scholarly journals Imaging of Glioblastoma Tumor-Associated Myeloid Cells Using Nanobodies Targeting Signal Regulatory Protein Alpha

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen De Vlaminck ◽  
Ema Romão ◽  
Janik Puttemans ◽  
Ana Rita Pombo Antunes ◽  
Daliya Kancheva ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Regulatory Protein ◽  
Myeloid Cells ◽  
Primary Brain Tumor ◽  
High Signal ◽  
Tumor Associated Macrophages ◽  
Single Domain Antibody ◽  
Stromal Compartment ◽  
Targeting Signal ◽  
Human Gbm

Glioblastoma (GBM) is the most common malignant primary brain tumor. Glioblastomas contain a large non-cancerous stromal compartment including various populations of tumor-associated macrophages and other myeloid cells, of which the presence was documented to correlate with malignancy and reduced survival. Via single-cell RNA sequencing of human GBM samples, only very low expression of PD-1, PD-L1 or PD-L2 could be detected, whereas the tumor micro-environment featured a marked expression of signal regulatory protein alpha (SIRPα), an inhibitory receptor present on myeloid cells, as well as its widely distributed counter-receptor CD47. CITE-Seq revealed that both SIRPα RNA and protein are prominently expressed on various populations of myeloid cells in GBM tumors, including both microglia- and monocyte-derived tumor-associated macrophages (TAMs). Similar findings were obtained in the mouse orthotopic GL261 GBM model, indicating that SIRPα is a potential target on GBM TAMs in mouse and human. A set of nanobodies, single-domain antibody fragments derived from camelid heavy chain-only antibodies, was generated against recombinant SIRPα and characterized in terms of affinity for the recombinant antigen and binding specificity on cells. Three selected nanobodies binding to mouse SIRPα were radiolabeled with 99mTc, injected in GL261 tumor-bearing mice and their biodistribution was evaluated using SPECT/CT imaging and radioactivity detection in dissected organs. Among these, Nb15 showed clear accumulation in peripheral organs such as spleen and liver, as well as a clear tumor uptake in comparison to a control non-targeting nanobody. A bivalent construct of Nb15 exhibited an increased accumulation in highly vascularized organs that express the target, such as spleen and liver, as compared to the monovalent format. However, penetration into the GL261 brain tumor fell back to levels detected with a non-targeting control nanobody. These results highlight the tumor penetration advantages of the small monovalent nanobody format and provide a qualitative proof-of-concept for using SIRPα-targeting nanobodies to noninvasively image myeloid cells in intracranial GBM tumors with high signal-to-noise ratios, even without blood-brain barrier permeabilization.

scholarly journals Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1411
Author(s):  
Don Carlo Ramos Batara ◽  
Moon-Chang Choi ◽  
Hyeon-Uk Shin ◽  
Hyunggee Kim ◽  
Sung-Hak Kim
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Molecular Target ◽  
Therapeutic Strategies ◽  
Homeostatic Mechanism ◽  
Cellular Context ◽  
Cellular Components

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

scholarly journals 5′-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat

2010 ◽  
Vol 128 (9) ◽  
pp. 2230-2239 ◽  
Author(s):  
Taichang Jang ◽  
Joy M. Calaoagan ◽  
Eunice Kwon ◽  
Steven Samuelsson ◽  
Lawrence Recht ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Tumor Development ◽  
Primary Brain Tumor ◽  
Protein Kinase Activity ◽  
Amp Activated Protein Kinase

Swallowing assessment in primary brain tumor patients with dysphagia

Neurology ◽  
1994 ◽  
Vol 44 (10) ◽  
pp. 1927-1927 ◽  
Author(s):  
H. B. Newton ◽  
C. Newton ◽  
D. Pearl ◽  
T. Davidson
Keyword(s):  
Brain Tumor ◽  
Primary Brain Tumor ◽  
Tumor Patients ◽  
Swallowing Assessment

PTEN – A MOLECULAR MARKER FOR THE DIAGNOSIS OF GLIOMA BABUL REDDY TATIREDDY

2021 ◽  
pp. 45-48
Author(s):  
Babul Reddy Tatireddy
Keyword(s):  
Brain Tumor ◽  
Literature Search ◽  
Recipient Cell ◽  
Primary Brain Tumor ◽  
The Novel ◽  
Cellular Phenotype ◽  
Therapeutic Approaches ◽  
Downstream Signaling ◽  
Novel Biomarkers ◽  
Biomarker Research

Glioblastoma is an uncommon primary brain tumor accounts for upto 15.4% of all primary brain tumors. Although several modern therapies against glioma are discovered, management is still a critical concern. The existing therapies were relatively inconsistent; moreover, the procedures as well are difcult to treat. These ineffective therapeutic approaches led researchers to identify the novel biomarkers that can be implemented with the existing therapies for better management. In this view, along with biomarker research, a literature search for exosomal PTEN detection in glioblastoma was conducted and the recent studies observed that exosomes can transport tumor-suppressive proteins (PTEN) and oncogenic mRNAs, microRNAs to a recipient cell, which subsequently activates the downstream signaling pathways and inuences the cellular phenotype. These exosomes facilitate the transfer of PTEN released from tumor cells to receipt cells that leads to tumor progression. Similarly, glioma was also associated with a reduction or loss of PTEN expression. Hence, our present review aimed to provide a holistic picture of glioblastoma, its pathogenesis and novel biomarkers with an emphasis on PTEN detection in exosomes for the early identication of glioblastoma

TAMI-31. GLIOBLASTOMA GENETIC DRIVERS DICTATE THE FUNCTION OF TUMOR-ASSOCIATED MACROPHAGES/MICROGLIA AND RESPONSES TO CSF1R INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi204-vi204
Author(s):  
Rohit Rao ◽  
Rong Han ◽  
Sean Ogurek ◽  
Lai Man Wu ◽  
Liguo Zhang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Tumor Therapy ◽  
Tumor Associated Macrophages ◽  
Transcriptomic Profiling ◽  
Angiogenic Therapy ◽  
Landscape Characterization ◽  
Specific Tumor ◽  
Glioma Growth ◽  
Human Gbm

Abstract Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth and progression. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment compositions and functions between the proneural-like and mesenchymal-like glioma models. We found that the growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal human GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas mesenchymal RAS-driven gliomas elicited TAMs enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and tumor mass in RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of microenvironment landscape characterization to optimally stratify glioma patients for TAM-targeted therapy.

scholarly journals Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Qi Chen ◽  
Jin Wu ◽  
Qing Ye ◽  
Feng Ma ◽  
Qian Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Brain Tumor ◽  
Zika Virus ◽  
Vaccine Candidate ◽  
Cell Subpopulation ◽  
Glioma Stem Cells ◽  
Intracerebral Injection ◽  
Potential Candidate ◽  
Orthotopic Model ◽  
Human Gbm

ABSTRACT Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy. IMPORTANCE Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemotherapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebral injection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.

scholarly journals Solitary vertebral metastatic glioblastoma in the absence of primary brain tumor relapse: a case report and literature review

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zu-Gui Li ◽  
Min-Ying Zheng ◽  
Qi Zhao ◽  
Kai Liu ◽  
Jia-Xing Du ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Case Report ◽  
Literature Review ◽  
Primary Brain Tumor ◽  
Tumor Relapse

scholarly journals Inflammation and Cancer: Extra- and Intracellular Determinants of Tumor-Associated Macrophages as Tumor Promoters

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Gabor J. Szebeni ◽  
Csaba Vizler ◽  
Klara Kitajka ◽  
Laszlo G. Puskas
Keyword(s):  
Tumor Microenvironment ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Therapeutic Interventions ◽  
Tumor Associated Macrophages ◽  
Poor Survival ◽  
Cell Functions ◽  
Intracellular Signals ◽  
Ontogenetic Diversity ◽  
Cell Dissemination

One of the hallmarks of cancer-related inflammation is the recruitment of monocyte-macrophage lineage cells to the tumor microenvironment. These tumor infiltrating myeloid cells are educated by the tumor milieu, rich in cancer cells and stroma components, to exert functions such as promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Our review highlights the ontogenetic diversity of tumor-associated macrophages (TAMs) and describes their main phenotypic markers. We cover fundamental molecular players in the tumor microenvironment including extra- (CCL2, CSF-1, CXCL12, IL-4, IL-13, semaphorins, WNT5A, and WNT7B) and intracellular signals. We discuss how these factors converge on intracellular determinants (STAT3, STAT6, STAT1, NF-κB, RORC1, and HIF-1α) of cell functions and drive the recruitment and polarization of TAMs. Since microRNAs (miRNAs) modulate macrophage polarization key miRNAs (miR-146a, miR-155, miR-125a, miR-511, and miR-223) are also discussed in the context of the inflammatory myeloid tumor compartment. Accumulating evidence suggests that high TAM infiltration correlates with disease progression and overall poor survival of cancer patients. Identification of molecular targets to develop new therapeutic interventions targeting these harmful tumor infiltrating myeloid cells is emerging nowadays.

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