scholarly journals The Eclectic Nature of Glioma-Infiltrating Macrophages and Microglia

2021 ◽  
Vol 22 (24) ◽  
pp. 13382
Author(s):  
Víctor A. Arrieta ◽  
Hinda Najem ◽  
Edgar Petrosyan ◽  
Catalina Lee-Chang ◽  
Peiwen Chen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Myeloid Cells ◽  
Glioma Cells ◽  
Current Understanding ◽  
Environmental Pressures ◽  
Molecular Features

Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors seem to be dictated by molecular features of glioma cells. Furthermore, increasing evidence underscores the significance of interactions between myeloid cells and glioma cells that allow them to evolve in a synergistic fashion to sustain tumor growth. In this review, we revisit the current understanding of glioma-infiltrating myeloid cells and their dialogue with tumor cells in consideration of their increasing recognition in response and resistance to immunotherapies as well as the immune impact of the current chemoradiotherapy used to treat gliomas.

TAMI-30. THERAPY INDUCED REPROGRAMMING DRIVES GLIOMA VASCULAR TRANSDIFFERENTIATION AND TUMOR RECURRENCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi204-vi204
Author(s):  
Sree Deepthi Muthukrishnan ◽  
Riki Kawaguchi ◽  
Pooja Nair ◽  
Rachna Prasad ◽  
Alvaro Alvarado ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Radiation Treatment ◽  
Glioma Cells ◽  
Chromatin Accessibility ◽  
Phenotype Switch ◽  
Aggressive Tumor ◽  
Functional States ◽  
Histone Acetyltransferase Activity

Abstract Therapy-resistant glioma cells elicit phenotypic plasticity leading to aggressive tumor recurrence. Here, we employed single-cell and whole transcriptomic analyses to uncover that a standard glioma treatment, radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of mesenchymal-like and vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is transdifferentiation to endothelial-like and pericyte-like cells. The transdifferentiated cells in turn promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth and recurrence post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation treatment inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation therapy reprograms tumor cells driving vascular transdifferentiation, and highlights HAT inhibitors as potential therapeutic target for preventing GBM relapse

scholarly journals TMIC-20. ELIMINATION OF SENESCENT ASTROCYTES IN THE BRAIN TUMOR MICROENVIRONMENT ATTENUATES GLIOBLASTOMA RECURRENCE AFTER RADIOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi251-vi251
Author(s):  
Eliot Fletcher-Sananikone ◽  
Bipasha Mukherjee ◽  
Sandeep Burma
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Glioma Cells ◽  
Cell Types ◽  
Normal Brain ◽  
High Doses

Abstract Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR) yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. During GBM therapy, the surrounding brain tissue is irradiated along with the tumor. IR induces senescence in multiple cell types, and senescent stromal cells are known to promote the growth of neighboring tumor cells by secreting cytokines which create a senescence-associated secretory phenotype (SASP). We hypothesize that IR-induced senescence of normal brain cells in the tumor microenvironment is a powerful driver of GBM recurrence. We intra-cranially irradiated C57BL/6J mice, and found evidence of widespread senescence, with the astrocytic population being highly susceptible. Genomic analyses of irradiated brains revealed an altered transcriptomic profile which included upregulation of CDKN1A (p21), a key enforcer of senescence, and increased expression of SASP proteins including HGF, the ligand for the RTK Met. We orthotopically implanted mock-irradiated or irradiated mice with a limiting number of syngeneic glioma cells. Pre-irradiation of mouse brains resulted in a striking increase in tumor growth and invasion driven by Met activation in the tumor cells. Importantly, irradiated p21-/- mouse brains did not exhibit SASP and failed to promote tumor growth. Irradiated primary astrocytes underwent senescence in vitro and promoted the migration of glioma cells, and this could be attenuated with HGF-neutralizing antibodies or by the Met inhibitor Crizotinib. These findings indicate that SASP factors (like HGF) in the irradiated brain microenvironment could drive GBM recurrence after radiotherapy via the activation of RTKs (like MET) in the tumor cells. Significantly, we found that senolytic drugs can selectively kill senescent astrocytes both in vitro and in vivo resulting in attenuated growth of glioma cells. These results are of great translational significance as they indicate that adjuvant therapy with senolytic drugs might attenuate GBM recurrence after radiotherapy.

scholarly journals OMRT-5. Therapy-induced reprogramming drives glioma vascular transdifferentiation and recurrence

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Sree Deepthi Muthukrishnan ◽  
Riki Kawaguchi ◽  
Pooja Nair ◽  
Rachna Prasad ◽  
Yue Qin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Radiation Treatment ◽  
Glioma Cells ◽  
Chromatin Accessibility ◽  
Trophic Factors ◽  
Transcriptomic Sequencing ◽  
Molecule Inhibitor ◽  
Distinct Cell ◽  
Phenotype Switch

Abstract Therapy-resistant glioma cells elicit remarkable phenotypic plasticity leading to aggressive tumor recurrence. Here, we used single-cell and whole transcriptomic sequencing to uncover that radiation treatment induces a dynamic shift in functional states of glioma cells allowing for acquisition of either stem-like, mesenchymal-like or vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is the vascular-like cell state, resulting in transdifferentiation to endothelial-like and pericyte-like cells in distinct cell clusters. The transdifferentiated endothelial-like and pericyte-like cells secrete trophic factors to support proliferation of tumor cells, and their selective ablation results in reduced tumor growth and recurrence post-treatment. Mechanistically, the acquisition of vascular-like phenotype is driven by increased acetylation and chromatin accessibility in vascular genes and in regions for binding of vascular specification transcription factors. Blocking histone acetylation using a small molecule inhibitor targeting P300 histone acetyltransferase activity prior to radiation treatment inhibits the vascular-like transdifferentiation of glioma cells and tumor growth. Our findings indicate that radiation therapy-induces rewiring of glioma cells that promotes vascular cell-like transdifferentiation, tumor growth and recurrence.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

scholarly journals IMMU-27. SINGLE CELL RNA-SEQUENCING IDENTIFIES NOVEL BONE MARROW DERIVED MYELOID CELLS IN GLIOBLASTOMA ASSOCIATED WITH TUMOR AGGRESSION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii110-ii110
Author(s):  
Christina Jackson ◽  
Christopher Cherry ◽  
Sadhana Bom ◽  
Hao Zhang ◽  
John Choi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Cell ◽  
Tumor Cells ◽  
Rna Sequencing ◽  
Metabolic Pathways ◽  
Myeloid Cells ◽  
Tumor Grade ◽  
Sequencing Data ◽  
Single Cell Rna Sequencing ◽  
Two Populations

Abstract BACKGROUND Glioma associated myeloid cells (GAMs) can be induced to adopt an immunosuppressive phenotype that can lead to inhibition of anti-tumor responses in glioblastoma (GBM). Understanding the composition and phenotypes of GAMs is essential to modulating the myeloid compartment as a therapeutic adjunct to improve anti-tumor immune response. METHODS We performed single-cell RNA-sequencing (sc-RNAseq) of 435,400 myeloid and tumor cells to identify transcriptomic and phenotypic differences in GAMs across glioma grades. We further correlated the heterogeneity of the GAM landscape with tumor cell transcriptomics to investigate interactions between GAMs and tumor cells. RESULTS sc-RNAseq revealed a diverse landscape of myeloid-lineage cells in gliomas with an increase in preponderance of bone marrow derived myeloid cells (BMDMs) with increasing tumor grade. We identified two populations of BMDMs unique to GBMs; Mac-1and Mac-2. Mac-1 demonstrates upregulation of immature myeloid gene signature and altered metabolic pathways. Mac-2 is characterized by expression of scavenger receptor MARCO. Pseudotime and RNA velocity analysis revealed the ability of Mac-1 to transition and differentiate to Mac-2 and other GAM subtypes. We further found that the presence of these two populations of BMDMs are associated with the presence of tumor cells with stem cell and mesenchymal features. Bulk RNA-sequencing data demonstrates that gene signatures of these populations are associated with worse survival in GBM. CONCLUSION We used sc-RNAseq to identify a novel population of immature BMDMs that is associated with higher glioma grades. This population exhibited altered metabolic pathways and stem-like potentials to differentiate into other GAM populations including GAMs with upregulation of immunosuppressive pathways. Our results elucidate unique interactions between BMDMs and GBM tumor cells that potentially drives GBM progression and the more aggressive mesenchymal subtype. Our discovery of these novel BMDMs have implications in new therapeutic targets in improving the efficacy of immune-based therapies in GBM.

scholarly journals EXTH-70. ENHANCEMENT OF ANTITUMOR ACTIVITY BY USING 5-ALA–MEDIATED SONODYNAMIC THERAPY TO INDUCE APOPTOSIS AND NECROSIS IN A MOUSE GLIOMA MODEL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Satoshi Suehiro ◽  
Takanori Ohnishi ◽  
Akihiro Inoue ◽  
Daisuke Yamashita ◽  
Masahiro Nishikawa ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
High Intensity Focused Ultrasound ◽  
Control Group ◽  
Normal Brain ◽  
Sonodynamic Therapy ◽  
Cytotoxic Effects

Abstract OBJECTIVE High invasiveness of malignant gliomas frequently causes local tumor recurrence. To control such recurrence, novel therapies targeted toward infiltrating glioma cells are required. Here, we examined cytotoxic effects of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas both in vitro and in vivo. METHODS In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated. RESULTS The 5-ALA-SDT inhibited cell growth and changed cell morphology. Flow cytometric analysis indicated that 5-ALA-SDT induced apoptotic cell death. The 5-ALA-SDT generated higher ROS than in the control group, and inhibition of ROS generation completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact. CONCLUSIONS The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1081-1081
Author(s):  
Ashley P Wright ◽  
Jodi D Bradley ◽  
Timothy Hagerty ◽  
Emily A Wyatt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Topoisomerase I Inhibitor ◽  
Polymeric Nanoparticle ◽  
Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

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