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23 pages, 40858 KiB

Open AccessArticle

STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death

by Janina Remy, Benedikt Linder, Ulrike Weirauch, Bryan W. Day, Brett W. Stringer, Christel Herold-Mende, Achim Aigner, Knut Krohn and Donat Kögel

Cancers 2022, 14(2), 339; https://doi.org/10.3390/cancers14020339 - 11 Jan 2022

Cited by 8 | Viewed by 3691

Abstract

Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with [...] Read more.

Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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19 pages, 3939 KiB

Open AccessArticle

Combinatorial Effect of PLK1 Inhibition with Temozolomide and Radiation in Glioblastoma

by Arvind Pandey, Satyendra C. Tripathi, Junhua Mai, Samir M. Hanash, Haifa Shen, Sankar Mitra and Robert C. Rostomily

Cancers 2021, 13(20), 5114; https://doi.org/10.3390/cancers13205114 - 12 Oct 2021

Cited by 8 | Viewed by 3015

Abstract

New strategies that improve median survivals of only ~15–20 months for glioblastoma (GBM) with the current standard of care (SOC) which is concurrent temozolomide (TMZ) and radiation (XRT) treatment are urgently needed. Inhibition of polo-like kinase 1 (PLK1), a multifunctional cell cycle regulator, [...] Read more.

New strategies that improve median survivals of only ~15–20 months for glioblastoma (GBM) with the current standard of care (SOC) which is concurrent temozolomide (TMZ) and radiation (XRT) treatment are urgently needed. Inhibition of polo-like kinase 1 (PLK1), a multifunctional cell cycle regulator, overexpressed in GBM has shown therapeutic promise but has never been tested in the context of SOC. Therefore, we examined the mechanistic and therapeutic impact of PLK1 specific inhibitor (volasertib) alone and in combination with TMZ and/or XRT on GBM cells. We quantified the effects of volasertib alone and in combination with TMZ and/or XRT on GBM cell cytotoxicity/apoptosis, mitochondrial membrane potential (MtMP), reactive oxygen species (ROS), cell cycle, stemness, DNA damage, DNA repair genes, cellular signaling and in-vivo tumor growth. Volasertib alone and in combination with TMZ and/or XRT promoted apoptotic cell death, altered MtMP, increased ROS and G2/M cell cycle arrest. Combined volasertib and TMZ treatment reduced side population (SP) indicating activity against GBM stem-like cells. Volasertib combinatorial treatment also significantly increased DNA damage and reduced cell survival by inhibition of DNA repair gene expression and modulation of ERK/MAPK, AMPK and glucocorticoid receptor signaling. Finally, as observed in-vitro, combined volasertib and TMZ treatment resulted in synergistic inhibition of tumor growth in-vivo. Together these results identify new mechanisms of action for volasertib that provide a strong rationale for further investigation of PLK1 inhibition as an adjunct to current GBM SOC therapy. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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17 pages, 4922 KiB

Open AccessArticle

Photodynamic Therapy Combined with Bcl-2/Bcl-xL Inhibition Increases the Noxa/Mcl-1 Ratio Independent of Usp9X and Synergistically Enhances Apoptosis in Glioblastoma

by Carolin Golla, Mayas Bilal, Annika Dwucet, Nicolas Bader, Jenson Anthonymuthu, Tim Heiland, Maximilian Pruss, Mike-Andrew Westhoff, Markus David Siegelin, Felix Capanni, Christian Rainer Wirtz, Richard Eric Kast, Marc-Eric Halatsch and Georg Karpel-Massler

Cancers 2021, 13(16), 4123; https://doi.org/10.3390/cancers13164123 - 17 Aug 2021

Cited by 11 | Viewed by 4314

Abstract

The purpose of this study was to assess in vitro whether the biological effects of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy are enhanced by inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in different glioblastoma models. Pre-clinical testing of a microcontroller-based device [...] Read more.

The purpose of this study was to assess in vitro whether the biological effects of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy are enhanced by inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in different glioblastoma models. Pre-clinical testing of a microcontroller-based device emitting light of 405 nm wavelength in combination with exposure to 5-ALA (PDT) and the Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax) was performed in human established and primary cultured glioblastoma cells as well as glioma stem-like cells. We applied cell count analyses to assess cellular proliferation and Annexin V/PI staining to examine pro-apoptotic effects. Western blot analyses and specific knockdown experiments using siRNA were used to examine molecular mechanisms of action. Bcl-2/Bcl-xL inhibition synergistically enhanced apoptosis in combination with PDT. This effect was caspase-dependent. On the molecular level, PDT caused an increased Noxa/Mcl-1 ratio, which was even more pronounced when combined with ABT-263 in a Usp9X-independent manner. Our data showed that Bcl-2/Bcl-xL inhibition increases the response of glioblastoma cells toward photodynamic therapy. This effect can be partly attributed to cytotoxicity and is likely related to a pro-apoptotic shift because of an increased Noxa/Mcl-1 ratio. The results of this study warrant further investigation. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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28 pages, 8550 KiB

Open AccessArticle

Targeting c-IAP1, c-IAP2, and Bcl-2 Eliminates Senescent Glioblastoma Cells Following Temozolomide Treatment

by Christian Schwarzenbach, Larissa Tatsch, Juliana Brandstetter Vilar, Birgit Rasenberger, Lea Beltzig, Bernd Kaina, Maja T. Tomicic and Markus Christmann

Cancers 2021, 13(14), 3585; https://doi.org/10.3390/cancers13143585 - 17 Jul 2021

Cited by 24 | Viewed by 3359

Abstract

Therapy of malignant glioma depends on the induction of O⁶-methylguanine by the methylating agent temozolomide (TMZ). However, following TMZ exposure, most glioma cells evade apoptosis and become senescent and are thereby protected against further anticancer therapy. This protection is thought to [...] Read more.

Therapy of malignant glioma depends on the induction of O⁶-methylguanine by the methylating agent temozolomide (TMZ). However, following TMZ exposure, most glioma cells evade apoptosis and become senescent and are thereby protected against further anticancer therapy. This protection is thought to be dependent on the senescent cell anti-apoptotic pathway (SCAP). Here we analyzed the factors involved in the SCAP upon exposure to TMZ in glioblastoma cell lines (LN-229, A172, U87MG) and examined whether inhibition of these factors could enhance TMZ-based toxicity by targeting senescent cells. We observed that following TMZ treatment, c-IAP2 and Bcl-2 were upregulated. Inhibition of these SCAP factors using non-toxic concentrations of the small molecule inhibitors, BV6 and venetoclax, significantly increased cell death, as measured 144 h after TMZ exposure. Most importantly, BV6 and venetoclax treatment of senescent cells strongly increased cell death after an additional 120 h. Moreover, Combenefit analyses revealed a significant synergy combining BV6 and venetoclax. In contrast to BV6 and venetoclax, AT406, embelin, and TMZ itself, teniposide and the PARP inhibitor pamiparib did not increase cell death in senescent cells. Based on these data, we suggest that BV6 and venetoclax act as senolytic agents in glioblastoma cells upon TMZ exposure. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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23 pages, 4129 KiB

Open AccessArticle

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide

by Julia Gerstmeier, Anna-Lena Possmayer, Süleyman Bozkurt, Marina E. Hoffmann, Ivan Dikic, Christel Herold-Mende, Michael C. Burger, Christian Münch, Donat Kögel and Benedikt Linder

Cancers 2021, 13(14), 3577; https://doi.org/10.3390/cancers13143577 - 16 Jul 2021

Cited by 14 | Viewed by 3211

Abstract

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and [...] Read more.

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D₃, while the low pH within tumors has been shown to promote the expression of the vitamin D₃-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D₃, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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18 pages, 4067 KiB

Open AccessArticle

Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

by Justyna M. Przystal, Hannes Becker, Denis Canjuga, Foteini Tsiami, Nicole Anderle, Anna-Lena Keller, Anja Pohl, Carola H. Ries, Martina Schmittnaegel, Nataliya Korinetska, Marilin Koch, Jens Schittenhelm, Marcos Tatagiba, Christian Schmees, Susanne C. Beck and Ghazaleh Tabatabai

Cancers 2021, 13(10), 2400; https://doi.org/10.3390/cancers13102400 - 15 May 2021

Cited by 33 | Viewed by 5067

Abstract

Glioblastoma is an aggressive primary tumor of the central nervous system. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting therapeutic approach. Tumor-associated macrophages represent an abundant population of tumor-infiltrating host cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) [...] Read more.

Glioblastoma is an aggressive primary tumor of the central nervous system. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting therapeutic approach. Tumor-associated macrophages represent an abundant population of tumor-infiltrating host cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We investigated combination treatments of anti-CSF1R alone or in combination with anti-PD1 antibodies in an orthotopic syngeneic glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies led to longterm survivors in vivo. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Our results identify CSF1R as a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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17 pages, 5178 KiB

Open AccessArticle

HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells

by Ping Shi, Lan B. Hoang-Minh, Jia Tian, Alice Cheng, Reemsha Basrai, Neil Kalaria, Joseph J. Lebowitz, Habibeh Khoshbouei, Loic P. Deleyrolle and Matthew R. Sarkisian

Cancers 2021, 13(7), 1644; https://doi.org/10.3390/cancers13071644 - 1 Apr 2021

Cited by 16 | Viewed by 4177

Abstract

Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma [...] Read more.

Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown. We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. While both inhibitors triggered rapid increases in acetylated alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on tumor cell cilia, we generated patient-derived glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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19 pages, 10754 KiB

Open AccessArticle

Integrin α10-Antibodies Reduce Glioblastoma Tumor Growth and Cell Migration

by Katarzyna Chmielarska Masoumi, Xiaoli Huang, Wondossen Sime, Anna Mirkov, Matilda Munksgaard Thorén, Ramin Massoumi and Evy Lundgren-Åkerlund

Cancers 2021, 13(5), 1184; https://doi.org/10.3390/cancers13051184 - 9 Mar 2021

Cited by 4 | Viewed by 3527

Abstract

Glioblastoma (GB) is the most common and the most aggressive form of brain tumor in adults, which currently lacks efficient treatment strategies. In this study, we investigated the therapeutic effect of function-blocking antibodies targeting integrin α10β1 on patient-derived-GB cell lines in vitro and [...] Read more.

Glioblastoma (GB) is the most common and the most aggressive form of brain tumor in adults, which currently lacks efficient treatment strategies. In this study, we investigated the therapeutic effect of function-blocking antibodies targeting integrin α10β1 on patient-derived-GB cell lines in vitro and in vivo. The in vitro studies demonstrated significant inhibiting effects of the integrin α10 antibodies on the adhesion, migration, proliferation, and sphere formation of GB cells. In a xenograft mouse model, the effect of the antibodies on tumor growth was investigated in luciferase-labeled and subcutaneously implanted GB cells. As demonstrated by in vivo imaging analysis and caliper measurements, the integrin α10-antibodies significantly suppressed GB tumor growth compared to control antibodies. Immunohistochemical analysis of the GB tumors showed lower expression of the proliferation marker Ki67 and an increased expression of cleaved caspase-3 after treatment with integrin α10 antibodies, further supporting a therapeutic effect. Our results suggest that function-blocking antibody targeting integrin α10β1 is a promising therapeutic strategy for the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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18 pages, 5103 KiB

Open AccessArticle

Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype

by Teresa Cejalvo, Ricardo Gargini, Berta Segura-Collar, Pablo Mata-Martínez, Beatriz Herranz, Diana Cantero, Yolanda Ruano, Daniel García-Pérez, Ángel Pérez-Núñez, Ana Ramos, Aurelio Hernández-Laín, María Cruz Martín-Soberón, Pilar Sánchez-Gómez and Juan M. Sepúlveda-Sánchez

Cancers 2020, 12(11), 3230; https://doi.org/10.3390/cancers12113230 - 2 Nov 2020

Cited by 18 | Viewed by 2599

Abstract

Background: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. Methods: [...] Read more.

Background: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. Methods: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. Results: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. Conclusions: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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18 pages, 14411 KiB

Open AccessArticle

Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics

by Tali Voloshin, Rosa Sara Schneiderman, Alexandra Volodin, Reuben Ruby Shamir, Noa Kaynan, Einav Zeevi, Lilach Koren, Anat Klein-Goldberg, Rom Paz, Moshe Giladi, Zeev Bomzon, Uri Weinberg and Yoram Palti

Cancers 2020, 12(10), 3016; https://doi.org/10.3390/cancers12103016 - 17 Oct 2020

Cited by 56 | Viewed by 5995

Abstract

Tumor Treating Fields (TTFields) are noninvasive, alternating electric fields within the intermediate frequency range (100–300 kHz) that are utilized as an antimitotic cancer treatment. TTFields are loco-regionally delivered to the tumor region through 2 pairs of transducer arrays placed on the skin. This [...] Read more.

Tumor Treating Fields (TTFields) are noninvasive, alternating electric fields within the intermediate frequency range (100–300 kHz) that are utilized as an antimitotic cancer treatment. TTFields are loco-regionally delivered to the tumor region through 2 pairs of transducer arrays placed on the skin. This novel treatment modality has been FDA-approved for use in patients with glioblastoma and malignant pleural mesothelioma based on clinical trial data demonstrating efficacy and safety; and is currently under investigation in other types of solid tumors. TTFields were shown to induce an anti-mitotic effect by exerting bi-directional forces on highly polar intracellular elements, such as tubulin and septin molecules, eliciting abnormal microtubule polymerization during spindle formation as well as aberrant cleavage furrow formation. Previous studies have demonstrated that TTFields inhibit metastatic properties in cancer cells. However, the consequences of TTFields application on cytoskeleton dynamics remain undetermined. In this study, methods utilized in combination to study the effects of TTFields on cancer cell motility through regulation of microtubule and actin dynamics included confocal microscopy, computational tools, and biochemical analyses. Mechanisms by which TTFields treatment disrupted cellular polarity were (1) interference with microtubule assembly and directionality; (2) altered regulation of Guanine nucleotide exchange factor-H1 (GEF-H1), Ras homolog family member A (RhoA), and Rho-associated coiled-coil kinase (ROCK) activity; and (3) induced formation of radial protrusions of peripheral actin filaments and focal adhesions. Overall, these data identified discrete effects of TTFields that disrupt processes crucial for cancer cell motility. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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22 pages, 2671 KiB

Open AccessArticle

Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo

by Marija Nešović, Aleksandra Divac Rankov, Ana Podolski-Renić, Igor Nikolić, Goran Tasić, Arianna Mancini, Silvia Schenone, Milica Pešić and Jelena Dinić

Cancers 2020, 12(6), 1570; https://doi.org/10.3390/cancers12061570 - 14 Jun 2020

Cited by 14 | Viewed by 3982

Abstract

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors [...] Read more.

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood–brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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Review

Jump to: Research

25 pages, 854 KiB

Open AccessReview

Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities

by Johannes K. Andersen, Hrvoje Miletic and Jubayer A. Hossain

Cancers 2022, 14(5), 1319; https://doi.org/10.3390/cancers14051319 - 4 Mar 2022

Cited by 51 | Viewed by 5034

Abstract

Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, [...] Read more.

Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia—collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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15 pages, 1185 KiB

Open AccessReview

APLN/APLNR Signaling Controls Key Pathological Parameters of Glioblastoma

by Roland E. Kälin and Rainer Glass

Cancers 2021, 13(15), 3899; https://doi.org/10.3390/cancers13153899 - 2 Aug 2021

Cited by 7 | Viewed by 3639

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM-expansion depends on a dense vascular network and, coherently, GBMs are highly angiogenic. However, new intratumoral blood vessels are often aberrant with consequences for blood-flow and vascular barrier function. Hence, [...] Read more.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM-expansion depends on a dense vascular network and, coherently, GBMs are highly angiogenic. However, new intratumoral blood vessels are often aberrant with consequences for blood-flow and vascular barrier function. Hence, the delivery of chemotherapeutics into GBM can be compromised. Furthermore, leaky vessels support edema-formation, which can result in severe neurological deficits. The secreted signaling peptide Apelin (APLN) plays an important role in the formation of GBM blood vessels. Both APLN and the Apelin receptor (APLNR) are upregulated in GBM cells and control tumor cell invasiveness. Here we summarize the current evidence on the role of APLN/APLNR signaling during brain tumor pathology. We show that targeting APLN/APLNR can induce anti-angiogenic effects in GBM and simultaneously blunt GBM cell infiltration. In addition, we discuss how manipulation of APLN/APLNR signaling in GBM leads to the normalization of tumor vessels and thereby supports chemotherapy, reduces edema, and improves anti-tumorigenic immune reactions. Hence, therapeutic targeting of APLN/APLNR signaling offers an interesting option to address different pathological hallmarks of GBM. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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32 pages, 4377 KiB

Open AccessReview

Noncoding RNAs in Glioblastoma: Emerging Biological Concepts and Potential Therapeutic Implications

by Uswa Shahzad, Stacey Krumholtz, James T. Rutka and Sunit Das

Cancers 2021, 13(7), 1555; https://doi.org/10.3390/cancers13071555 - 28 Mar 2021

Cited by 26 | Viewed by 3912

Abstract

Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), [...] Read more.

Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), which have been linked to many important developmental and disease processes and are being pursued as clinical and therapeutic targets. Molecular phenotyping studies of glioblastoma (GBM), the most common and lethal cancer of the adult brain, revealed that several ncRNAs are frequently dysregulated in its pathogenesis. Additionally, ncRNAs regulate many important aspects of glioma biology including tumour cell proliferation, migration, invasion, apoptosis, angiogenesis, and self-renewal. Here, we present an overview of the biogenesis of the different classes of ncRNAs, discuss their biological roles, as well as their relevance to gliomagenesis. We conclude by discussing potential approaches to therapeutically target the ncRNAs in clinic. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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25 pages, 1632 KiB

Open AccessEditor’s ChoiceReview

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

by Alexander Ou, Martina Ott, Dexing Fang and Amy B. Heimberger

Cancers 2021, 13(3), 437; https://doi.org/10.3390/cancers13030437 - 24 Jan 2021

Cited by 69 | Viewed by 6822

Abstract

Glioblastoma remains one of the deadliest and treatment-refractory human malignancies in large part due to its diffusely infiltrative nature, molecular heterogeneity, and capacity for immune escape. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes substantively to a wide variety [...] Read more.

Glioblastoma remains one of the deadliest and treatment-refractory human malignancies in large part due to its diffusely infiltrative nature, molecular heterogeneity, and capacity for immune escape. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes substantively to a wide variety of protumorigenic functions, including proliferation, anti-apoptosis, angiogenesis, stem cell maintenance, and immune suppression. We review the current state of knowledge regarding the biological role of JAK/STAT signaling in glioblastoma, therapeutic strategies, and future directions for the field. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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18 pages, 9878 KiB

Open AccessReview

Satellitosis, a Crosstalk between Neurons, Vascular Structures and Neoplastic Cells in Brain Tumours; Early Manifestation of Invasive Behaviour

by Prospero Civita, Ortenzi Valerio, Antonio Giuseppe Naccarato, Mark Gumbleton and Geoffrey J. Pilkington

Cancers 2020, 12(12), 3720; https://doi.org/10.3390/cancers12123720 - 11 Dec 2020

Cited by 12 | Viewed by 5238

Abstract

The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse, invasive, high-grade gliomas. They are recognised as perineuronal satellitosis when clusters of neoplastic glial cells surround neurons cell bodies and perivascular satellitosis [...] Read more.

The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse, invasive, high-grade gliomas. They are recognised as perineuronal satellitosis when clusters of neoplastic glial cells surround neurons cell bodies and perivascular satellitosis when such tumour cells surround blood vessels infiltrating Virchow–Robin spaces. In this review, we provide an overview of emerging knowledge regarding how interactions between neurons and glioma cells can modulate tumour evolution and how neurons play a key role in glioma growth and progression, as well as the role of perivascular satellitosis into mechanisms of glioma cells spread. At the same time, we review the current knowledge about the role of perineuronal satellitosis and perivascular satellitosis within the tumour microenvironment (TME), in order to highlight critical knowledge gaps in research space. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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26 pages, 2147 KiB

Open AccessReview

The Role of Translocator Protein TSPO in Hallmarks of Glioblastoma

by Laura-Marie Ammer, Arabel Vollmann-Zwerenz, Viktoria Ruf, Christian H. Wetzel, Markus J. Riemenschneider, Nathalie L. Albert, Philipp Beckhove and Peter Hau

Cancers 2020, 12(10), 2973; https://doi.org/10.3390/cancers12102973 - 14 Oct 2020

Cited by 40 | Viewed by 6344

Abstract

Glioblastoma (GBM) is the most fatal primary brain cancer in adults. Despite extensive treatment, tumors inevitably recur, leading to an average survival time shorter than 1.5 years. The 18 kDa translocator protein (TSPO) is abundantly expressed throughout the body including the central nervous [...] Read more.

Glioblastoma (GBM) is the most fatal primary brain cancer in adults. Despite extensive treatment, tumors inevitably recur, leading to an average survival time shorter than 1.5 years. The 18 kDa translocator protein (TSPO) is abundantly expressed throughout the body including the central nervous system. The expression of TSPO increases in states of inflammation and brain injury due to microglia activation. Not least due to its location in the outer mitochondrial membrane, TSPO has been implicated with a broad spectrum of functions. These include the regulation of proliferation, apoptosis, migration, as well as mitochondrial functions such as mitochondrial respiration and oxidative stress regulation. TSPO is frequently overexpressed in GBM. Its expression level has been positively correlated to WHO grade, glioma cell proliferation, and poor prognosis of patients. Several lines of evidence indicate that TSPO plays a functional part in glioma hallmark features such as resistance to apoptosis, invasiveness, and proliferation. This review provides a critical overview of how TSPO could regulate several aspects of tumorigenesis in GBM, particularly in the context of the hallmarks of cancer proposed by Hanahan and Weinberg in 2011. Full article

(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)

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