Signaling pathway and molecular subgroups of medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. Although multimodality treatment regimens including surgery, radiotherapy and chemotherapy have greatly improved disease outcome, about one-third of MB patient remains incurable, and many long-term survivors are suffered from deleterious effects due to aggressive treatment. Understanding the signaling pathways and the genetic mechanisms contributed to MB development would be the key to develop novel therapeutic treatment strategies for improving survival and outcome of MB. In this review, we discuss the biological signaling pathways involved in MB pathogenesis. We also go through the current international consensus of four core MB subgroups namely, SHH, WNT, Group 3 and Group 4. This is adopted based on the knowledge of genomic complexity of MB as analyzed by recent high-throughput genomic technology. We talk about immunohistochemistry assays established to determine molecular subgroup affiliation. In the last part of review, we discuss how identification of molecular subgroups is going to change our routine disease diagnosis and clinical management.     

Risk Stratification of Childhood Medulloblastoma Using Integrated Diagnosis: Discrepancies with Clinical Risk Stratification

BackgroundRecent genomic studies identified four discrete molecular subgroups of medulloblastoma (MB), and the risk stratification of childhood MB in the context of subgroups was refined in 2015. In this study, we investigated the effect of molecular subgroups on the risk stratification of childhood MB.MethodsThe nCounter® system and a customized cancer panel were used for molecular subgrouping and risk stratification in archived tissues.ResultsA total of 44 patients were included in this study. In clinical risk stratification, based on the presence of residual tumor/metastasis and histological findings, 24 and 20 patients were classified into the average-risk and high-risk groups, respectively. Molecular subgroups were successfully defined in 37 patients using limited gene expression analysis, and DNA panel sequencing additionally classified the molecular subgroups in three patients. Collectively, 40 patients were classified into molecular subgroups as follows: WNT (n = 7), SHH (n = 4), Group 3 (n = 8), and Group 4 (n = 21). Excluding the four patients whose molecular subgroups could not be determined, among the 17 average-risk group patients in clinical risk stratification, one patient in the SHH group with the TP53 variant was reclassified as very-high-risk using the new risk classification system. In addition, 5 out of 23 patients who were initially classified as high-risk group in clinical risk stratification were reclassified into the low- or standard-risk groups in the new risk classification system.ConclusionThe new risk stratification incorporating integrated diagnosis showed some discrepancies with clinical risk stratification. Risk stratification based on precise molecular subgrouping is needed for the tailored treatment of MB patients.     

Prognostic Significance of Ror2 and Wnt5a Expression in Medulloblastoma

Medulloblastoma (MB) is a clinically and biologically heterogeneous group of tumors, and currently classified into four molecular subgroups (Wnt, Shh, Group 3 and Group 4). Intracellular signaling of the Wnt pathway has been divided into two classes: the “canonical” and the “non‐canonical” signaling pathway. The canonical signaling pathway is a well‐established, β‐catenin‐dependent signaling pathway in MB. In contrast, very little research about the non‐canonical WNT signaling pathway in MB exists. In order to identify the roles of Wnt‐5a and Ror2, two non‐canonical WNT pathway‐related genes, we studied 76 cases of MB with immunohistochemistry and quantitative real‐time PCR and correlated the results with clinicopathological and other molecular parameters and prognosis. Wnt5a and Ror2 were immunopositive in 20 (29.4%) and 35 (51.5%) of 68 cases, respectively. There were positive associations among protein expressions of Wnt5a, Ror2 and β‐catenin. Ror2 mRNA levels were well correlated with immunoexpression. Ror2 mRNA expression was significantly associated with CTNNB1 mutation. High Ror2 mRNA expression was an independent favorable prognostic factor. In conclusion, our study demonstrates the first attempt to identify Wnt5a and Ror2 as additional mechanisms contributing to dysregulation of the non‐canonical WNT signaling pathway in MB. Ror2 may play a role as an oncosuppressor in MB.     

肿瘤中雌激素信号转导通路的研究进展

雌激素（estrogen,E₂）可通过特异性结合并激活其受体传递信号,广泛调控机体的各种功能,如生殖功能、骨骼及其它组织的分化和维持等。雌激素受体属于核受体超家族,有3个亚类即雌激素受体α（estrogenreceptorα,ERα）、ERβ和最近发现的G蛋白偶联受体——GPR（G protein-coupled receptor）30/GPER（G protein-coupled estrogen receptor）。典型的ER作     

Update on recurrent mutations in angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T cell lymphoma (PTCL), defined by genetic alterations that induce abnormal immune activity and inflammatory disorders. Through recent discoveries using genomic studies, the identification of various recurrent mutations has provided greater insight and changed our understanding of the molecular genetics of the disease. By acknowledging these recurrent mutations and their affected pathways, the diagnosis, prognosis, treatment, and survival of AITL can be improved. In this review, we summarize the known recurrent mutations present in the molecular pathogenesis of AITL by emphasizing the effects of mutations on signaling pathways and genes, as well as the multistep process of AITL development.     

Pathology,diagnostics, and classification of medulloblastoma

Medulloblastoma (MB) is the most common CNS embryonal tumor. While the overall cure rate is around 70%, patients with high‐risk disease continue to have poor outcome and experience long‐term morbidity. MB is among the tumors for which diagnosis, risk stratification, and clinical management has shown the most rapid advancement. These advances are largely due to technological improvements in diagnosis and risk stratification which now integrate histomorphologic classification and molecular classification. MB stands as a prototype for other solid tumors in how to effectively integrate morphology and genomic data to stratify clinicopathologic risk and aid design of innovative clinical trials for precision medicine. This review explores the current diagnostic and classification of MB in modern neuropathology laboratories.     

An update on the molecular pathology of urinary bladder tumors

Urothelial carcinoma is the fourth most common tumors after prostate cancer, lung, and colorectal carcinoma but the second most common urologic malignancy. Urothelial carcinoma composed more than 90% of bladder tumors while squamous cell carcinoma and adenocarcinomas composed 5% and 2% respectively. The intense research involving the different molecular aspects of bladder cancer has provided a great insight into identifying more about molecular profiling and pathways of bladder cancer.In this review, we will highlight the general concepts of the molecular features; profiling and classification as well as the molecular pathways for bladder carcinomas, especially urothelial carcinoma. Also, we will discuss the advances of molecular biomarkers for screening, early diagnosis, surveillance and potential prognosis of urothelial carcinoma of the bladder. Studies showed that accumulation of genetic alterations involving the clonal expansion of altered cells with growth advantages through sequential multi-step pathways results in progression of bladder tumors.The accumulated research data from literature has revealed that the genomic signatures of urothelial carcinoma are required to subclassify bladder cancer into genetically distinct subgroups. These findings could improve the understating of pathogenesis as well as will provide new therapeutic modules e.g. targeted therapy.     

The Role of Chromatin Remodeling in Medulloblastoma

The unexpectedly high frequency and universality of alterations to the chromatin machinery is one of the most striking themes emerging from the current deluge of cancer genomics data. Medulloblastoma (MB), a malignant pediatric brain tumor, is no exception to this trend, with a wealth of recent studies indicating multiple alterations at all levels of chromatin processing. MB is typically now regarded as being composed of four major molecular entities (WNT, SHH, Group 3 and Group 4), which vary in their clinical and biological characteristics. Similarities and differences across these subgroups are also reflected in the specific chromatin modifiers that are found to be altered in each group, and each new cancer genome sequence or microarray profile is adding to this important knowledge base. These data are fundamentally changing our understanding of tumor developmental pathways, not just for MB but also for cancer as a whole. They also provide a new class of targets for the development of rational, personalized therapeutic approaches. The mechanisms by which these chromatin remodelers are dysregulated in MB, and the consequences both for future basic research and for translation to the clinic, will be examined here.     

dsRNA sensors and plasmacytoid dendritic cells in host defense and autoimmunity

The innate immune system detects viruses through molecular sensors that trigger the production of type I interferons (IFN-I) and inflammatory cytokines. As viruses vary tremendously in size, structure, genomic composition, and tissue tropism, multiple sensors are required to detect their presence in various cell types and tissues. In this review, we summarize current knowledge of the diversity, specificity, and signaling pathways downstream of viral sensors and ask whether two distinct sensors that recognize the same viral component are complementary, compensatory, or simply redundant. We also discuss why viral sensors are differentially distributed in distinct cell types and whether a particular cell type dominates the IFN-I response during viral infection. Finally, we review evidence suggesting that inappropriate signaling through viral sensors may induce autoimmunity. The picture emerging from these studies is that disparate viral sensors in different cell types form a dynamic and integrated molecular network that can be exploited for improving vaccination and therapeutic strategies for infectious and autoimmune diseases.     

ERK activation of p21 activated kinase-1 (Pak1) is critical for medulloblastoma cell migration

We previously identified that overexpression of the platelet-derived growth factor receptor (PDGFR) is associated with metastatic medulloblastoma (MB) and showed that PDGF treatment increases ERK activity and promotes MB cell migration. In this study, we investigated whether ERK regulates Rac1/Pak1 signaling and is critically linked to MB cell migration. Herein we demonstrate that PDGF-BB treatment of MB cells induces concomitant activation of PDGFRβ, MEK1/ERK, Rac1 and Pak1, but suppresses Rho activity, which together significantly promotes cell migration. Conversely, cells transfected with either PDGFRβ or Pak1 siRNA or treated with an inhibitor of Rac1 (NSC23766) or N-myristoyltransferase-1 (Tris-dipalladium) are unable to activate Rac1 or Pak1 in response to PDGF, and consequently, are unable to undergo PDGF-mediated cell migration. Furthermore, we also demonstrate that either chemical inhibition of MEK/ERK (U0126) or stable downregulation of PDGFRβ by shRNA similarly results in the loss of PDGF-induced ERK phosphorylation and abolishes Rac1/Pak1 activation and cell migration in response to PDGF. However, specific depletion of Pak1 by siRNA has no effect on PDGF-induced ERK phosphorylation, indicating that in MB cells ERK signaling is Pak1-independent, but PDGF-induced migration is dependent on ERK-mediated activation of Pak1. Finally, using tissue microarrays, we detect phosphorylated Pak1 in 53% of medulloblastomas and show that immunopositivity is associated with unfavorable outcome. We conclude that Rac1/Pak1 signaling is critical to MB cell migration and is functionally dependent on PDGFRβ/ERK activity.     

Concurrent inhibition of TGF-β and mitogen driven signaling cascades in Dupuytren's disease - non-surgical treatment strategies from a signaling point of view

Dupuytren’s disease (DD) is a benign progressive fibro-proliferative disorder of the fascia palmaris of the hand. Currently, treatment consists of surgical excision with a relatively high recurrence rate and risk of complications. To improve long-term outcome of DD treatment, research focus has shifted towards molecular targets for DD as an alternative to surgery. Therefore, complete and exact understanding of the cause of DD is needed.Transforming growth factor (TGF)-β is considered a key player in DD. We recently showed that increased TGF-β expression in DD correlates not only with elevated expression and activation of downstream Smad effectors, but also with overactive ERK1/2 MAP kinase signaling. Both TGF-β/Smad and non-Smad signaling pathways increase expression of key fibrotic markers and contractility of Dupuytren’s myofibroblasts. What is not yet known is whether these two signaling cascades each accelerate DD autonomously, successively or in conjunction. Elucidation of this mechanism will help develop new potential non-surgical treatments.We hypothesize that TGF-β-induced short-term activation of the MAPK pathway leads to an autonomous non-Smad driven fibrosis. Therefore, successful treatment strategies will target not only TGF-β/Smad, but also intracellular MAPK signaling. In this review we discuss possible scenarios in which such a drift from TGF-β induced Smad signaling to autonomous non-Smad signaling could be observed in DD. The potential therapeutic effects of small cytokine signaling cascades inhibitors, such as TGF-β type I receptor-, (pan-) tyrosine- or ERK1/2 MAP-kinase inhibitor will be highlighted. To abrogate the fibrotic trait and the recurrence of DD, we speculate on sequential and co-application of such molecules in order to provide possible new non-operative strategies for DD.     

Cytokines and immunodeficiency diseases: critical roles of the γc-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways

Summary: In this review, we discuss the role of cytokines and their signaling pathways in immunodeficiency. We focus primarily on severe combined immunodeficiency (SCID) diseases as the most severe forms of primary immunodeficiencies, reviewing the different genetic causes of these diseases. We focus in particular on the range of forms of SCID that result from defects in cytokine‐signaling pathways. The most common form of SCID, X‐linked SCID, results from mutations in the common cytokine receptor γ‐chain, which is shared by the receptors for interleukin (IL)‐2, IL‐4, IL‐7, IL‐9, IL‐15, and IL‐21, underscoring that X‐linked SCID is indeed a disease of defective cytokine signaling. We also review the signaling pathways used by these cytokines and the phenotypes in humans and mice with defects in the cytokines or signaling pathways. We also briefly discuss other cytokines, such as interferon‐γ and IL‐12, where mutations in the ligand or receptor or signaling components also cause clinical disease in humans.     

Innate immunity in allergy

Innate immune system quickly responds to invasion of microbes and foreign substances through the extracellular and intracellular sensing receptors, which recognize distinctive molecular and structural patterns. The recognition of innate immune receptors leads to the induction of inflammatory and adaptive immune responses by activating downstream signaling pathways. Allergy is an immune‐related disease and results from a hypersensitive immune response to harmless substances in the environment. However, less is known about the activation of innate immunity during exposure to allergens. New insights into the innate immune system by sensors and their signaling cascades provide us with more important clues and a framework for understanding allergy disorders. In this review, we will focus on recent advances in the innate immune sensing system.     

Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke

Stroke is one of the leading causes of mortality and morbidity in advanced countries of the world. Despite the fact that reactive oxygen and nitrogen species (ROS and RNS) are the by-products of normal metabolic processes and mediate important physiological processes, they can inflict damage to the cell if produced in excess due to oxidative stress. In the present review, we focus on the cellular and molecular aspects of ROS and RNS generation and its role in the pathogenesis of stroke produced by hypoxia-reperfusion (H-R) phenomena that elicit oxidative stress. We outline the reasons for the vulnerability of the brain to ischaemic insult, chronic infection and inflammation as well as the natural defence mechanisms against radical mediated injury. We deal with the effect of ROS and RNS on intracellular signaling pathways together with the phenomena of apoptosis, mitochondrial injury and survival associated with these pathways. The intracellular signaling mechanisms influenced by reactive species can have significant effects on the outcome of the condition. Future studies should focus on understanding the molecular mechanisms involved in the action of anti-radicals agents, and their mode of action.     

Group I metabotropic glutamate receptors prevent endothelial programmed cell death independent from MAP kinase p38 activation in rat

Activation of Group I metabotropic glutamate receptors (mGluRs) prevents neuronal programmed cell death (PCD), but the role of these receptors in the vascular endothelial cell (EC) system has not been defined. Since ECs are principal targets for ischemic free radical injury, we examined whether the mGluR system could modulate vascular PCD. Activation of the Group I mGluR system, but not antagonism, addressed two distinct pathways of PCD by preventing the destruction of genomic DNA and maintaining EC membrane asymmetry. The induction of nitric oxide (NO)-induced PCD in ECs paralleled the specific activation of the MAP kinase p38 pathway, but the vascular protection conferred by the Group I mGluR system appears to rely on more downstream cellular pathways. We provide initial evidence for Group I mGluRs to prevent NO-induced vascular injury and offer new directions for vascular disease treatment.     

骨性关节炎发生发展中的分子信号通路

文题释义：骨性关节炎：由多因素引起关节软骨纤维化、溃疡、皲裂、脱失等的退行性疾病,病理表现为关节软骨变形破坏、软骨下骨硬化或囊变、滑膜病变、关节囊挛缩、关节边缘骨质增生等。可以导致关节疼痛、畸形和活动功能障碍,进而增加心血管事件的发生率及全因死亡率,是目前常见且难治的骨科疾病之一。 信号通路：当细胞要发生某种反应时,信号从细胞外到细胞内传递了一种信息,细胞要根据这种信息来做出反应,信号通路是指能将细胞外的分子信号经细胞膜传入细胞内发挥效应的一系列酶促反应通路。这些细胞外的分子信号(配体)包括神经递质、生长因子、细胞因子、激素以及其他小分子化合物等。 背景：骨性关节炎是一种难治愈且严重影响患者生活质量、给社会带来沉重的经济负担的退行性疾病。现今对骨性关节炎的治疗只能在短期内改善关节功能,无法改变骨性关节炎的病理进程,目前还没有针对退行性关节疾病的预防或再生疗法。信号通路已经在多领域对疾病的发生、发展以及治疗机制作出了分子水平上的阐释,因此,调节信号通路可以作为骨性关节炎的潜在治疗手段。 目的：了解骨性关节炎的发生、发展规律,并为今后的临床诊断、治疗扩展思路。 方法：中文以“骨性关节炎;信号通路;EGFR;Hedgehog;NF-kB;Notch”为检索词,检索CNKI、万方、维普、中国生物医学文献数据库;英文以“osteoarthritis;signaling pathway;EGFR;Hedgehog;NF-kB;signaling”为检索词,检索PubMed、MEDLINE数据库,收录2008至2019年间发表的与骨性关节炎有关的信号通路相关的文献报道。 结果与结论：正常的软骨功能依赖多种信号通路的调节,骨性关节炎的发生、发展也受到相应信号通路的调节,这可为分子水平上了解骨性关节炎的发生、发展机制,同时也为临床的诊断、治疗提供新的思路：通过基因修饰、药物治疗等方法调节信号通路是潜在的骨性关节炎治疗手段。但信号通路的相关研究普遍存在这样一个问题：对信号通路的研究大多是孤立的,缺乏对多通路协同作用的研究,而骨性关节炎的发生和发展可能涉及多通路协同作用。 ORCID: 0000-0001-8363-3046(张璇) 中国组织工程研究杂志出版内容重点：人工关节;骨植入物;脊柱;骨折;内固定;数字化骨科;组织工程