling pathway is able to reverse
the suppressive activity of tumor-derived CD4
+
, CD8
+
, and γδ T
reg
cells, directly.
In accordance with recent studies, the activated TLR8 signaling pathway is able
to inhibit the production of cAMP molecules in tumor cells and block the conversion
of naïve and tumor specific T cells into senescent cells which has been triggered by
tumor formation. This process increases the anti-tumor immunity in in vivo condi-
tion. Furthermore, the signaling pathway of hTLR8 suppresses metabolism in tumor
cells in which may lead to downregulation of cAMP amounts in senescent T cells
and tumor cells. Hence, it seems that the signaling pathway of hTLR8 within T
reg
cells is able to regulate the metabolism of T
reg
cells in which results in inhibition of
T
reg
-suppressive function. The hTLR8 expression increases in colorectal and lung
cancers (Basith et al. 2012; Behzadi and Behzadi 2016; Behzadi et al. 2019; Boozari
et al. 2019; Dajon et al. 2017; Huang et al. 2018; Saghazadeh and Rezaei 2020; Tanji
et al. 2015; Vasilakos and Tomai 2013; Wang et al. 20 20 ).
9.11.8.2 TLR8 SNPs and Their Role
No TLR8 SNP was detected as a pivotal agent in cancers.
9.11.8.3 TLR8 SNP in Urinary Bladder Cancer
No meta-analysis was found regarding the association of TLR8 gene and BCa.
9.11.9 TLR9
9.11.9.1 Structure and Function
TLR9, the main member of the TLR9 family with the locus position of 3p21.3 on
genomic chromosome (Table 9.2) is expressed in the presence of microbial
unmethylated cytosine-phosphate-guanine (CpG) DNA (Fig. 9.2) belonging to
bacteria, fungi, protozoa, and viruses. The TLR of 9 is expressed by innate immune
cells of eosinophils, MΦs, monocytes, myeloid and plasmacytoid DCs and
neutrophils, the adaptive immune cells of B, and the non-immune cells,
e.g. endothelial- and epithelial cells (Table 9.2).
The anti-cancer positive effects of TLR9 antagonist like CpG have been
recognized. The previous studies indicate that high expression of TLR9 gene may
support the process of tumor proliferation in patients with oral squamous cell
carcinoma. The expression of TLR9 gene increases in pancreatic, multiple myeloma
cells, breast, prostate, esophageal squamous cells, lung, cervical, renal, ovarian, and
gastric cancers (Ayala-Cuellar et al. 2019; Basith et al. 2012; Behzadi and Behzadi
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 311
https://t.me/medicina_free
2016; Behzadi et al. 2019; Boozari et al. 2019; Dajon et al. 2017; Huang et al. 2018;
Saghazadeh and Rezaei 2020; Wang et al. 2020).
9.11.9.2 TLR9 SNPs and Their Role
The SNPs of rs352140 and rs187084 (C/T) in TLR9 gene are associated with breast
and colon cancers (in women), respectively. Besides, the SNPs of rs352139 (A/G)
and rs352144 (A/C) in promoter region of TLR9 gene have correlation with colorec-
tal cancer. In an investigation, it has been shown that the SNPs of 11381G/C variant
in 3’UTR region, 1486 T/C rs187084, rs5743836 and P545P 2848 A > G
rs352140 in TLR9 gene are associated with cervical cancer. Moreover, the SNPs
of 1237 T > C (rs5743836) and P545P 2848 A > G (rs352140) in TLR9 gene are
in correlation with Hodgkin’s lymphoma (Gomaz et al. 2012; Medvedev 2013;
Semlali et al. 2018).
9.11.9.3 TLR9 SNP in Urinary Bladder Cancer
In a meta-analysis study done by Zhang et al. shows that the SNP of rs352140 in
TLR9 gene contributes in cancer development (Zhang et al. 2013). In another meta-
analysis done by Wan et al. the SNP of rs187084 in TLR9 gene raises up the risk of
different cancers and in particular cervical cancer while the SNPs of rs352140 and
rs5743836 in TLR9 gene have preventive effect on cancer development in alimen-
tary tract and breast cancers (Wan et al. 2014). Singh et al. showed in their study that
there is no association with the SNP of G2848A in TLR9 gene and the BCa (Singh
et al. 2013).
9.11.10 TLR10
9.11.10.1 Structure and Function
The TLR10 is known as a member of TLR2 family which its gene is located within
the cluster gene of TLR10-TLR1-TLR6 on chromosomal position of 4p14. It links to
its ligands of Diacyl- and Triacyl lipoproteins. The molecules of TLR10 are
expressed by both of innate (e.g., eosinophils, MΦs, monocytes, neutrophils and
myeloid and plasmacytoid DCs) and adaptive immune cells (e.g., B, T cells and
T
regs
) and also by the non-immune cells of endothelial- and epithelial cells. The
TLR10 is able to homodimerize with itself (TLR10/TLR10) and heterodimerize with
its phylogenetic related molecules of TLR1 (TLR1/TLR10) and TLR2 (TLR2/
TLR10) (Table 9.2). The TLR10 has an anti-inflammatory role which makes it
unique among TLR molecules. Mourits et al. have shown that the extra- and
intracellular TLR10 molecules are expressed within human CD45+ CD14+
monocytes. The heterodimer of TLR1/TLR10 and homodimer of TLR10/TLR10
are able to bind with diacetylated lipoproteins and the heterodimer of TLR2/TLR10
links to triacetylated lipoproteins. Due to this fact, it seems that the TLR10
molecules resembling TLRs 1 and 2 encompass hydrophobic binding site (Behzadi
and Behzadi 2016; Behzadi et al. 2019; Boozari et al. 2019; Dajon et al. 2017;
Mourits et al. 2020; Saghazadeh and Rezaei 2020; Wang et al. 2020).
312 P. Behzadi
https://t.me/medicina_free
9.11.10.2 TLR10 SNPs and Their Role
According to previous report, the T allele SNP of rs7696175 in TLR10 gene has
significant relation with breast cancer (Kutikhin 2011). Kim et al. have shown that
the SNP of M326T (rs11466653) in TLR10 gene is an effective biomarker for tumor
growth in papillary thyroid cancer (Kim et al. 2013).
9.11.10.3 TLR10 SNP in Urinary Bladder Cancer
No meta-analysis was found regarding the association of TLR10 gene and BCa.
9.12 Conclusion
Despite the use of different scientific disciplines including genomics,
transcriptomics, metabolomics, etc., there are many questions regarding the role of
versatile SNPs in different genes of TLRs and their association with BCa. There is a
long way to complete our knowledge regarding different SNPs in TLRs genes which
may lead to BCa. To date, there are just a few numbers of recognized SNPs in TLR
genes and in particular TLR4 gene which are positively associated with BCa. We are
in the beginning of this way.
Acknowledgements I have special thanks to Prof. Syed Sameer, the editor of the present book for
his sincere guidance, help, and support.
References
Afsharimoghaddam A, Soleimani M, Lashay A, Dehghani M, Sepehri Z (2016) Controversial roles
played by toll like receptor 4 in urinary bladder cancer; a systematic review. Life Sci 158:31–36
Al-Ahmadie H, Netto GJ (2020) Updates on the genomics of bladder cancer and novel molecular
taxonomy. Adv Anat Pathol 27:36–43
Andersson KE, McCloskey KD (2014) Lamina propria: the functional center of the bladder?
Neurourol Urodyn 33:9–16
Angrini M, Varthaman A, Cremer I (2020) Toll-like receptors (TLRs) in the tumor microenviron-
ment (TME): a dragon-like weapon in a non-fantasy game of thrones. In: Tumor microenviron-
ment. Springer, Berlin, pp 145–173
Ayala-Cuellar AP, Cho J, Choi KC (2019) Toll-like receptors: a pathway alluding to cancer control.
J Cell Physiol 234:21707–21715
Ayari C, Bergeron A, LaRue H, Ménard C, Fradet Y (2011) Toll-like receptors in normal and
malignant human bladders. J Urol 185:1915–1921
Basith S, Manavalan B, Lee G, Kim SG, Choi S (2011) Toll-like receptor modulators: a patent
review (2006–2010). Expert Opin Ther Pat 21:927–944
Basith S, Manavalan B, Yoo TH, Kim SG, Choi S (2012) Roles of toll-like receptors in cancer: a
double-edged sword for defense and offense. Arch Pharm Res 35:1297–1316
Behzadi P (2020) Classical chaperone-usher (CU) adhesive fimbriome: uropathogenic Escherichia
coli (UPEC) and urinary tract infections (UTIs). Folia Microbiol 65:45–65
Behzadi E, Behzadi P (2016) The role of toll-like receptors (TLRs) in urinary tract infections
(UTIs). Central Eur J Urol 69:404
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 313
https://t.me/medicina_free
Behzadi P, Behzadi E, Ranjbar R (2016) IL-12 family cytokines: general characteristics, pathogenic
microorganisms, receptors, and signalling pathways. Acta Microbiol Immunol Hung 63:1–25
Behzadi P, Behzadi E, Pawlak-Adamska EA (2019) Urinary tract infections (UTIs) or genital tract
infections (GTIs)? It’s the diagnostics that count. GMS Hyg Infect Control 14:14
Behzadi P, Urbán E, Matuz M, Benkő R, Gajdács M (2020) The role of gram-negative bacteria in
urinary tract infections: current concepts and therapeutic options. In: Advances in experimental
medicine and biology. Springer, New York
Besaratinia A, Cockburn M, Tommasi S (2013) Alterations of DNA methylome in human bladder
cancer. Epigenetics 8:1013–1022
Boozari M, Butler AE, Sahebkar A (2019) Impact of curcumin on toll-like receptors. J Cell Physiol
234:12471–12482
Cancer Genome Atlas Research Network (2014) Comprehens ive molecular characterization of
urothelial bladder carcinoma. Nature 507:315–322
Cheng D, Hao Y, Zhou W, Ma Y (2014) Association between toll-like receptor 3 polymorphisms
and cancer risk: a meta-analysis. Tumor Biol 35:7837–7846
Chi H, Li C, Zhao FS, Zhang L, Ng TB, Jin G, Sha O (2017) Anti-tumor activity of toll-like receptor
7 agonists. Front Pharmacol 8:304
Choi W et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder
cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165
Compérat EM et al (2019) Grading of urothelial carcinoma and the new World Health Organisation
classification of Tumours of the urinary system and male genital organs. Eur Urol Focus
5:457–466
Cornejo KM, Rice-Stitt T, Wu C-L (2020) Updates in staging and reporting of genitourinary
malignancies. Arch Pathol Lab Med 144:305–319
Czerniak B, Dinney C, McConkey D (2016) Origins of bladder cancer. Annu Rev Pathol Mech Dis
11:149–174
Dajon M, Iribarren K, Cremer I (2017) Toll-like receptor stimulation in cancer: a pro-and anti-tumor
double-edged sword. Immunobiology 222:89–100
Damrauer JS et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of
breast cancer biology. Proc Natl Acad Sci 111:3110–3115
deLeeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3+ tumor-
infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res
18:3022–3029
Ernst O et al (2019) The cAMP pathway amplifies early MyD88-dependent and type I interferon-
independent LPS-induced interleukin-10 expression in mouse macrophages. Mediat Inflamm
2019:3451461
Gajdács M, Behzadi P (2020) Cytokines—the diamonds and pearls of biological systems. In:
Behzadi P (ed) Cytokines, 1st edn. InTechOpen, London, pp 1–7
García-Perdomo HA, Usubillaga-Velasquez JP, Zapata-Copete JA, Reis LO (2019) Mutations in
CDKN2A and the FGFR3 genes on bladder cancer diagnosis: a systematic review and meta-
analysis. World J Urol 37:2001–2007
Godfroy JI III, Roostan M, Moroz YS, Korendovych IV, Yin H (2012) Isolated toll-like receptor
transmembrane domains are capable of oligomerization. PLoS One 7:e48875
Gomaz A, Pavelić J, Matijević Glavan T (2012) The polymorphisms in toll-like receptor genes and
cancer risk. Period Biol 114:461–469
Guo CC, Czerniak B (2019) Bladder cancer in the genomic era. Arch Pathol Lab Med 143:695–704
Hedegaard J et al (2016) Comprehensive transcriptional analysis of early-stage urothelial carci-
noma. Cancer Cell 30:27–42
Hickling DR, Sun TT, Wu XR (2017) Anatomy and physiology of the urinary tract: relation to host
defense and microbial infection. In: Urinary tract infections: molecular pathogenesi s and clinical
management. ASM Press, Washington, DC, pp 1–25
Huang L, Xu H, Peng G (2018) TLR-mediated metabolic reprogramming in the tumor microenvi-
ronment: potential novel strategies for cancer immunotherapy. Cell Mol Immunol 15:428–437
314 P. Behzadi
https://t.me/medicina_free
Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE (2016) The 2016 WHO classification
of tumours of the urinary system and male genital organs—part B: prostate and bladder tumours.
Eur Urol 70:106–119
Ingersoll MA, Albert M (2013) From infection to immunotherapy: host immune responses to
bacteria at the bladder mucosa. Mucosal Immunol 6:1041–1053
Jalanko T, de Jong JJ, Gibb EA, Seiler R, Black PC (2020) Genomic subtyping in bladder cancer.
Curr Urol Rep 21:1–10
Javaid N, Choi S (2020) Toll-like receptors from the perspective of cancer treatment. Cancer 12:297
Kamat AM et al (2016) Bladder cancer. Lancet 388:2796–2810
Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461
Khan A, Khan Z, Warnakulasuriya S (2016) Cancer-associated toll-like receptor modulation and
insinuation in infection susceptibility: association or coincidence? Ann Oncol 27:984– 997
Kim SK, Park HJ, Hong IK, Chung J-H, Eun YG (2013) A missense polymorphism (rs11466653,
Met326Thr) of toll-like receptor 10 (TLR10) is associated with tumor size of papillary thyroid
carcinoma in the Korean population. Endocrine 43:161–169
Kutikhin AG (2011) Association of polymorphisms in TLR genes and in genes of the toll-like
receptor signaling pathway with cancer risk. Hum Immunol 72:1095–1116
Li D, Jin Y, Sun Y, Lei J, Liu C (2014a) Knockdown of toll-like receptor 4 inhibits human NSCLC
cancer cell growth and inflammatory cytokine secretion in vitro and in vivo. Int J Oncol
45:813–821
Li F, An S, Hou L, Chen P, Lei C, Tan W (2014b) Red and processed meat intake and risk of
bladder cancer: a meta-analysis. Int J Clin Exp Med 7:2100
Li J, Yang F, Wei F, Ren X (2017) The role of toll-like receptor 4 in tumor microenvironment.
Oncotarget 8:66656
Li C, Fu X, He H, Chen C, Wang Y, He L (2020) The biogenesis, functions, and roles of circRNAs
in bladder cancer. Cancer Manag Res 12:3673–3689
Lopez FV (2020) Molecular subtyping bladder cancer: is it ready for clinical practice? Turk J Med
Sci 50:1677–1678
Lopez-Beltran A, Henriques V, Montironi R, Cimadamore A, Raspollini MR, Cheng L (2019)
Variants and new entities of bladder cancer. Histopathology 74:77–96
Loras A et al (2019) Integrative metabolomic and transcriptomic analysis for the study of bladder
cancer. Cancer 11:686
Mansour B et al (2020) Bladder cancer-related microbiota: examining differences in urine and
tissue samples. Sci Rep 10:11042. https://doi.org/10.1038/s41598-020-67443-2
Medvedev AE (2013) Toll-like receptor polymorphisms, inflammatory and infectious diseases,
allergies, and cancer. J Interf Cytokine Res 33:467–484
Meeks JJ et al (2020) Genomic heterogeneity in bladder cancer: challenges and possible solutions to
improve outcomes. Nat Rev Urol 17(5):259–270
Mourits VP et al (2020) The role of toll-like receptor 10 in modulation of trained immunity.
Immunology 159:289–297
Mouw KW (2017) DNA repair pathway alterations in bladder cancer. Cancer 9:28
Nissar S, Sameer AS, Rasool R, Qadri Q, Chowdri NA, Rashid F (2017) Role of TLR4 gene
polymorphisms in the colorectal cancer risk modulation in ethnic Kashmiri population—a case–
control study. Egypt J Med Hum Genet 18:53–59
Ohadian Moghadam S, Nowroozi MR (2019) Toll-like receptors: the role in bladder cancer
development, progression and immunotherapy. Scand J Immunol 90:e12818
Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T (2012) Structural analyses of
human toll-like receptor 4 polymorphisms D299G and T399I. J Biol Chem 287:40611–40617
Okazaki S et al (2017) Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy
in patients with metastatic colorectal cancer. Int J Cancer 141:1222–1230
O'neill LA, Golenbock D, Bowie AG (2013) The history of toll-like receptors—redefining innate
immunity. Nat Rev Immunol 13:453–
460
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 315
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана