Search

Background: Percutaneous coronary intervention (PCI) of left main (LM) chronic total occlusions (CTO) has received limited study., Methods: We compared the clinical and procedural characteristics and outcomes of patients who underwent LM versus non-LM CTO PCI at 41 US and non-US centers between 2012 and 2024., Results: During the study period 85 of 15,254 CTO PCIs (0.6%) performed in 14,969 patients were LM CTO PCIs. LM CTO PCI patients were older, had higher rates of dyslipidemia and heart failure and most (88.8%) had prior coronary artery bypass graft surgery (CABG). They were more likely to have moderately or severely calcified lesions (80.7% vs. 45.7%, p < 0.001) and had higher J-CTO (2.76 ± 1.17 vs. 2.37 ± 1.26, p = 0.008), PROGRESS-CTO MACE (3.56 vs. 2.57, p < 0.001), Mortality (2.45 vs. 1.68, p < 0.001), Pericardiocentesis (2.74 vs. 1.87, p < 0.001), Acute MI (1.72 vs. 0.89, p < 0.001) and Perforation (3.21 vs. 2.19, p < 0.001) scores. There was no difference in technical success (80.5% vs. 87.2%, p = 0.086) or major cardiovascular adverse events (MACE) (2.4% vs. 2.0%, p = 0.700). LM CTO PCI patients with and without prior CABG surgery had similar technical success and MACE. The retrograde approach in prior CABG patients was more likely to be performed through saphenous vein grafts., Conclusions: LM CTO PCI is infrequently performed, is associated with high comorbidity burden and angiographic complexity but can be performed with high success and acceptable complication rates., (© 2024 Wiley Periodicals LLC.)

The impact of diabetes mellitus (DM) on the outcomes of bifurcation percutaneous coronary intervention (PCI) has received limited study. We compared the procedural characteristics and outcomes of patients with and without DM in 1,302 bifurcation PCIs (1,147 patients) performed at 5 centers between 2013 and 2024. The prevalence of DM was 33.8% (n = 388). Patients with diabetes were younger and had more cardiovascular risk factors and greater angiographic complexity, including more main vessel calcification and more frequent stenoses in the left main, proximal left anterior descending, and right coronary artery. There was no difference in technical (95.5% vs 94.9%, p = 0.613) or procedural success (90.2% vs 91.3%, p = 0.540); provisional stenting was used less frequently in patients with diabetes (64.5% vs 71.1%, p = 0.015). Patients with diabetes had higher rates of repeat in-hospital PCI and acute kidney injury. Other in-hospital outcomes were similar after adjusting for confounders. During a median follow-up of 1,095 days, diabetes was independently associated with greater incidence of major adverse cardiovascular events (hazard ratio [HR] 2.04, 95% confidence intervals [CI] 1.52 to 2.72, p <0.001), myocardial infarction (HR 1.94, 95% CI 1.05 to 3.25, p = 0.033), death (HR 2.26, 95% CI 1.46 to 3.51, p <0.001), and target (HR 1.6, 95% CI 1.01 to 2.66, p = 0.045) and nontarget (HR 2.00, CI 1.06 to 3.78, p = 0.032) vessel revascularization. Patients with DM who underwent bifurcation PCI had greater risk of in-hospital repeat-PCI and major adverse cardiac events during follow-up than did those without diabetes., Competing Interests: Declaration of competing interest Dr. Brilakis receives consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor Circulation), Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), CSI, Elsevier, GE Healthcare, IMDS, Medtronic, and Teleflex; research support from Boston Scientific, GE Healthcare; is owner, Hippocrates LLC; and is shareholder in MHI Ventures, Cleerly Health, and Stallion Medical. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There are limited comparative data on the use of plaque modification devices during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We compared intravascular lithotripsy (IVL) with rotational atherectomy (RA) for lesion preparation in patients who underwent CTO PCI across 50 US and non-US centers from 2019 to 2024. Of 15,690 patients who underwent CTO PCI during the study period, 436 (2.78%) underwent IVL and 381 (2.45%) RA. Patients treated with IVL had more co-morbidities and more complex CTO lesions. Antegrade wiring was the most used initial and successful crossing strategy for lesions treated with both IVL and RA, although the retrograde approach was more frequently used in IVL cases. Procedure and fluoroscopy times, and air kerma radiation doses and contrast volumes, were greater in patients treated with RA than those treated with IVL. There were no significant differences between the groups in technical success (97.2% vs 95.3%, p = 0.20), procedural success (94.7% vs 91.8%, p = 0.14), and in-hospital major adverse cardiac events (MACEs) (3.0% vs 4.2%, p = 0.47). However, coronary artery perforations were more frequent in patients who underwent RA (9.5% vs 3.2%, p <0.001). Multivariable logistic regression analysis revealed that IVL compared with RA was not independently associated with technical success, procedural success, or in-hospital MACE. In patients who undergo CTO PCI, IVL is associated with similar in-hospital MACE, technical success, and procedural success but lower incidence of coronary artery perforation compared with RA., Competing Interests: Declaration of competing interest Dr. Jaffer reports sponsored research for Canon, Siemens, Shockwave, Teleflex, Boston Scientific, HeartFlow, and Neovasc; consultant/speakers fees from Magenta Medical, Philips, Biotronik, Mercator, Terumo (Canon), Abiomed, Shockwave, DurVena, Intravascular Imaging Inc., Medtronic, and FastWave; equity interest in Intravascular Imaging Inc., DurVena, and FastWave; and Massachusetts General Hospital licensing arrangements: Terumo, Canon, and SpectraWAVE, for which Dr. Jaffer has the right to receive royalties. Dr. Azzalini received consulting fees from Teleflex, Abiomed, GE Healthcare (Little Chalfont, United Kingdom), Reflow Medical, Shockwave, and Cardiovascular Systems, Inc.; received a research grant by Abiomed; serves on the advisory board of Abiomed and GE Healthcare; and owns equity in Reflow Medical. Dr. Davies receives speaking honoraria from Abiomed, Asahi Intec, Boston Sci, Medtronic, Shockwave, and Teleflex; and serves on advisory boards for Abiomed, Avinger, Boston Sci, Medtronic, Rampart, and Shockwave. Dr. Sandoval receives consulting/speaker honoraria from Abbott Diagnostics, Roche Diagnostics, Zoll, and Philips; is JACC Advances associate editor; and reports Patent 20,210,401,347. Dr. Brilakis receives consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor Circulation), Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), CSI, Elsevier, GE Healthcare, IMDS, Medtronic, and Teleflex; research support from Boston Scientific, GE Healthcare; is owner, Hippocrates LLC; and is shareholder in MHI Ventures, Cleerly Health, Stallion Medical. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The Medtronic Micra VR and Abbott AVEIR VR are the leadless pacemakers (LPM) currently available in the United States (US). Micra VR employs fixation tines and the AVEIR VR uses an active fixation helix. Micra VR requires fixation before electrical measurements are obtained, while R-waves may be mapped by AVEIR VR without fixation. Little comparative data is available for these LPMs. Accordingly, we compared the incidences of procedure-related major adverse clinical events (MACE) and device problems in the US for Micra VR and AVEIR VR during 2022-2024., Methods: We searched the FDA's Manufacturer and User Facility Device Experience (MAUDE) database for US reports of MACE and device problems that were filed from April 2022 to December 2023 for AVEIR VR, and from June 2022 to April 2024 for Micra VR. Totals for US-registered LPM implants were obtained from the manufacturers' product performance reports., Results: During the study period, 5990 AVEIR VR and 10 940 Micra VR implants were registered in the US. We found 305 MAUDE reports for AVEIR VR (5.1%), versus 541 MAUDE reports for Micra VR (4.9%) (p = .702). The incidence of MACE was 0.72% (43/5990) for AVEIR VR versus 0.59% (65/10 940) for Micra VR, (p = .387). The incidences of procedure-related death, cardiac perforation. cardiac arrest, emergency pericardial drainage or reparative surgery were similar for both LPMs (p > .05). Micra VR had more unacceptable thresholds requiring LPM replacement compared to AVEIR VR (95;0.9% vs. 24;0.4%; p = .001). AVEIR VR had a statistically higher incidence of device dislodgement during (32) and after (21) implant compared to Micra VR (53 (0.9%) vs. 46 (0.4%), p < .001)., Conclusions: Micra VR and AVEIR VR have similar procedural safety profiles, including the incidences of death and perforation. However, device problems differed significantly, possibly related to their design differences. Compared to Micra VR, AVEIR VR appears to have an advantageous threshold measurement capability but is more prone to device dislodgement., (© 2024 Wiley Periodicals LLC.)

In complex chronic total occlusion (CTO) percutaneous coronary interventions (PCI), a retrograde crossing strategy is often necessary. Recently, the Japanese retrograde (JR) CTO score was developed using a simple 4-item tool. This score showed a good performance in predicting guidewire crossing failure in patients undergoing primary retrograde CTO PCI. We evaluated the JR-CTO score’s performance in patients treated at 44 centers between 2013 and 2024 as part of the Prospective Global Registry for the Study of CTO Intervention (PROGRESS-CTO). In an independent cohort, although the JR-CTO score showed an association with crossing and technical failure, its predictive ability for both outcomes was modest.

Background: The impact of peripheral artery disease (PAD) on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is not well studied., Methods: We analyzed the association of PAD with CTO-PCI outcomes using data from the PROGRESS-CTO registry of procedures performed at 47 centers between 2012 and 2023., Results: The prevalence of PAD among 12 961 patients who underwent CTO PCI during the study period was 13.9% (1802). PAD patients were older, more likely to be current smokers, and had higher rates of dyslipidemia, diabetes, cerebrovascular disease, hypertension, prior myocardial infarction, PCI, and coronary artery bypass graft surgery. Their PROGRESS-CTO (1.35 vs 1.22; P < .001) and J-CTO (2.63 vs 2.33; P < .001) scores were higher, lesion length was longer, and angiographic characteristics were more complex. Their access site was more likely to be bifemoral (33.6% vs 30.9%; P = .024) compared with patients with no PAD. Technical (82.9% vs 87.7%; P < .001) and procedural (80.5% vs 86.6%; P < .001) success rates were lower in patients with PAD, while the incidence of major adverse cardiovascular events (MACE) was higher (3.1% vs 1.8%; P < .001), with higher mortality (0.8% vs 0.4%; P = .034), acute myocardial infarction rate (0.9% vs 0.4%; P = .010), and perforations rate (6.6% vs 4.5%; P < .001). In multivariable analysis, PAD was associated with higher MACE (odds ratio [OR]: 1.53; 95% CI, 1.01-2.26; P = .038) and lower technical success (OR: 0.82; 95% CI, 0.69-0.99; P = .039)., Conclusions: PAD patients undergoing CTO PCI have higher comorbidity burden, more complex CTOs, higher MACE, and lower technical success.

Accumulating data shows that altered metabolic activity contributes to glioma development. Recently, modulation of SSADH (succinic semialdehyde dehydrogenase) expression, implicated in the catabolism of GABA neurotransmitter, was shown to impact glioma cell properties, such as proliferation, self-renewal and tumorigenicity. The purpose of this study was to investigate the clinical significance of SSADH expression in human gliomas. Using public single-cell RNA-sequencing data from glioma surgical resections, we initially grouped cancer cells according to ALDH5A1 (Aldehyde dehydrogenase 5 family member A1) expression, which encodes SSADH. Gene ontology enrichment analysis of genes differentially expressed between cancer cells expressing high or low levels of ALDH5A1, highlighted enrichment in genes implicated in cell morphogenesis and motility. In glioblastoma cell lines, ALDH5A1 knockdown inhibited cell proliferation, induced apoptosis and reduced their migratory potential. This was accompanied by a reduction in the mRNA levels of the adherens junction molecule ADAM-15 and deregulation in the expression of EMT biomarkers, with increased CDH1 and decreased vimentin mRNA levels. Evaluation of SSADH expression in a cohort of 95 gliomas using immunohistochemistry showed that SSADH expression was significantly elevated in cancer tissues compared to normal brain tissues, without any significant correlation with clinicopathological characteristics. In summary, our data show that SSADH is upregulated in glioma tissues irrespective of the histological grade and its expression sustains glioma cell motility., (© 2023. The American Society for Experimental Neurotherapeutics, Inc.)

Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal progress in patients' prognosis. Emerging molecular targets and mechanisms have revealed novel approaches for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetic research and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination of chemoand immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could possibly be used against the most common malignant tumors of childhood, such as medulloblastomas, high-grade gliomas and ependymomas., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.

Sex presents a vital determinant of a person's physiology, anatomy, and development. Recent clinical studies indicate that sex is also involved in the differential manifestation of various diseases, affecting both clinical outcome as well as response to therapy. Genetic and epigenetic changes are implicated in sex bias and regulate disease onset, including the inactivation of the X chromosome as well as sex chromosome aneuploidy. The differential expression of X-linked genes, along with the presence of sex-specific hormones, exhibits a significant impact on immune system function. Several studies have revealed differences between the two sexes in response to infections, including respiratory diseases and COVID-19 infection, autoimmune disorders, liver fibrosis, neuropsychiatric diseases, and cancer susceptibility, which can be explained by sex-biased immune responses. In the present review, we explore the input of genetic and epigenetic interplay in the sex bias underlying disease manifestation and discuss their effects along with sex hormones on disease development and progression, aiming to reveal potential new therapeutic targets. KEY MESSAGES: Sex is involved in the differential manifestation of various diseases. Epigenetic modifications influence X-linked gene expression, affecting immune response to infections, including COVID-19. Epigenetic mechanisms are responsible for the sex bias observed in several respiratory and autoimmune disorders, liver fibrosis, neuropsychiatric diseases, and cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.

The transcriptional co-activators Yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) have emerged as significant regulators of a wide variety of cellular and organ functions with impact in early embryonic development, especially during the expansion of the neural progenitor cell pool. YAP/TAZ signalling regulates organ size development, tissue homeostasis, wound healing and angiogenesis by participating in a complex network of various pathways. However, recent evidence suggests an association of these physiologic regulatory effects of YAP/TAZ with pro-oncogenic activities. Herein, we discuss the physiological functions of YAP/TAZ as well as the extensive network of signalling pathways that control their expression and activity, leading to brain tumour development and progression. Furthermore, we describe current targeting approaches and drug options including direct YAP/TAZ and YAP-TEA domain transcription factor (TEAD) interaction inhibitors, G-protein coupled receptors (GPCR) signalling modulators and kinase inhibitors, which may be used to successfully attack YAP/TAZ-dependent tumours., (© 2021 British Neuropathological Society.)

The SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) is a prominent member of the Suppressor of Variegation 3-9 (SUV39)-related protein lysine methyltransferases (PKMTs), comprising three isoforms that differ in length and domain composition. SETDB1 is widely expressed in human tissues, methylating Histone 3 lysine 9 (H3K9) residues, promoting chromatin compaction and exerting negative regulation on gene expression. SETDB1 has a central role in normal physiology and nervous system development, having been implicated in the regulation of cell cycle progression, inactivation of the X chromosome, immune cells function, expression of retroelements and formation of promyelocytic leukemia (PML) nuclear bodies (NB). SETDB1 has been frequently deregulated in carcinogenesis, being implicated in the pathogenesis of gliomas, melanomas, as well as in lung, breast, gastrointestinal and ovarian tumors, where it mainly exerts an oncogenic role. Aberrant activity of SETDB1 has also been implicated in several neuropsychiatric, cardiovascular and gastrointestinal diseases, including schizophrenia, Huntington's disease, congenital heart defects and inflammatory bowel disease. Herein, we provide an update on the unique structural and biochemical features of SETDB1 that contribute to its regulation, as well as its molecular and cellular impact in normal physiology and disease with potential therapeutic options.

Epigenetic changes that regulate chromatin structure have a major impact in genome stabilization and maintenance of cellular homeostasis, been recently implicated in the pathophysiology of central nervous system (CNS). Aberrant expression and dysregulation of histone modification enzymes has been associated with the development of several CNS disorders, revealing these enzymes as putative targets for drug development and novel therapeutic approaches. SETDB1 is a histone lysine methyltransferase responsible for the di- and tri-methylation of histone 3 (H3) at lysine (K) 9 in euchromatic regions further promoting gene silencing through heterochromatin formation. By this way, SETDB1 has been shown to regulate gene expression and influence normal cellular homeostasis required for nervous system function while it is also implicated in the pathogenesis of CNS disorders. Among them, brain tumors, schizophrenia, Huntington's disease, autism spectrum disorders along with alcohol-induced fetal neurobehavioral deficits and Prader-Willi syndrome are representative examples, indicating the aberrant expression and function of SETDB1 as a common pathogenic factor. In this review, we focus on SETDB1-associated molecular mechanisms implicated in CNS physiology and disease while we further discuss current pharmacological approaches targeting SETDB1 enzymatic activity with beneficial effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate in the widespread changes of gene expression that characterize the metastatic phenotype. At the chromatin level, active and repressive histone post-translational modifications (PTM) in association with pleiotropic transcription factors regulate pivotal genes involved in the initiation of the EMT process as well as in intravasation and anoikis resistance, playing a central role in the progression of tumors. Herein, we discuss the main epigenetic mechanisms associated with the different steps of metastatic process, focusing in particular on the prominent role of histone modifications and the modifying enzymes that mediate transcriptional regulation of genes associated with tumor progression. We further discuss the development of novel treatment strategies targeting the reversibility of histone modifications and highlight their importance in the future of cancer therapy.

Epigenetic regulation of gene expression has been ultimately linked to cancer development, with posttranslational histone modifications representing attractive targets for disease monitoring and therapy. Emerging data have demonstrated histone lysine (K) methylation by methyltransferase SETDB1 as a common denominator of gene regulation in several cancer types. SETDB1 reversibly catalyzes the di- and trimethylation of histone 3 (H3) K9 in euchromatic regions of chromosomes, inhibiting gene transcription within these regions and promoting a switch from euchromatic to heterochromatic states. Recent studies have implicated aberrant SETDB1 activity in the development of various types of cancers, including brain, head and neck, lung, breast, gastrointestinal, ovarian, endometrial and prostate cancer, mesothelioma, melanoma, leukemias, and osteosarcoma. Although its role has not been fully elucidated in every case, most data point toward a pro-oncogenic potential of SETDB1 via the downregulation of critical tumor-suppressive genes. Less commonly, however, SETDB1 can also acquire a tumor-suppressive role, depending on cancer type and stage. Here we provide an updated overview of the cellular and molecular effects underlying SETDB1 activity in cancer development and progression along with current targeting strategies in different cancer types, with promising effects either as a standalone therapy or in conjunction with other therapeutic agents., (©2020 American Association for Cancer Research.)

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past decade, extracellular stress and intracellular DNA damage have been shown to disturb proteostasis leading to Endoplasmic Reticulum (ER) stress that is implicated in the regulation of gene expression and the pathogenesis of several tumor types, including gliomas. Upon ER stress induction, neoplastic cells activate the adaptive mechanism of unfolded protein response (UPR), an integrated signaling system that either restores ER homeostasis or induces cell apoptosis. Recently, the manipulation of the UPR has emerged as a new therapeutic target in glioma treatment. General UPR activators or selective GRP78, ATF6 and PERK inducers have been detected to modulate cell proliferation and induce apoptosis of glioma cells. At the same time, target-specific UPR inhibitors and small molecule proteostasis disruptors, work in reverse to increase misfolded proteins and cause a dysregulation in protein maturation and sorting, thus preventing the growth of neoplastic cells. Herein, we discuss the pathogenic implication of ER stress in gliomas onset and progression, providing an update on the current UPR modifying agents that can be potentially used in glioma treatment., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Glioblastoma, a grade IV astrocytoma, is considered as the most malignant intracranial tumor, characterized by poor prognosis and therapy resistance. Tumor heterogeneity that often leads to distinct functional phenotypes contributes to glioblastoma (GB) indispensable growth and aggressiveness. The complex interaction of neoplastic cells with tumor microenvironment (TME) along with the presence of cancer stem-like cells (CSCs) largely confers to extrinsic and intrinsic GB heterogeneity. Recent data indicate that glioma cells secrete a variety of soluble immunoregulatory factors to attract different cell types to TME including astrocytes, endothelial cells, circulating stem cells, and a range of immune cells. These further induce a local production of cytokines, chemokines, and growth factors which upon crosstalk with extracellular matrix (ECM) components reprogram immune cells to inflammatory or anti-inflammatory phenotypes and manipulate host's immune response in favor of cancer growth and metastasis. Herein, we provide an overview of the immunobiologic factors that orchestrate the complex network of glioma cells and TME interactions in an effort to identify potential therapeutic targets for GB malignancy. Current therapeutic schemes and advances in targeting GB-TME crosstalk are further discussed. KEY MESSAGES: • Intrinsic and extrinsic tumor heterogeneity affects GB growth and aggressiveness. • GB cells secrete growth factors and chemoattractants to recruit immune cells to TME. • GAMs are a critical cell type in promoting GB growth. • GAMs change from pro-inflammatory, anti-tumor M1 phenotype to pro-tumorigenic M2. • Novel therapeutic agents target the crosstalk of neoplastic cells with TME.