|Year : 2019 | Volume
| Issue : 1 | Page : 35-43
Low expression of pentraxin 3 and nuclear factor-like 2 implying a relatively longer overall survival time in gliomas
Hui-Hsuan Ke1, Dueng-Yuan Hueng2, Wen-Chiuan Tsai3
1 Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan
2 Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3 Department of Pathology, Tri-Service General Hospital; Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, Taiwan
|Date of Submission||31-Aug-2018|
|Date of Decision||08-Jan-2019|
|Date of Acceptance||16-Jan-2019|
|Date of Web Publication||22-Feb-2019|
Dr. Wen-Chiuan Tsai
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Neihu 114, Taipei
Source of Support: None, Conflict of Interest: None
Pentraxin 3 (PTX3) and nuclear factor-like 2 (Nrf2) are known to induce tumor progression in certain malignancies but act as tumor suppressors in other human neoplasms. In this study, we not only tested the association between PTX3 expression and the World Health Organization (WHO) tumor grading system but also evaluated overall patient survival under variable expression of PTX3 and Nrf2 in primary brain tumors (PBTs). Immunohistochemistry (IHC) was performed for PTX3 and Nrf2 in 10 nonneoplastic brain tissues and 197 PBTs. IHC scores were calculated as the degree of cytoplasmic and nuclear PTX3 and Nrf2 staining intensity multiplied by the percentage of positively stained tissue area. The correlation between PTX3 and Nrf2 IHC scores and tumor grades as well as overall survival time was analyzed by Pearson product-moment correlation and Kaplan–Meier estimate. According to our results, PTX3 IHC scores showed a positive correlation with the WHO grades of gliomas and meningiomas. In addition, we also observed that higher PTX3 expression was associated with poor prognosis in gliomas but not in meningiomas. The concordance between PTX3 and Nrf2 immunohistochemistry (IHC) scores was analyzed using linear regression analysis. When compared to groups with high IHC scores for either one or both biomarkers, gliomas with low expression of both PTX3 and Nrf2 showed significantly better prognosis. In conclusion, we demonstrated that high PTX3 expression implied aggressive tumor behavior and shorter survival time in glioma patients. In addition, our results also showed that gliomas with low PTX3 and Nrf2 immunohistochemical expression could imply a longer overall survival time. Therefore, the combination of lower PTX3 and Nrf2 immunohistochemical expression may be important in offering a better prognosis in gliomas, although the detailed mechanism is yet to be elucidated.
Keywords: Glioma, immunohistochemical staining scores, meningioma, nuclear factor-like 2, pentraxin 3
|How to cite this article:|
Ke HH, Hueng DY, Tsai WC. Low expression of pentraxin 3 and nuclear factor-like 2 implying a relatively longer overall survival time in gliomas. Chin J Physiol 2019;62:35-43
|How to cite this URL:|
Ke HH, Hueng DY, Tsai WC. Low expression of pentraxin 3 and nuclear factor-like 2 implying a relatively longer overall survival time in gliomas. Chin J Physiol [serial online] 2019 [cited 2019 Sep 18];62:35-43. Available from: http://www.cjphysiology.org/text.asp?2019/62/1/35/252836
| Introduction|| |
The two most common types of primary brain tumors (PBTs) are gliomas and meningiomas, which are classified by the World Health Organization (WHO) into Grades I–IV and I–III, respectively. Clinical manifestations of PBTs include headache, nausea, involuntary seizure, paraplegia, and even death due to tumor mass effect and resulting neuroelectric physiological disturbances. Curative treatment for PBTs is currently limited to complete tumor resection. However, brain tissue loss after extensive tumor resection may also induce severe complications and mortality. Recent literature has shown the benefits of adjuvant radiotherapy or chemotherapy after subtotal tumor resection, as well as reductions in the recurrence rates of gliomas and meningiomas., Certainly, severe delayed complications also arise from intracranial radiotherapy and chemotherapy, including cerebral and spinal radionecrosis, leukoencephalopathy, headache and seizure, cognitive dysfunction, aseptic meningitis, and primary central nervous system (CNS) non-Hodgkin's lymphoma. Therefore, uncovering molecular targets specific to gliomas has become important in novel treatment methods, including isocitrate dehydrogenase 1/2 (IDH 1/2), TP53, alpha-thalassemia/mental retardation syndrome X-linked, and O-6-methylguanine-DNA methyltransferase (MGMT). Selective immune checkpoint inhibitors have also been evaluated as novel target therapies. However, many are still undergoing clinical trials. Since most PBTs lack these well-known transformation initiating factors, it is believed that PBT is a multifactorial neoplasm rather than a single risk factor disease.
Reactive oxidative species and inflammatory response are two important elements conducive to glioma formation., Pentraxin 3 (PTX3), a member of the pentraxin family, is a component of the humoral immune system., The complement cascade response is regulated by C1q, ficolin-1, and factor H that are activated by PTX3 expression., PTX3 production during the inflammatory response depends on tumor necrosis factor-alpha and interleukin-1 beta secreted by neutrophils, macrophages, fibroblasts, smooth muscle cells, and endothelial cells. It has been hypothesized that PTX3 deficiency induces angiogenesis, proliferation of tumor-activating macrophages, oxidative DNA damage, and TP53 mutation., Therefore, PTX3 plays an important role in the inhibition of carcinogenesis. On the contrary, increased PTX3 expression has been shown to positively correlate with tumor progression and poor prognosis of gliomas, lung cancer, and prostatic, pancreatic, gastric, breast  malignancies, as well as head-and-neck squamous cell carcinomas. The detailed molecular mechanism behind the role of PTX3 in carcinogenesis is yet to be elucidated.
Nuclear factor-like 2 (Nrf2) is a transcription factor involved in key cellular signaling pathways, including nuclear factor-κB,, p53,, and mTOR. Thus, it has been reasoned that Nrf2 assumes properties of anti-inflammation, detoxification, and tumor suppression., Ironically, overexpression of Nrf2 has been linked to poor survival rates and drug resistance in many human malignancies, including gliomas, endometrial carcinomas,, and pancreatic cancers., Recent studies have demonstrated that PTX3 and Nrf2 act as inducers of anti-apoptotic proteins, epidermal growth factor receptor (EGFR), and Bcl-xL, respectively., The divergent roles of PTX3 and Nrf2 in cancer progression and prevention might depend on cellular resources and cancer cell differentiation.,
In our previous study, we observed that higher Nrf2 expression correlated with advanced malignancies and poor prognosis. In addition, Tung et al. also explained the suppression of PTX3 could inhibit glioma cell proliferation and invasion in both in vitro and in vivo studies. In this study, we demonstrated that higher expression of PTX3 positively correlated with the WHO grades of gliomas and meningiomas. In addition, most gliomas with PTX3 overexpression also exhibited higher Nrf2 expression. Prognosis of tumors with high levels of both Nrf2 and PTX3 was worse than those immunostained for only one or neither of the two proteins. These findings may provide valuable information to clinical physicians and pathologists for accurately predicting patient survival and tumor behavior.
| Materials and Methods|| |
Tissue microarray construction
Paraffin-embedded tumor tissues were obtained, and two sets of tissue microarray slides were constructed. The tissue microarrays comprised 86 gliomas and 111 meningiomas belonging to various WHO grades. The histological differentiation of tumors was assessed at Tri-Service General Hospital. A core measuring 2 mm in diameter was taken from a selected area of each paraffin-embedded tumor tissue to construct corresponding microarray. Patient samples were obtained from 1991 to 2005. None of the patients had received radiation or chemotherapy before surgery. The pathological diagnosis of each case was independently reviewed by at least two experienced clinical pathologists. The histopathological differentiation of these brain tumors was determined according to the criteria of the WHO tumor classification. This study, numbered as 098-05-295, was approved by Institutional Review Board, Tri-Service General Hospital.
Tissue microarray sections were dewaxed in xylene, rehydrated in alcohol, and immersed in 3% hydrogen peroxide for 5 min to suppress endogenous peroxidase activity. Antigen retrieval was performed by heating (100°C) each section for 30 min in 0.01 M sodium citrate buffer (pH 6.0). After three washes (each for 5 min in phosphate-buffered saline [PBS]), sections were incubated for 1 h at room temperature with polyclonal mouse anti-rabbit PTX3 antibody (1:100, Thermo Fisher Scientific, MA, USA) and polyclonal rabbit anti-human Nrf2 antibody (1:50, Santa Cruz, CA, USA) diluted in PBS. After three washes (each for 5 min in PBS), tissue sections were incubated with biotin-labeled secondary immunoglobulin (1:100, DAKO, Glostrup, Denmark) for 1 h at room temperature. After three additional washes, peroxidase activity was developed with 3-amino-9-ethylcarbazole chromogenic substrate (DAKO, Glostrup, Denmark) at room temperature. To evaluate PTX3 and Nrf2 expression, the IHC scores were calculated as the intensity of cytoplasmic and nuclear staining multiplied by the percentage of positively stained areas. The tissue microarray slides showed uniform staining as observed in the original paraffin-embedded specimens. The intensity of PTX3 and Nrf2 staining was scored on a scale of 0 (absence of staining), 1+ (weak staining), 2+ (moderate staining), and 3+ (strong staining), as previously described. Tissues with <5% of tumor cells with cytoplasmic staining were considered IHC negative. Since minimizing technique bias, twice of PTX3 and Nrf2 IHC stains were performed on glioma and meningioma tissue microarrays in this study. In addition, normal duodenal mucosa and endometrial adenocarcinoma tissue were used as positive controls for PTX3 and Nrf2 expression, respectively. Furthermore, some IHC biomarkers were immunostained using above protocols to reclassify all included gliomas based on the updated WHO grading system for CNS tumors and to detect putative PTX3-related factors. These biomarkers were detected using following: monoclonal mouse anti-human IDH1 R132H antibody (1:100, Dianova, Hamburg, Germany), polyclonal rabbit anti-human alpha-thalassemia/mental retardation syndrome X-linked antibody (1:100, ATLAS, Stockholm, Sweden), polyclonal rabbit anti-human histone H3, K27M mutant (H3 K27M) antibody (1:100, Millipore, California, USA), polyclonal rabbit anti-human trimethyl-histone H3, Lys27 (H3 K27 me3) antibody (1:1000, Millipore, California, USA), monoclonal mouse anti-human EGFR antibody (1:100, Thermo Fisher Scientific, Massachusetts, USA), monoclonal mouse anti-human EGFRvIII antibody (1:100, Absolute, Oxford, UK), polyclonal rabbit anti-human AXL antibody (1:50, Sigma-Aldrich, MO, USA), monoclonal mouse anti-human phospho-AXL (Y779) antibody (1:50, R and D system, Minnesota, USA), monoclonal mouse anti-human p53 antibody (1:100, DAKO, CA, USA), monoclonal mouse anti-human neurofilament antibody (1:100, DAKO, CA, USA), monoclonal mouse anti-human platelet-derived growth factor receptor-alpha (PDGFRA) antibody (1:100, Santa Cruz, Texas, USA), polyclonal rabbit anti-human neurofibromin (NF1) antibody (1:100, Abcam, Cambridge, UK), and polyclonal rabbit anti-human nuclear hormone receptor 77 (NUR77) antibody (1:100, Abcam, Cambridge, UK) diluted in PBS. All of the included antibodies except PTX3 and Nrf2 were performed by IHC stain on glioma tissue microarray for one time.
Statistical analysis was performed using the Student's t-test to detect the variation of PTX3 IHC scores between nonneoplastic brain tissues and low-to-high-grade PBTs. The Pearson product-moment correlation test was employed to analyze the relationship between PTX3 expression and the WHO grading system for gliomas and meningiomas. We also performed univariate and multivariate analysis to evaluate PTX3 expression-related factors. Finally, the survival time was calculated from the date of surgery to the date of death. Patients with 5 years of follow-up, including 60 meningioma patients and 67 glioma patients, were divided into two groups based on whether they were above or below the cutoff point set for PTX3 and Nrf2 IHC scores. Statistical analysis of overall survival time was performed using the Kaplan–Meier survival estimate. To evaluate the independent prognostic factors in gliomas, all 67 glioma cases with 5 years of follow-up period were included in multivariate analysis.
| Results|| |
Pentraxin 3 expression in nonneoplastic brain tissues and gliomas
Of all glial cell neoplasms, 1 pilocytic astrocytoma; 2 diffuse astrocytoma, IDH-mutant; 10 diffuse astrocytomas, IDH-wild type; 3 anaplastic astrocytomas, IDH-mutant; 7 anaplastic astrocytomas, IDH-wild type; 6 glioblastomas, IDH-mutant; 30 glioblastomas, IDH-wild type; 13 diffuse midline gliomas, H3 K27M mutant; 2 oligodendrogliomas, IDH-mutant; 2 oligodendrogliomas, IDH-wild type; 3 anaplastic oligodendrogliomas, IDH-mutant; and 7 anaplastic oligodendrogliomas, IDH-wild type were included in this study. We also included 86 benign meningiomas, 18 atypical meningiomas, and 7 anaplastic meningiomas in our tissue microarray. To compare PTX3 expression levels in nonneoplastic brain tissues and PBTs, we evaluated PTX3 IHC scores in tissue microarrays. Most of the nonneoplastic brain tissues showed negative to weak staining. High PTX3 expression was observed in nearly all astrocytomas. The average IHC scores of Grades I to IV astrocytomas were as follows: pilocytic astrocytoma: 10; diffuse astrocytoma, IDH1-mutant, and IDH1-wild type: 25 and 28.85; anaplastic astrocytoma, IDH1-mutant, and IDH1-wild type: 31.67 and 37.86; glioblastoma, IDH1-mutant, and IDH1-wild type: 47.5 and 64.14; oligodendroglioma, NOS: 26.25; anaplastic astrocytoma, NOS: 36; and diffuse midline glioma, H3 K27M-mutant: 90.38 [Table 1]. We observed positive correlation between PTX3 expression and the WHO grades of astrocytomas [P = 0.002, [Table 1]. Similarly, the average PTX3 staining scores of all Grade II and Grade III oligodendrogliomas were higher than that of nonneoplastic brain tissues. However, no clear statistical trend was observed for the WHO grades of oligodendrocytic neoplasms [P = 0.693, [Table 1]. In general, we observed that average IHC scores positively correlated with the WHO grades for all gliomas (P = 0.001) [Table 1] and [Figure 1]. The univariate analysis showed that gender, tumor grade, H3 K27M, and AXL mutation were risk factors for PTX3 overexpression. Multivariate analysis revealed that gender, tumor grade, IDH1-R132H, loss of MGMT expression, and overexpression of EGFRvIII, NF1, AXL, p-AXL, NUR77, and loss of H3 K27 me3 were the putative risk factors associated with PTX3 overexpression [Table 2].
|Figure 1: Representative hematoxylin and eosin staining of 10 nonneoplastic brain tissue (a), 1 pilocytic astrocytoma (b), 12 diffuse astrocytomas (c), 10 anaplastic astrocytomas (d), and 36 glioblastomas (e); and representative immunohistochemical staining of pentraxin 3 in 10 nonneoplastic brain tissue (f), 1 pilocytic astrocytoma (g), 12 diffuse astrocytoma (h), 10 anaplastic astrocytoma (i), and 36 glioblastomas (j). Twice of pentraxin 3 immunohistochemical staining on glioma tissue microarrays were performed in this study (×400)|
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|Table 2: Univariate and multivariate analysis of risk factors associated with a positive PTX3 expression in 86 gliomas|
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Pentraxin 3 expression in normal meninges and meningiomas
PTX3 expression in meningiomas has not been well established in previous literature. The immunohistochemical staining for PTX3 in normal meninges revealed negative results. In contrast, most meningiomas revealed focal to extensive PTX3 expression. Our data demonstrated that PTX3 IHC scores positively correlated with the WHO grades of meningiomas (P < 0.001) [Table 3] and [Figure 2].
|Table 3: The correlation of the average PTX3 immunohistochemistry staining and clinicopathological parameters of 111 meningiomas|
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|Figure 2: Representative hematoxylin and eosin staining of 86 benign meningiomas (a), 18 atypical meningiomas (b), and 7 anaplastic meningiomas (c); and representative immunohistochemical staining of pentraxin 3 in 86 benign meningiomas (d), 18 atypical meningiomas (e), and 7 anaplastic meningiomas (f). Twice of pentraxin 3 immunohistochemical staining were performed on meningioma tissue microarrays in this study (×400)|
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Discrimination between low-grade and high-grade primary brain tumors by pentraxin 3 immunohistochemical staining
Since there are many treatment methods and variable prognoses offered for various grades of gliomas, we performed Student's t-test to assess the suitability of PTX3 immunohistochemical staining in distinguishing high- and low-grade gliomas. The WHO Grades I and II gliomas were classified as low-grade tumors, whereas Grades III and IV gliomas were considered high-grade tumors. We observed that IHC scores for PTX3 in high-grade gliomas were significantly higher than those of low-grade tumors [P < 0.001, [Figure 3]a.
|Figure 3: Comparison of pentraxin 3 immunohistochemical staining scores between 10 nonneoplastic brain tissues, 17 low-grade gliomas, and 69 high-grade gliomas (a); and comparison of pentraxin 3 immunohistochemical staining scores between 86 benign meningiomas, 18 atypical meningiomas, and 7 anaplastic meningiomas (b). The statistical method was performed by Student's t-test. Twice of pentraxin 3 immunohistochemical stains were performed in this study. Twice of pentraxin 3 immunohistochemical staining on glioma and meningioma tissue microarrays were performed in this study. The average immunohistochemical staining scores of each case were reviewed by two doctors. These error bars mean standard deviation (P < 0.05 implies statistical significance)|
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The WHO Grade I meningiomas are defined as benign tumors based on predictable tumor behavior and slow disease progression. In contrast, high recurrence rates and aggressive tumor behavior are found in Grades II and III meningiomas. Therefore, precise classification is important for these brain malignancies. In this study, high-grade atypical and anaplastic meningiomas showed significantly higher PTX3 IHC scores [P < 0.001, [Figure 3]b compared to benign meningiomas. Therefore, PTX3 immunohistochemical staining may be a useful tool for clinical physicians and pathologists to precisely evaluate tumor characteristics and make better prognosis.
The concordance of pentraxin 3 and nuclear factor-like 2 immunohistochemical staining in gliomas
PTX3 and Nrf2 both exhibit anti-apoptotic and anti-inflammatory properties in tumorigenesis. Therefore, we evaluated the interaction between these biomarkers in PBTs. Linear regression analysis showed that high PTX3 expression in gliomas was associated with high Nrf2 expression [R = 0.663, [Figure 4]a. However, the relationship between PTX3 and Nrf2 was not statistically significant [R = 0.121, [Figure 4]b.
|Figure 4: Linear regression analysis was performed on pentraxin 3 and Nrf2 immunohistochemical staining scores in 86 gliomas (a) and 111 meningiomas (b). The statistical method was performed by linear regression test. Twice of pentraxin 3 and Nrf2 immunohistochemical staining on glioma and meningioma tissue microarrays were performed in this study. The average immunohistochemical staining scores were reviewed by two doctors|
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The relationship between pentraxin 3 and nuclear factor-like 2 expression and overall survival time in gliomas
Of the included cases, 60 meningiomas and 67 gliomas with 5 years of follow-up were analyzed, after dividing them into two groups based on PTX3 immunostaining scores. To have equal number of patients in each high or low expression group, the cutoff point for the PTX3 immunostaining score was set at 30 for gliomas and 70 for meningiomas. As shown in [Figure 5]a and [Figure 5]b, higher PTX3 immunostaining scores were significantly associated with shorter overall survival in glioma patients but not in meningioma patients. Furthermore, our multivariate analysis indicated that old age, PTX3 overexpression, loss of alpha-thalassemia/mental retardation syndrome X-linked expression, and PDGFRA activation might be the risk factors related to poor prognosis [Table 4]. According to our previous study, higher Nrf2 expression was also associated with shorter survival time in gliomas. For evaluating the concordance of PTX3 and Nrf2 expression with prognosis in gliomas, we divided gliomas into four groups based on the IHC scores, including low PTX3 (PTX3low) and low Nrf2 (Nrf2low) (PTX3 < 30 and Nrf2 < 70), high PTX3 (PTX3high) and Nrf2low (PTX3 > 30 and Nrf2 < 70), PTX3low, and high Nrf2 (Nrf2high) (PTX3 < 30 and Nrf2 > 70), as well as PTX3high and Nrf2high (PTX3 > 30 and Nrf2 > 70). Our results revealed that PTX3low and Nrf2low groups exhibited the best prognosis among all groups [Figure 6]. Furthermore, there was no significant difference in survival time between the remaining groups.
|Figure 5: Relationship between overall survival rate and pentraxin 3 immunohistochemical staining scores in 67 gliomas (a) and 60 meningiomas (b). Survival rates were analyzed using the Kaplan–Meier survival test. Twice of pentraxin 3 immunohistochemical staining on glioma and meningioma tissue microarrays were performed in this study. The average immunohistochemical staining scores of each case were reviewed by two doctors (P < 0.05 implies statistical significance)|
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|Figure 6: Relationship between pentraxin 3 and Nrf2 expression in 67 gliomas with overall survival time. Survival rates were analyzed using the Kaplan–Meier survival test. Twice of pentraxin 3 and Nrf2 immunohistochemical staining on glioma tissue microarrays were performed in this study. The average immunohistochemical staining scores of each case were reviewed by two doctors (P < 0.05 implies statistical significance)|
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| Discussion|| |
A recent study  demonstrated that suppression of PTX3 was able to induce cell cycle arrest and impair glioma cell proliferation. Consistent with this study, our results demonstrated that PTX3 expression not only correlated with advanced tumor grades but it was also associated with poor prognosis in gliomas. In addition, we demonstrated strong and extensive expression of PTX3 in high-grade meningiomas. The application of PTX3 immunohistochemical staining can be a useful tool to predict tumor recurrence and invasive behavior in gliomas and meningiomas. Besides, the discrimination between brain tumors and adjacent gliosis is not easy due to similar histological appearance. Our data suggest that PTX3 expression can assist pathologists to evaluate tumor margin and clearance more accurately based on the differences in the intensities of PTX3 immunohistochemical staining between nonneoplastic brain tissues and PBTs.
PTX3 has been viewed as an oncosuppressor in several malignancies in the past literature due to its role in inhibiting complement-dependent, inflammation-promoting pathways, cell-matrix interaction, and tumor angiogenesis. In this study, the phenomenon of PTX3 overexpression was frequently observed in high-grade gliomas and meningiomas with poor prognosis, which suggests that PTX3 may be, instead, an important contributor to tumor cell proliferation and invasion. Although the detailed mechanism of the oncogenic role of PTX3 is still unclear, a possible explanation is that the modulation of cytotoxic inflammation by PTX3 could possibly decrease the strength of humoral immunity against tumor invasion. It is also reported  that the activation of EGFR by PTX3 might be a likely mechanism that promotes cancer cell metastasis. According to previous studies, the “bright side” of Nrf2 depends upon antioxidants and suppression of tumor-initiating inflammation. In contrast, the “dark side” of Nrf2 emphasizes on the cytoprotective characteristics of tumor cells, which prevent endogenous reactive oxygen species generation and increase chemoresistance. Although the association between PTX3 and Nrf2 is not well-established, both of them effectively protect cancer cells from therapeutic damage. Therefore, we tested the concordance between PTX3 and Nrf2 expression in gliomas. It was observed that low expression of both biomarkers indicated better tumor prognosis as compared to their individual or combined overexpression.
Higher expression of PTX3 was correlated with advanced astrocytomas for gliomas but not for oligodendrogliomas. Although increased PTX3 IHC scores were associated with high-grade tumors for the latter two types, the data were not statistically significant. A possible explanation is that inadequate number of oligodendroglioma cases was included in the study. Similarly, when compared to benign meningiomas, higher PTX3 IHC scores correlated with advanced tumor grades in most of the meningeal neoplasms although no significant difference in PTX3 expression was found between WHO Grades II and III tumors. According to the WHO classification of meningiomas, discrimination between atypical and anaplastic meningiomas requires distinguishing mitotic structures based on histological analysis. Therefore, PTX3 immunostaining could effectively help pathologists to determine WHO grades of gliomas and meningiomas more easily and accurately.
The current study demonstrated that PTX3 is a reliable predictor of WHO tumor grade and behavior in gliomas and meningiomas. Although the detailed mechanism still requires further elucidation, the phenomenon of concordance between PTX3 and Nrf2 expression in aggressive tumors may imply key oncogenic interactions between these two factors. Furthermore, the suppression of both PTX3 and Nrf2 revealed longer overall patient survival time as compared to individual expression of either PTX3 or Nrf2 in gliomas. The application of PTX3 and Nrf2 immunostaining could be particularly beneficial toward making better prognosis, due to its ability to identify aggressive tumor behavior in gliomas when either one or both biomarkers stain positively. In the future, both PTX3 and Nrf2 may represent potential therapeutic targets to improve overall survival in glioma patients.
Financial support and sponsorship
This study was financially supported by Tri-Service General Hospital (TSGH-C107-073-059, TSGH-C107-190) and National Defense Medical Center, Taiwan, R.O.C. (MAB-108-081).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC Press; 2016. p. 16-122.
Klinger DR, Flores BC, Lewis JJ, Hatanpaa K, Choe K, Mickey B, et al.
Atypical meningiomas: Recurrence, reoperation, and radiotherapy. World Neurosurg 2015;84:839-45.
Viaccoz A, Lekoubou A, Ducray F. Chemotherapy in low-grade gliomas. Curr Opin Oncol 2012;24:694-701.
Lee AW, Foo W, Chappell R, Fowler JF, Sze WM, Poon YF, et al.
Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1998;40:35-42.
Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY, et al.
CNS complications of radiotherapy and chemotherapy. Lancet 2009;374:1639-51.
Graus F, René R. Clinical and pathological advances on central nervous system paraneoplastic syndromes. Rev Neurol (Paris) 1992;148:496-501.
Sierra del Rio M, Rousseau A, Soussain C, Ricard D, Hoang-Xuan K. Primary CNS lymphoma in immunocompetent patients. Oncologist 2009;14:526-39.
Chen R, Cohen AL, Colman H. Targeted therapeutics in patients with high-grade gliomas: Past, present, and future. Curr Treat Options Oncol 2016;17:42.
Tan AC, Heimberger AB, Menzies AM, Pavlakis N, Khasraw M. Immune checkpoint inhibitors for brain metastases. Curr Oncol Rep 2017;19:38.
Rinaldi M, Caffo M, Minutoli L, Marini H, Abbritti RV, Squadrito F, et al.
ROS and brain gliomas: An overview of potential and innovative therapeutic strategies. Int J Mol Sci 2016;17. pii: E984.
Roesch S, Rapp C, Dettling S, Herold-Mende C. When immune cells turn bad-tumor-associated microglia/macrophages in glioma. Int J Mol Sci 2018;19. pii: E436.
Presta M, Camozzi M, Salvatori G, Rusnati M. Role of the soluble pattern recognition receptor PTX3 in vascular biology. J Cell Mol Med 2007;11:723-38.
Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 2005;23:337-66.
Bottazzi B, Vouret-Craviari V, Bastone A, De Gioia L, Matteucci C, Peri G, et al.
Multimer formation and ligand recognition by the long pentraxin PTX3. Similarities and differences with the short pentraxins C-reactive protein and serum amyloidPcomponent. J Biol Chem 1997;272:32817-23.
Deban L, Jarva H, Lehtinen MJ, Bottazzi B, Bastone A, Doni A, et al.
Binding of the long pentraxin PTX3 to factor H: Interacting domains and function in the regulation of complement activation. J Immunol 2008;181:8433-40.
Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, et al.
PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 2015;160:700-14.
Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis 2009;30:1073-81.
Locatelli M, Ferrero S, Martinelli Boneschi F, Boiocchi L, Zavanone M, Maria Gaini S, et al.
The long pentraxin PTX3 as a correlate of cancer-related inflammation and prognosis of malignancy in gliomas. J Neuroimmunol 2013;260:99-106.
Infante M, Allavena P, Garlanda C, Nebuloni M, Morenghi E, Rahal D, et al.
Prognostic and diagnostic potential of local and circulating levels of pentraxin 3 in lung cancer patients. Int J Cancer 2016;138:983-91.
Stallone G, Cormio L, Netti GS, Infante B, Selvaggio O, Fino GD, et al.
Pentraxin 3: A novel biomarker for predicting progression from prostatic inflammation to prostate cancer. Cancer Res 2014;74:4230-8.
Kondo S, Ueno H, Hosoi H, Hashimoto J, Morizane C, Koizumi F, et al.
Clinical impact of pentraxin family expression on prognosis of pancreatic carcinoma. Br J Cancer 2013;109:739-46.
Choi B, Lee EJ, Song DH, Yoon SC, Chung YH, Jang Y, et al.
Elevated pentraxin 3 in bone metastatic breast cancer is correlated with osteolytic function. Oncotarget 2014;5:481-92.
Choi B, Lee EJ, Park YS, Kim SM, Kim EY, Song Y, et al.
Pentraxin-3 silencing suppresses gastric cancer-related inflammation by inhibiting chemotactic migration of macrophages. Anticancer Res 2015;35:2663-8.
Chang WC, Wu SL, Huang WC, Hsu JY, Chan SH, Wang JM, et al.
PTX3 gene activation in EGF-induced head and neck cancer cell metastasis. Oncotarget 2015;6:7741-57.
Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, et al.
KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 2009;36:131-40.
Kim JE, You DJ, Lee C, Ahn C, Seong JY, Hwang JI, et al.
Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell Signal 2010;22:1645-54.
Bui CB, Shin J. Persistent expression of nqo1 by p62-mediated nrf2 activation facilitates p53-dependent mitotic catastrophe. Biochem Biophys Res Commun 2011;412:347-52.
You A, Nam CW, Wakabayashi N, Yamamoto M, Kensler TW, Kwak MK, et al.
Transcription factor Nrf2 maintains the basal expression of Mdm2: An implication of the regulation of p53 signaling by Nrf2. Arch Biochem Biophys 2011;507:356-64.
Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, Hirohashi S, et al.
Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway. Cancer Res 2010;70:9095-105.
Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 2010;13:1713-48.
Hu R, Saw CL, Yu R, Kong AN. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: Antioxidant coupled with antiinflammatory. Antioxid Redox Signal 2010;13:1679-98.
Tsai WC, Hueng DY, Lin CR, Yang TC, Gao HW. Nrf2 expressions correlate with WHO grades in gliomas and meningiomas. Int J Mol Sci 2016;17. pii: E722.
Li K, Zhong C, Wang B, He J, Bi J. Nrf2 expression participates in growth and differentiation of endometrial carcinoma cells in vitro
and in vivo
. J Mol Histol 2014;45:161-7.
Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, et al.
High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res 2010;70:5486-96.
Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, et al.
Nrf2 is overexpressed in pancreatic cancer: Implications for cell proliferation and therapy. Mol Cancer 2011;10:37.
Soini Y, Eskelinen M, Juvonen P, Kärjä V, Haapasaari KM, Saarela A, et al.
Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract 2014;210:35-9.
Niture SK, Jaiswal AK. Nrf2-induced antiapoptotic bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med 2013;57:119-31.
Magrini E, Mantovani A, Garlanda C. The dual complexity of PTX3 in health and disease: A balancing act? Trends Mol Med 2016;22:497-510.
Gambhir L, Checker R, Sharma D, Sandur SK. Diverging role of Nrf2 in cancer progression and prevention. Biomed Res J 2015;2:57-82. [Full text]
Tung JN, Ko CP, Yang SF, Cheng CW, Chen PN, Chang CY, et al.
Inhibition of pentraxin 3 in glioma cells impairs proliferation and invasion in vitro
and in vivo
. J Neurooncol 2016;129:201-9.
Ning C, Li YY, Wang Y, Han GC, Wang RX, Xiao H, et al.
Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1β/IL-17A axis. Mucosal Immunol 2015;8:1275-84.
Ronca R, Alessi P, Coltrini D, Di Salle E, Giacomini A, Leali D, et al.
Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer. J Pathol 2013;230:228-38.
Ronca R, Giacomini A, Di Salle E, Coltrini D, Pagano K, Ragona L, et al.
Long-pentraxin 3 derivative as a small-molecule FGF trap for cancer therapy. Cancer Cell 2015;28:225-39.
Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, et al.
Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 2008;29:1235-43.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]