|Year : 2016 | Volume
| 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
Chih-Kung Lin1, Chun-Chieh Ting2, Wen-Chiuan Tsai3, Yuan-Wu Chen4, Dueng-Yuan Hueng5
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 Publication||10-Aug-2016|
| Abstract|| |
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 2019 Jun 24];59:294-300. Available from: http://www.ijpmonline.org/text.asp?2016/59/3/294/188122
Yuan-Wu Chen, Dueng-Yuan Hueng
These authors contributed equally to this work
| Introduction|| |
The primary brain tumor is one of the leading causes of cancer-related mortality. The most common primary central nervous system tumor is glioma, followed by meningioma. The World Health Organization pathological grading is an important criterion used to predict therapeutic outcome and prognosis. 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.
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. 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. 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. Arakawa et al. reported frequent gene amplification and overexpression of DcR3 in glioblastoma.
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. 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. 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. 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., 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. 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. In mammals, the TLR family consists of at least 12 members expressed predominantly on the surface of macrophages and various immune cells. LPS is specifically recognized by TLR4., More recent studies have demonstrated TLRs expressions in a broad variety of tumor tissues and tumor cell lines.,,, 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. 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. 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.
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|| |
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).
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|| |
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|| |
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. 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., The WHO grading system for gliomas depends on nuclear atypism, mitotic activity, and the presence of necrosis and microvascular hyperplasia.,,, 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.,
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. 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. 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.,, Elevated DcR3 mRNA is associated with advanced-stage gastric cancer. While serum DcR3 level is also elevated in renal cell cancer, gastric cancer, oral squamous cell carcinoma, and hepatocellular carcinoma.,, 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. 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. 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. 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|| |
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.
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Dr. Dueng-Yuan Hueng
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei
Republic of China
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]
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