Resistance to apoptosis should not be taken as a hallmark of cancer

In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.

COVID-19-associated monocytic encephalitis(CAME):histological and proteomic evidence from autopsy

Severe neurological symptoms are associated with Coronavirus disease 2019(COVID-19).However,the morphologic features,pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection.In this study,neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining,ultrastructural examination under electron microscopy,and an image threshold method,in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals.Differentially expressed proteins were identified by quantitative proteomic assays.Histopathological findings included neurophagocytosis,microglia nodules,satellite phenomena,extensive edema,focal hemorrhage,and infarction,as well as infiltrating mononuclear cells.Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes,severe damage of the blood-brain barrier(BBB)and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+monocytes and occasionally CD4+/CD8+T lymphocytes.Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses,autophagy and cellular metabolism in COVID-19 patient brains compared with control brains.Proteins involved in brain development,neuroprotection,and extracellular matrix proteins of the basement membrane were downregulated,potentially caused by the activation of transforming growth factorβreceptor and vascular endothelial growth factor signaling pathways.Thus,our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis(CAME)and suggest potential therapeutic targets.

Contribution of cancer stem cells to tumor vasculogenic mimicry

Vasculogenic mimicry(VM),a newly-defined pattern of tumor blood supply,provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis.The biological features of the tumor cells that form VM remain unknown.Cancer stem cells(CSCs)are believed to be tumorinitiating cells,capable of self-renewal and multipotent differentiation,which resemble normal stem cells in phenotype and function.Recently CSCs have been shown to contribute to VM formation as well as angiogenesis.These findings challenge the previous understanding of the cellular basis of VM formation.In this review,we present evidence for participation of CSCs in VM formation.We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche.Based on the importance of VM in tumor progression,it constitutes a novel therapeutic target for cancer.

The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression

Background:Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors,especially glioblastoma(GBM).The ubiquitin-proteasome system(UPS)mediates a reversible,stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM.To this end,developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease.This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM.Based on the molecular identification,functional characterization,and mechanism investigation,we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM.Methods:We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase.Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT,UBA and WWE domain-containing E3 ubiquitin ligase 1(HUWE1)in GBM.dCas9 synergistic activation mediator system and recombinant adeno-associated virus(rAAV)were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts.Results:Low expression of HUWE1 was closely associated with worse prognosis of GBM patients.The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1,leading to the inactivation of downstream Delta-like 1(DLL1)-NOTCH1 signaling pathways,inhibited the proliferation,invasion,and migration of GBM cells in vitro and in vivo.A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts.Conclusions:The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression.Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.

EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma

Platelet-derived growth subunit A(PDGFA)plays critical roles in development of glioblastoma(GBM)with substantial evidence from TCGA database analyses and in vivo mouse models.So far,only platelet-derived growth receptor a(PDGFRA)has been identified as receptor for PDGFA.However,PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database.

A glycolysis-based ten-gene signature correlates with the clinical outcome, molecular subtype and IDH1 mutation in glioblastoma

Reprogrammed metabolism is a hallmark of cancer. Glioblastoma（GBM） tumor cells predominantly utilize aerobic glycolysis for the biogenesis of energy and intermediate nutrients. However, in GBM, the clinical significance of glycolysis and its underlying relations with the molecular features such as IDH1 mutation and subtype have not been elucidated yet. Herein, based on glioma datasets including TCGA（The Cancer Genome Atlas）, REMBRANDT（Repository for Molecular Brain Neoplasia Data） and GSE16011 we established a glycolytic gene expression signature score（GGESS） by incorporating ten glycolytic genes. Then we performed survival analyses and investigated the correlations between GGESS and IDH1 mutation as well as the molecular subtypes in GBMs. The results showed that GGESS independently predicted unfavorable prognosis and poor response to chemotherapy of GBM patients. Notably, GGESS was high in GBMs of mesenchymal subtype but low in IDH1-mutant GBMs. Furthermore, we found that the promoter regions of tumor-promoting glycolytic genes were hypermethylated in IDH1-mutant GBMs.Finally, we found that high GGESS also predicted poor prognosis and poor response to chemotherapy when investigating IDH1-wild type GBM patients only. Collectively, glycolysis represented by GGESS predicts unfavorable clinical outcome of GBM patients and is closely associated with mesenchymal subtype and IDH1 mutation in GBMs.

Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.