scholarly journals Bip inhibition in glioma stem cells promotes radiation-induced immunogenic cell death

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Wei Yang ◽  
Zenghe Xiu ◽  
Yuping He ◽  
Wenpeng Huang ◽  
Yanyan Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Tumor Regression ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
High Dose ◽  
Immunogenic Cell Death ◽  
Radiation Induced ◽  
High Doses ◽  
Molecular Patterns

Abstract Tumor regression in sites distant to the irradiated field are thought to be associated with emission of damage-associated molecular patterns (DAMPs) molecules and generation of immunogenic cell death (ICD). Glioma stem cells (GSCs) are resistant to high doses of radiation, and ultimately select the outgrowth of a more aggressive tumor. This study showed high-dose IR triggered fewer DAMPs molecules exposure and release in GSCs comparing to matched non-GSCs. Downregulation of binding immunoglobulin protein (Bip) promoted IR-mediated endoplasmic reticulum stress to generate DAMPs molecules by PERK and IRE1-α phosphorylation, and increased dendritic cells mature and effector T lymphocytes activation. GSCs treated with Bip knockdown and IR efficiently prevented tumor generation, and reduced post-radiotherapy tumor recurrence. These data suggest that Bip plays a critical role in inhibition of IR-induced ICD in GSCs, and Bip inhibition may be a promising strategy on adjuvant therapy by ameliorating tumor immune microenvironment.

scholarly journals EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

2015 ◽  
Vol 4 (2) ◽  
pp. 226-238 ◽  
Author(s):  
Sung-Hak Kim ◽  
Kaushal Joshi ◽  
Ravesanker Ezhilarasan ◽  
Toshia R. Myers ◽  
Jason Siu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Glioma Stem Cells ◽  
Dependent Manner ◽  
Radiation Induced

A Photoactivated Ir(III) Complex Targets Cancer Stem Cells and Induces Secretion of Damage-associated Molecular Patterns in Melamoma Cells Characteristic of Immunogenic Cell Death

2021 ◽  
Author(s):  
Gloria Vigueras ◽  
Lenka Markova ◽  
Vojtech Novohradsky ◽  
Alicia Marco ◽  
Natalia Cutillas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Immunogenic Cell Death ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Several anticancer chemotherapies, while eliminating the bulk of tumor cells, often fail, as they do not obliterate a small fraction of malignant cancer stem cells (CSCs). Thus, developing chemotherapeutics capable...

scholarly journals A novel mouse model of radiation-induced cancer survivorship diseases of the gut

2017 ◽  
Vol 313 (5) ◽  
pp. G456-G466 ◽  
Author(s):  
Cecilia Bull ◽  
Dilip Malipatlolla ◽  
Marie Kalm ◽  
Fei Sjöberg ◽  
Eleftheria Alevronta ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Cancer Survivorship ◽  
Animal Health ◽  
High Dose ◽  
Compensatory Mechanism ◽  
Term Survival ◽  
Radiation Induced ◽  
High Doses

A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury. NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.

scholarly journals Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2566
Author(s):  
María Julia Lamberti ◽  
Annunziata Nigro ◽  
Vincenzo Casolaro ◽  
Natalia Belén Rumie Vittar ◽  
Jessica Dal Col
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Current Status ◽  
Immunogenic Cell Death ◽  
Basal Expression ◽  
Antigen Presenting ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

scholarly journals Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zetao Chen ◽  
Yihong Chen ◽  
Yan Li ◽  
Weidong Lian ◽  
Kehong Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Smad Pathway ◽  
Tgf Β1

AbstractGlioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

scholarly journals Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 130
Author(s):  
Michal Kielbik ◽  
Izabela Szulc-Kielbik ◽  
Magdalena Klink
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Adaptive Immune Response ◽  
Ovarian Cancer Cells ◽  
Immunogenic Cell Death ◽  
Antigen Presenting ◽  
Molecular Patterns

Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.

scholarly journals Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 930
Author(s):  
Rianne D. W. Vaes ◽  
Lizza E. L. Hendriks ◽  
Marc Vooijs ◽  
Dirk De Ruysscher
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Tumor Cells ◽  
Immunogenic Cell Death ◽  
Type I ◽  
Future Studies ◽  
Regulated Cell Death ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

scholarly journals Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Anna Danielsson ◽  
Kristell Barreau ◽  
Teresia Kling ◽  
Magnus Tisell ◽  
Helena Carén
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Cellular Response ◽  
Glioma Stem Cells ◽  
Proliferation And Differentiation ◽  
Radiation Resistant ◽  
Radiation Induced ◽  
Induced Changes ◽  
Regulatory Functions

Abstract Background Radiation is an important therapeutic tool. However, radiotherapy has the potential to promote co-evolution of genetic and epigenetic changes that can drive tumour heterogeneity, formation of radioresistant cells and tumour relapse. There is a clinical need for a better understanding of DNA methylation alterations that may follow radiotherapy to be able to prevent the development of radiation-resistant cells. Methods We examined radiation-induced changes in DNA methylation profiles of paediatric glioma stem cells (GSCs) in vitro. Five GSC cultures were irradiated in vitro with repeated doses of 2 or 4 Gy. Radiation was given in 3 or 15 fractions. DNA methylation profiling using Illumina DNA methylation arrays was performed at 14 days post-radiation. The cellular characteristics were studied in parallel. Results Few fractions of radiation did not result in significant accumulation of DNA methylation alterations. However, extended dose fractionations changed DNA methylation profiles and induced thousands of differentially methylated positions, specifically in enhancer regions, sites involved in alternative splicing and in repetitive regions. Radiation induced dose-dependent morphological and proliferative alterations of the cells as a consequence of the radiation exposure. Conclusions DNA methylation alterations of sites with regulatory functions in proliferation and differentiation were identified, which may reflect cellular response to radiation stress through epigenetic reprogramming and differentiation cues.

scholarly journals Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
K. Hayashi ◽  
F. Nikolos ◽  
Y. C. Lee ◽  
A. Jain ◽  
E. Tsouko ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Activation ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Prostaglandin E ◽  
Immunogenic Cell Death ◽  
Tumor Cell Death ◽  
Dendritic Cell Activation ◽  
Drug Induced ◽  
Molecular Patterns

AbstractInduction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.

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