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Year : 2016  |  Volume : 59  |  Issue : 3  |  Page : 294-300
A tissue microarray study of toll-like receptor 4, decoy receptor 3, and external signal regulated kinase 1/2 expressions in astrocytoma

1 Department of Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan, Republic of China
2 National Defense Medical Center, Graduate Institute of Pathology and Parasitology, Taipei, Taiwan, Republic of China
3 Department of Pathology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan, Republic of China
4 Department of Oral and Maxillofacial Surgery, National Defense Medical Center; School of Dentistry, National Defense Medical Center, Taipei, Taiwan, Republic of China
5 Department of Neurological Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan, Republic of China

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Date of Web Publication10-Aug-2016


Introduction: Decoy receptor 3 (DcR3) functions as a death decoy inhibiting apoptosis mediated by the tumor necrosis factor receptor family. It is highly expressed in many tumors and its expression can be regulated by the MAPK/ERK signaling pathway and ERK is a vital member of this pathway. Toll-like receptor 4 (TLR4) is expressed on immune cells. Increased TLR4 expression has been associated with various types of cancers. Material and Methods: The study was conducted to investigate the expression of DcR3, ERK1/2, and TLR4 in astrocytomas and evaluate if they are validating markers for discriminating glioblastoma from anaplastic astrocytoma in limited surgical specimen. Expression of DcR3, ERK1/2, and TLR4 was determined by immunohistochemical staining of tissue microarray from 48 paraffin-embedded tissues. A binary logistic regression method was used to generate functions that discriminate between anaplastic astrocytomas and glioblastomas. Results: The expression of TLR4 and DcR3 was significantly higher in glioblastomas than in anaplastic astrocytomas. DcR3 could discriminate anaplastic astrocytomas from glioblastomas with high sensitivity (93.8%), specificity (90%), and accuracy (92.3%). Conclusion: Our results suggest that DcR3 may be a useful marker for discriminating anaplastic astrocytomas from glioblastomas.

Keywords: Astrocytoma, decoy receptor 3, external signal regulated kinase 1/2, glioblastoma, immunostaining score, toll-like receptor 4

How to cite this article:
Lin CK, Ting CC, Tsai WC, Chen YW, Hueng DY. A tissue microarray study of toll-like receptor 4, decoy receptor 3, and external signal regulated kinase 1/2 expressions in astrocytoma. Indian J Pathol Microbiol 2016;59:294-300

How to cite this URL:
Lin CK, Ting CC, Tsai WC, Chen YW, Hueng DY. A tissue microarray study of toll-like receptor 4, decoy receptor 3, and external signal regulated kinase 1/2 expressions in astrocytoma. Indian J Pathol Microbiol [serial online] 2016 [cited 2022 Sep 29];59:294-300. Available from:

Yuan-Wu Chen, Dueng-Yuan Hueng
These authors contributed equally to this work

   Introduction Top

The primary brain tumor is one of the leading causes of cancer-related mortality.[1] The most common primary central nervous system tumor is glioma, followed by meningioma.[2] The World Health Organization pathological grading is an important criterion used to predict therapeutic outcome and prognosis.[3] Astrocytic tumors are divided into four grades based on histologic characteristics, namely well-circumscribed pilocytic astrocytoma (Grade I), diffuse astrocytoma (Grade II), anaplastic astrocytoma (Grade III), and glioblastoma (Grade IV). The capability of gliomas for tumor migration and infiltration are two determining factors for poor prognosis. Cell–cell and cell-matrix interactions may play an important role in malignant glioma invasion.[4]

Decoy receptor 3 (DcR3) is a recently identified soluble decoy receptor that competes with Fas in binding to Fas ligand (FasL) and inhibits FasL-induced apoptosis.[5] In recent studies, the DcR3 gene has been amplified in about half of primary lung, colon, and liver tumors and its messenger RNA is expressed in tumor cells.[6] These findings suggest that certain tumor cells expressing the DcR3 molecule may escape from the apoptotic cascade. The DcR3 gene is located on chromosome 20q13, a site that is amplified in astrocytic tumors by comparative genomic hybridization analysis.[7] Arakawa et al. reported frequent gene amplification and overexpression of DcR3 in glioblastoma.[8]

Exogenous insulin-like growth factor binding protein-2 induces proliferation, invasion, and chemoresistance in glioma cells via integrin β1/external signal regulated kinase (ERK) signaling, suggesting that targeting this pathway could represent a potential therapeutic strategy for the treatment of gliomas.[9] Bradykinin displays an important role in cancer, and activation of kinin B1 and B2 receptors may contribute to glioblastoma progression in vitro. Furthermore, PI3K/AKT and ERK 1/2 signaling may be a target for adjuvant treatment of glioblastoma with a possible impact on tumor proliferation.[10] Quercetin, a traditional Chinese medicinal herb, is an important flavonoid and has anti-cancer activity. It might inhibit the viability and migration and promote the senescence and apoptosis of glioma cells by suppressing the Ras/mitogen-activated protein kinase (MAPK)/ERK and PI3K/AKT signaling pathways.[11] In addition, evidence suggest that the MAPK/ERK pathway is activated in many human tumors and that ERK may be a parameter for predicting prognosis in various cancers such as breast cancer, colon cancer, pancreatic cancer, gastric cancer, and cholangiocarcinoma.[12],[13] Kim et al. found that LPS induces DcR3 release in human intestinal epithelial cells, which appears to be via the activation of MAPK, such as ERK1/2 and c-Jun NH2-terminal protein kinase (JNK). The LPS-induced DcR3 release in SW480 cells is abolished by ERK1/2 and JNK inhibitors.[14] Taking stock of these reports, this study posits that DcR3 and ERK1/2 are closely related.

Toll-like receptors (TLRs) are type I transmembrane proteins with extracellular domains composed largely of leucine-rich repeats and intracellular signaling domains that play a crucial role in inflammation and host defense against invading microorganisms through the recognition of pathogen-associated molecular patterns such as LPS, lipopeptides, dsRNA, and bacterial DNA.[15] In mammals, the TLR family consists of at least 12 members expressed predominantly on the surface of macrophages and various immune cells.[16] LPS is specifically recognized by TLR4.[17],[18] More recent studies have demonstrated TLRs expressions in a broad variety of tumor tissues and tumor cell lines.[19],[20],[21],[22] Their activated signaling pathways in cancer cells may have profound consequences on tumor growth by promoting cancer progression, anti-apoptotic activity, and resistance to host immune responses.[23] The Fas pathway is described as an activator of the glioblastoma proliferation by increasing the pathogenicity of this tumor. The LPS pathway depending on TLR4 could limit the glioblastoma spreading resulted from TLR4 signal transduction pathways neutralize proliferation and migration induced by Fas pathway activation in glioblastoma cell lines.[24] Other study observed heightened TLR4 levels in glioblastoma multiforme (GBM) tumor samples as compared to adjacent normal tissue. Since the pro-inflammatory cytokine tumor necrosis factor (TNF)-α induces NF-κB activation in GBM and as several common signaling mediators are involved in TNF-α and TLR4-mediated NF-κB activation, TNF-α induced TLR4 was abrogated in cells transfected with dominant negative I-κB and HIF-1α siRNA. It indicates that TNF-α triggered TLR4-HIF-1α and NF-κB TLR4 feed-forward loops act in tandem to sustain inflammatory response in glioma.[25]

This study aimed to investigate the expressions of DcR3, ERK1/2, and TLR4 in astrocytomas and determine whether DcR3, ERK1/2, or TLR4 immunostaining score can be used to aid the discriminate between anaplastic astrocytoma and glioblastoma.

   Materials and Methods Top

The Ethics Review Committees of Tri-service General Hospital approved this study and the requirement for informed consent was waived. Forty-eight paraffin-embedded tissues were retrieved. These consisted of 38 cases of astrocytoma with varying differentiation, including 12 diffuse astrocytomas, 10 anaplastic astrocytomas, 16 glioblastomas, and 10 normal brain tissues. All of the cases were from newly diagnosed patients who had not received previous surgery, radiotherapy, radiosurgery, or chemotherapy. The hematoxylin and eosin stained slides of all tumors were reviewed by two pathologists. Tumor differentiation of tumors was based on the WHO grading system. One core tissue sample (2 mm) was taken from a representative area of each paraffin-embedded tumor tissue and tissue microarray slides were constructed.


Paraffin sections (5 μm thick) were dewaxed in xylene, rehydrated in an alcohol series, immersed in 3% hydrogen peroxide for 10 min to suppress endogenous peroxidase activity, heated (100°C) 30 min in 0.01 mol/L sodium citrate buffer (pH 6.0) to retrieve antigen, rinsed three times in phosphate buffered saline (PBS) for 5 min, and incubated 1 h at room temperature with mouse monoclonal antibody to human DcR3 (1:100 Santa Cruz Biotechnology, CA, USA), mouse monoclonal antibody to human TLR4 (1:100 Santa Cruz Biotechnology, CA, USA), and rabbit monoclonal anti-human ERK1/2 antibody (1:100 Epitomics) diluted in PBS. After incubation with primary antibody, sections were washed three times with PBS for 5 min, incubated with horseradish peroxidase-labeled rabbit anti-mouse immunoglobulin diluted in PBS (DAKO, Carpinteria, CA, USA; 1 h at room temperature), washed three times, incubated with a solution of diaminobenzidine at room temperature to visualize peroxidase activity, and mounted, dried, and examined under a light microscope. Sections of normal brain tissue were used as a negative control, lung adenocarcinoma was used as a positive control of DcR3, thyroid carcinoma was used as a positive control of ERK1/2 and TLR4 antibodies.

For evaluating immunoreactivity and histologic appearance, all tissue microarray experiments were repeated twice by VENTANA automated BenchMark XT immunohistochemical (IHC)/in-situ hybridization staining instrument. The slides were concurrently examined and scored by two investigators. In this study, cytoplasmic immunoreactivity for TLR4 and DcR3, and cytoplasmic as well as nuclear staining of ERK1/2 on tumor cells was recorded.

The intensity of tumor cell staining was scored on a 4-point scale from 0 to 3 as follows: 0 (no staining), 1 (weak intensity), 2 (moderate intensity), and 3 (strong intensity). The percentage of immunoreactive tumor cells was graded on a 5-point scale (0, <5%; 1, 5–10%; 2, 11–25%; 3, 26–50%, and 4, ≥50% of stained cells). Immunostaining score (range: 0–12) was determined by multiplying the score based on a percentage of stained tumor cells (0-4) by the intensity score (0-3).[26]

Statistical analysis

Immunostaining scores in astrocytoma specimens were compared with scores in the normal brain tissue. All results were expressed as a mean ± standard error of the mean. Comparisons were performed using MANOVA. While a binary logistic regression method was used to generate functions that discriminated between anaplastic astrocytoma and glioblastoma. The level of statistical significance was set at P < 0.05. SPSS (Statistical Product and Service Solutions, IBM) 11.5 version was used for statistical analysis.

   Results Top

Immunostaining scores for TLR4, DcR3, and ERK1/2 in astrocytomas were presented in [Table 1] and the representative specimens were shown in [Figure 1].
Table 1: Immunostaining expression of TLR4, DcR3 and Erk1/2 in normal brain tissue and astrocytoma by multivariate general linear models

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Figure 1: H and E staining of (A0) normal brain, (B0) diffuse astrocytoma, (C0) anaplastic astrocytoma, and (D0) glioblastoma. Immunohistochemical analysis of toll-like receptor 4 in (A1) normal brain, (B1) diffuse astrocytoma, (C1) anaplastic astrocytoma, and (D1) glioblastoma; decoy receptor 3 in (A2) normal brain, (B2) diffuse astrocytoma, (C2) anaplastic astrocytoma, and (D2) glioblastoma; and external signal regulated kinase in (A3) normal brain, (B3) diffuse astrocytoma, (C3) anaplastic astrocytoma, and (D3) glioblastoma (original magnification, ×400)

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Immunostaining scores of toll-like receptor 4, decoy receptor 3, and external signal regulated kinase 1/2 in astrocytomas

The TLR4 immunostaining score was significantly higher in astrocytomas than in normal brain tissue (2.16 ± 0.79; P < 0.001). Furthermore, the intensity, percentage of stained cells, and TLR4 immunostaining score were all significantly higher in glioblastomas than in diffuse or anaplastic astrocytomas (P < 0.05 for anaplastic astrocytomas and P < 0.001 in diffuse astrocytomas, by post hoc test of MANOVA) [Table 1]. However, all of the above variables were comparable between diffuse and anaplastic astrocytomas.

The immunostaining score of DcR3 was significantly higher in astrocytomas than in the normal brain tissue (2.03 ± 0.82; P < 0.001). The intensity, percentage of stained cells, and DcR3 immunostaining score were all significantly higher in glioblastoma than in diffuse or anaplastic astrocytomas (P < 0.05 for anaplastic astrocytoma and P < 0.001 in diffuse astrocytoma, by post hoc test of MANOVA) [Table 1]. However, all of these variables were similar between diffuse and anaplastic astrocytomas.

In addition, the ERK1/2 immunostaining score was significantly higher in astrocytomas than in normal brain tissue (2.16 ± 1.08; P < 0.001). The intensity, percentage of stained cells, and ERK1/2 immunostaining score were all significantly higher in glioblastomas than in diffuse astrocytomas (P < 0.05, by post hoc test of MANOVA) [Table 1]. However, all of these variables were comparable between diffuse and anaplastic astrocytomas or between glioblastomas and anaplastic astrocytomas.

Decoy receptor 3 immunostaining score was a useful marker for distinguishing anaplastic astrocytomas from glioblastomas

The binary logistic regression function for DcR3 (Omnibus test χ2 = 17.11, P < 0.001) was found to be:

Such that P > 0.5 indicated glioblastoma and P < 0.5 indicated anaplastic astrocytoma. The total DcR3 immunostaining score discriminated between anaplastic astrocytoma and glioblastoma with high sensitivity (93.8%), specificity (90.0%), and accuracy (92.3%) [Table 2]. Binary logistic regression showed that the percentage of stained TLR4 cells could discriminate between anaplastic astrocytoma and glioblastoma with high sensitivity (93.8%), low specificity (60%), and fair accuracy (80.8%) [Table 2]. However, ERK1/2 could not be used to distinguish anaplastic astrocytoma from glioblastoma [Table 2].
Table 2: The data of each immunostaining expression to discriminate between anaplastic astrocytoma and glioblastoma by Binary Logistic regression

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   Discussion Top

Astrocytoma is the most common primary brain tumor and is considered to have a multifactorial etiopathogenesis. Genetic polymorphisms, such as those affecting DNA repair, inflammation, and angiogenesis, and metabolic genes are related to brain carcinogenesis.[27] Cell proliferation is also considered to be an important factor in gliomagenesis and a correlation between cell cycle control and risk of glioma risk been confirmed in recent studies.[28],[29] The WHO grading system for gliomas depends on nuclear atypism, mitotic activity, and the presence of necrosis and microvascular hyperplasia.[30],[31],[32],[33] Various genetic alterations, such as TP53 and PTEN mutations, epidermal growth factor receptor gene amplification, and loss of chromosomes 7 and 10, may play a role in the tumorigenesis of astrocytomas.[34],[35]

Stereotactic biopsy is often performed for diagnostic purpose before treating patients whose imaging studies highly suggest glioma. Undoubtedly, the regional heterogeneity of glioblastoma is remarkable and poses challenges to histopathologic diagnosis on specimens obtained by stereotaxic needle biopsies. Indications cited for biopsy include diagnosis and/or the “inoperability” of the tumor. Despite this, stereotactic biopsy is frequently performed on patients harboring large gliomas that are exerting a significant mass effect, even though resection might be more appropriate and produce a more favorable result. Other patients often undergo a “staged” procedure, that is, biopsy followed by resection at a later date. However, stereotactic biopsy is frequently inaccurate in providing a correct diagnosis and is associated with additional risk and cost. If a stereotactic biopsy is performed, expert neuropathology consultation should be sought.[36] Approximately, two hundred individuals are newly diagnosed GBM annually in Taiwan. The current standard strategy for newly diagnosed GBM is surgical resection followed by adjuvant radiotherapy with temozolomide (TMZ). Target drug bevacizumab (Avastin) is used for the patients that are failure after receiving standard radiation therapy and TMZ or recurrent glioblastoma. Both Avastin and TMZ have shown efficacy in conjunction with radiation in the treatment of recurrent GBM, and Avastin been shown in vitro and in animal models to alter GBM cell migration.[37] Because according to the provisions of the National Health Insurance, both Avastin and TMZ are subject to prior review and approval prior to use by the Health Insurance Department in Taiwan. Hence, accurate diagnosis or reduce discrepancy in stereotactic biopsy is important for glioblastoma treatment. Thus, there is a need to develop biomarkers that will allow pathologists to make more accurate diagnosis in the stereotactic biopsy.

DcR3 belongs to the family of TNF receptors (TNFRs) and lacks a transmembrane domain in its sequence. It is a secreted 35-kDa protein and functions as a death decoy, inhibiting apoptosis mediated by the TNFR family. Frequent gene amplification has been detected in malignant tumors of the lung, colon, and brain.[5],[8],[38] Elevated DcR3 mRNA is associated with advanced-stage gastric cancer.[39] While serum DcR3 level is also elevated in renal cell cancer, gastric cancer, oral squamous cell carcinoma, and hepatocellular carcinoma.[6],[40],[41] In this study, the immunostaining scores of DcR3 are drastically increased in glioblastoma. By binary logistic regression analysis, the immunostaining score of DcR3 is a useful marker for discriminate anaplastic astrocytoma from glioblastoma (total accuracy, 92.3%). These findings support that escape from TNFR-mediated apoptosis involving DcR3 is important in gliomagenesis.

Pharmacological agents targeting the DcR3 protein may impede tumor progression in patients with astrocytoma, especially glioblastoma. In a recent study, DcR3 and ERK1/2 expression levels are significantly higher in patients with TNM stage II–IV gastric cancer. The expressions of DcR3 and ERK1/2 correlate with tumor invasion and TNM stage.[13] However, the study lacks data on the expression of IHC stains in gastric cancer patients. In the present study, ERK1/2 expression level cannot distinguish between glioblastoma and anaplastic astrocytoma.

A growing body of evidence indicates that chronic inflammation may be one of the most important factors contributing to tumor development and progression. Most solid tumors contain many nonmalignant cells, including immune and endothelial cells, which are important in inflammation. Inflammatory cells provide proteases that facilitate tumor invasion and matrix remodeling, along with chemokines, growth factors, and angiogenic and lymphangiogenic factors. TLRs are expressed on a variety of cell types, including immune cells, endothelial cells, cardiac myocytes, and intestinal cells. TLR4 on tumor cells is reported to play a role in immune surveillance and facilitate tumor growth and chemoresistance.[19] Its expression is found in various types of tumor cells. TLR4-MyD88 signaling may function upstream of NF-κB in cells involved in inflammation-associated cancer. Increases in the NF-κB activity in tumor microenvironment result in chronic inflammation and substantial pro-tumorigenic effects.[42] The results here suggest that TLR4 is significantly more highly expressed in glioblastomas than in diffuse or anaplastic astrocytomas. By binary logistic regression analysis, the percentage of stained tumor cells can discriminate between anaplastic astrocytoma and glioblastoma but only with a fair accuracy (80.8%).

   Conclusion Top

The overexpression of DcR3 in glioblastoma and the immunostaining scores of DcR3 suggest that DcR3 is a useful biomarker for distinguishing anaplastic astrocytoma from glioblastoma. This study is the first report to investigate the expressions of TLR4 and ERK1/2 in astrocytoma. Both TLR4 and ERK1/2 promote tumor growth in astrocytoma, while TLR4 overexpression may play an important role in tumor progression from Grade II to Grade III astrocytoma to glioblastoma. The expression of DcR3, TLR4, and ERK1/2 can be increased in reactive gliosis resulted from infections or inflammatory conditions. This is a possible limitation of our study.


This study was supported by a grant from Tri-Service General Hospital (TSGH-C102-072, TSGH-C101-009-S06, and TSGH-C102-009-S06) Taiwan, Republic of China.

Financial support and sponsorship

This study was supported by a grant from Tri-Service General Hospital (TSGH-C102-072, TSGH-C101-009-S06, and TSGH-C102-009-S06) Taiwan, Republic of China.

Conflicts of interest

There are no conflicts of interest.

   References Top

Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5-26.  Back to cited text no. 1
Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. Epidemiology of primary brain tumors: Current concepts and review of the literature. Neuro Oncol 2002;4:278-99.  Back to cited text no. 2
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Classification of Tumours of the Central Nervous System. Lyon: IARC Press; 2007. p. 8-172.  Back to cited text no. 3
Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 2004;36:1046-69.  Back to cited text no. 4
Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998;396:699-703.  Back to cited text no. 5
Wu Y, Han B, Sheng H, Lin M, Moore PA, Zhang J, et al. Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients. Int J Cancer 2003;105:724-32.  Back to cited text no. 6
Nishizaki T, Ozaki S, Harada K, Ito H, Arai H, Beppu T, et al. Investigation of genetic alterations associated with the grade of astrocytic tumor by comparative genomic hybridization. Genes Chromosomes Cancer 1998;21:340-6.  Back to cited text no. 7
Arakawa Y, Tachibana O, Hasegawa M, Miyamori T, Yamashita J, Hayashi Y. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol 2005;109:294-8.  Back to cited text no. 8
Han S, Li Z, Master LM, Master ZW, Wu A. Exogenous IGFBP-2 promotes proliferation, invasion, and chemoresistance to temozolomide in glioma cells via the integrin ß1-ERK pathway. Br J Cancer 2014;111:1400-9.  Back to cited text no. 9
Nicoletti NF, Erig TC, Zanin RF, Pereira TC, Bogo MR, Campos MM, et al. Mechanisms involved in kinin-induced glioma cells proliferation: The role of ERK1/2 and PI3K/Akt pathways. J Neurooncol 2014;120:235-44.  Back to cited text no. 10
Pan HC, Jiang Q, Yu Y, Mei JP, Cui YK, Zhao WJ. Quercetin promotes cell apoptosis and inhibits the expression of MMP-9 and fibronectin via the AKT and ERK signalling pathways in human glioma cells. Neurochem Int 2015;80:60-71.  Back to cited text no. 11
Wang J. Expression of ERK1/2 protein in cholangiocarcinoma relation with TNM stages. Shandong Med 2008;48:60-1.  Back to cited text no. 12
Yang D, Fan X, Yin P, Wen Q, Yan F, Yuan S, et al. Significance of decoy receptor 3 (Dcr3) and external-signal regulated kinase 1/2 (Erk1/2) in gastric cancer. BMC Immunol 2012;13:28.  Back to cited text no. 13
Kim S, Fotiadu A, Kotoula V. Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. Clin Immunol 2005;115:286-94.  Back to cited text no. 14
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783-801.  Back to cited text no. 15
Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 2007;13:460-9.  Back to cited text no. 16
Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4:499-511.  Back to cited text no. 17
Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335-76.  Back to cited text no. 18
Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 2005;65:5009-14.  Back to cited text no. 19
He W, Liu Q, Wang L, Chen W, Li N, Cao X. TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 2007;44:2850-9.  Back to cited text no. 20
Szczepanski MJ, Czystowska M, Szajnik M, Harasymczuk M, Boyiadzis M, Kruk-Zagajewska A, et al. Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res 2009;69:3105-13.  Back to cited text no. 21
Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, Nowak-Markwitz E, et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene 2009;28:4353-63.  Back to cited text no. 22
O'Neill LA. When signaling pathways collide: Positive and negative regulation of toll-like receptor signal transduction. Immunity 2008;29:12-20.  Back to cited text no. 23
Sarrazy V, Vedrenne N, Billet F, Bordeau N, Lepreux S, Vital A, et al. TLR4 signal transduction pathways neutralize the effect of Fas signals on glioblastoma cell proliferation and migration. Cancer Lett 2011;311:195-202.  Back to cited text no. 24
Tewari R, Choudhury SR, Ghosh S, Mehta VS, Sen E. Involvement of TNFα-induced TLR4-NF-κB and TLR4-HIF-1α feed-forward loops in the regulation of inflammatory responses in glioma. J Mol Med (Berl) 2012;90:67-80.  Back to cited text no. 25
Lin CK, Tsai WC, Lin YC, Yu JC. Biomarkers distinguishing mammary fibroepithelial neoplasms: A tissue microarray study. Appl Immunohistochem Mol Morphol 2014;22:433-41.  Back to cited text no. 26
Gu J, Liu Y, Kyritsis AP, Bondy ML. Molecular epidemiology of primary brain tumors. Neurotherapeutics 2009;6:427-35.  Back to cited text no. 27
Pinto GR, Yoshioka FK, Silva RL, Clara CA, Santos MJ, Almeida JR, et al. Prognostic value of TP53 Pro47Ser and Arg72Pro single nucleotide polymorphisms and the susceptibility to gliomas in individuals from Southeast Brazil. Genet Mol Res 2008;7:207-16.  Back to cited text no. 28
Rajaraman P, Wang SS, Rothman N, Brown MM, Black PM, Fine HA, et al. Polymorphisms in apoptosis and cell cycle control genes and risk of brain tumors in adults. Cancer Epidemiol Biomarkers Prev 2007;16:1655-61.  Back to cited text no. 29
Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol 1993;3:255-68.  Back to cited text no. 30
Gagner JP, Law M, Fischer I, Newcomb EW, Zagzag D. Angiogenesis in gliomas: Imaging and experimental therapeutics. Brain Pathol 2005;15:342-63.  Back to cited text no. 31
Nelson SJ, Cha S. Imaging glioblastoma multiforme. Cancer J 2003;9:134-45.  Back to cited text no. 32
Cha S. Update on brain tumor imaging. Curr Neurol Neurosci Rep 2005;5:169-77.  Back to cited text no. 33
Lang FF, Miller DC, Koslow M, Newcomb EW. Pathways leading to glioblastoma multiforme: A molecular analysis of genetic alterations in 65 astrocytic tumors. J Neurosurg 1994;81:427-36.  Back to cited text no. 34
von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 1993;3:19-26.  Back to cited text no. 35
Jackson RJ, Fuller GN, Abi-Said D, Lang FF, Gokaslan ZL, Shi WM, et al. Limitations of stereotactic biopsy in the initial management of gliomas. Neuro Oncol 2001;3:193-200.  Back to cited text no. 36
Shields LB, Kadner R, Vitaz TW, Spalding AC. Concurrent bevacizumab and temozolomide alter the patterns of failure in radiation treatment of glioblastoma multiforme. Radiat Oncol 2013;8:101.  Back to cited text no. 37
Mild G, Bachmann F, Boulay JL, Glatz K, Laffer U, Lowy A, et al. DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer. Int J Cancer 2002;102:254-7.  Back to cited text no. 38
Wu Y, Guo E, Yu J, Xie Q. High DcR3 expression predicts stage pN2-3 in gastric cancer. Am J Clin Oncol 2008;31:79-83.  Back to cited text no. 39
Macher-Goeppinger S, Aulmann S, Wagener N, Funke B, Tagscherer KE, Haferkamp A, et al. Decoy receptor 3 is a prognostic factor in renal cell cancer. Neoplasia 2008;10:1049-56.  Back to cited text no. 40
Tu HF, Liu CJ, Liu SY, Chen YP, Yu EH, Lin SC, et al. Serum decoy receptor 3 level: A predictive marker for nodal metastasis and survival among oral cavity cancer patients. Head Neck 2011;33:396-402.  Back to cited text no. 41
Lee CH, Wu CL, Shiau AL. Toll-like receptor 4 signaling promotes tumor growth. J Immunother 2010;33:73-82.  Back to cited text no. 42

Correspondence Address:
Dr. Dueng-Yuan Hueng
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei
Republic of China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.188122

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