Cells

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19 pages, 4543 KiB

Open AccessArticle

Isolated Peptide from Spider Venom Modulates Dendritic Cells In Vitro: A Possible Application in Oncoimmunotherapy for Glioblastoma

by Felipe Cezar de Mato, Natália Barreto, Gabriel Cordeiro, Jaqueline Munhoz, Amanda Pires Bonfanti, Thomaz A. A. da Rocha-e-Silva, Rafael Sutti, Priscilla B. M. Cruz, Livia R. Sanches, André Luis Bombeiro, Ghanbar Mahmoodi Chalbatani, Liana Verinaud and Catarina Rapôso

Cells 2023, 12(7), 1023; https://doi.org/10.3390/cells12071023 - 27 Mar 2023

Cited by 1 | Viewed by 1646

Abstract

Dendritic cells (DCs) vaccine is a potential tool for oncoimmunotherapy. However, it is known that this therapeutic strategy has failed in solid tumors, making the development of immunoadjuvants highly relevant. Recently, we demonstrated that Phoneutria nigriventer spider venom (PnV) components are cytotoxic to [...] Read more.

Dendritic cells (DCs) vaccine is a potential tool for oncoimmunotherapy. However, it is known that this therapeutic strategy has failed in solid tumors, making the development of immunoadjuvants highly relevant. Recently, we demonstrated that Phoneutria nigriventer spider venom (PnV) components are cytotoxic to glioblastoma (GB) and activate macrophages for an antitumor profile. However, the effects of these molecules on the adaptive immune response have not yet been evaluated. This work aimed to test PnV and its purified fractions in DCs in vitro. For this purpose, bone marrow precursors were collected from male C57BL6 mice, differentiated into DCs and treated with venom or PnV-isolated fractions (F1—molecules < 3 kDa, F2—3 to 10 kDa and F3—>10 kDa), with or without costimulation with human GB lysate. The results showed that mainly F1 was able to activate DCs, increasing the activation-dependent surface marker (CD86) and cytokine release (IL-1β, TNF-α), in addition to inducing a typical morphology of mature DCs. From the F1 purification, a molecule named LW9 was the most effective, and mass spectrometry showed it to be a peptide. The present findings suggest that this molecule could be an immunoadjuvant with possible application in DC vaccines for the treatment of GB. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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17 pages, 4853 KiB

Open AccessArticle

Rnd3 Is a Crucial Mediator of the Invasive Phenotype of Glioblastoma Cells Downstream of Receptor Tyrosine Kinase Signalling

by Beatriz Almarán, Guillem Ramis, Silvia Fernández de Mattos and Priam Villalonga

Cells 2022, 11(23), 3716; https://doi.org/10.3390/cells11233716 - 22 Nov 2022

Cited by 1 | Viewed by 1700

Abstract

Enhanced invasiveness is one of the defining biological traits of glioblastoma cells, which exhibit an infiltrative nature that severely hinders surgical resection. Among the molecular lesions responsible for GBM aggressiveness, aberrant receptor tyrosine kinase (RTK) signalling is well-characterised. Enhanced RTK signalling directly impacts [...] Read more.

Enhanced invasiveness is one of the defining biological traits of glioblastoma cells, which exhibit an infiltrative nature that severely hinders surgical resection. Among the molecular lesions responsible for GBM aggressiveness, aberrant receptor tyrosine kinase (RTK) signalling is well-characterised. Enhanced RTK signalling directly impacts a myriad of cellular pathways and downstream effectors, which include the Rho GTPase family, key regulators of actin cytoskeletal dynamics. Here, we have analysed the functional crosstalk between oncogenic signals emanating from RTKs and Rho GTPases and focused on the specific contribution of Rnd3 to the invasive phenotype of GBM in this context. We found that RTK inhibition with a panel of RTK inhibitors decreased cell motility and cell invasion and promoted dramatic actin cytoskeleton reorganisation through activation of the RhoA/Rho-associated protein kinase 1 (ROCK) axis. RTK inhibition also significantly decreased Rnd3 expression levels. Consistently, shRNA-mediated Rnd3 silencing revealed that Rnd3 depletion promoted substantial changes in the actin cytoskeleton and reduced cell motility and invasion capacity, recapitulating the effects observed upon RTK inhibition. Our results indicate that Rnd3 is a crucial mediator of RTK oncogenic signalling involved in actin cytoskeletal reorganisation, which contributes to determining the invasive phenotype of GBM cells. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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19 pages, 4490 KiB

Open AccessArticle

Targeting Acid Ceramidase Inhibits Glioblastoma Cell Migration through Decreased AKT Signaling

by Cyntanna C. Hawkins, Amber B. Jones, Emily R. Gordon, Sarah E. Williford, Yuvika Harsh, Julia K. Ziebro, Catherine J. Landis, Sajina Gc, David K. Crossman, Sara J. Cooper, Sasanka Ramanadham, Ninh Doan and Anita B. Hjelmeland

Cells 2022, 11(12), 1873; https://doi.org/10.3390/cells11121873 - 9 Jun 2022

Cited by 10 | Viewed by 3241

Abstract

Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the [...] Read more.

Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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19 pages, 13976 KiB

Open AccessArticle

The Cytoskeleton Effectors Rho-Kinase (ROCK) and Mammalian Diaphanous-Related (mDia) Formin Have Dynamic Roles in Tumor Microtube Formation in Invasive Glioblastoma Cells

by Kathryn N. Becker, Krista M. Pettee, Amanda Sugrue, Kevin A. Reinard, Jason L. Schroeder and Kathryn M. Eisenmann

Cells 2022, 11(9), 1559; https://doi.org/10.3390/cells11091559 - 5 May 2022

Cited by 9 | Viewed by 2613

Abstract

Glioblastoma (GBM) is a progressive and lethal brain cancer. Malignant control of actin and microtubule cytoskeletal mechanics facilitates two major GBM therapeutic resistance strategies—diffuse invasion and tumor microtube network formation. Actin and microtubule reorganization is controlled by Rho-GTPases, which exert their effects through [...] Read more.

Glioblastoma (GBM) is a progressive and lethal brain cancer. Malignant control of actin and microtubule cytoskeletal mechanics facilitates two major GBM therapeutic resistance strategies—diffuse invasion and tumor microtube network formation. Actin and microtubule reorganization is controlled by Rho-GTPases, which exert their effects through downstream effector protein activation, including Rho-associated kinases (ROCK) 1 and 2 and mammalian diaphanous-related (mDia) formins (mDia1, 2, and 3). Precise spatial and temporal balancing of the activity between these effectors dictates cell shape, adhesion turnover, and motility. Using small molecules targeting mDia, we demonstrated that global agonism (IMM02) was superior to antagonism (SMIFH2) as anti-invasion strategies in GBM spheroids. Here, we use IDH-wild-type GBM patient-derived cell models and a novel semi-adherent in vitro system to investigate the relationship between ROCK and mDia in invasion and tumor microtube networks. IMM02-mediated mDia agonism disrupts invasion in GBM patient-derived spheroid models, in part by inducing mDia expression loss and tumor microtube network collapse. Pharmacological disruption of ROCK prevented invasive cell-body movement away from GBM spheres, yet induced ultralong, phenotypically abnormal tumor microtube formation. Simultaneously targeting mDia and ROCK did not enhance the anti-invasive/-tumor microtube effects of IMM02. Our data reveal that targeting mDia is a viable GBM anti-invasion/-tumor microtube networking strategy, while ROCK inhibition is contraindicated. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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15 pages, 2920 KiB

Open AccessArticle

Unraveling of Functional Activity of Primary Hippocampal Neuron-Glial Networks in Photodynamic Therapy Based on Tetracyanotetra(aryl)porphyrazines

by Maria O. Savyuk, Victoria D. Turubanova, Tatiana A. Mishchenko, Svetlana A. Lermontova, Larisa G. Klapshina, Dmitri V. Krysko and Maria V. Vedunova

Cells 2022, 11(7), 1212; https://doi.org/10.3390/cells11071212 - 4 Apr 2022

Cited by 7 | Viewed by 1827

Abstract

The current efforts in photodynamic therapy (PDT) of brain cancer are focused on the development of novel photosensitizers with improved photodynamic properties, targeted specific localization, and sensitivity to the irradiation dose, ensuring the effectiveness of PDT with fewer side effects for normal nerve [...] Read more.

The current efforts in photodynamic therapy (PDT) of brain cancer are focused on the development of novel photosensitizers with improved photodynamic properties, targeted specific localization, and sensitivity to the irradiation dose, ensuring the effectiveness of PDT with fewer side effects for normal nerve tissue. Here, we characterize the effects of four photosensitizers of the tetracyanotetra(aryl)porphyrazine group (pz I–IV) on the functional activity of neuron-glial networks in primary hippocampal cultures in their application in normal conditions and under PDT. The data revealed that the application of pz I–IV leads to a significant decrease in the main parameters of the functional calcium activity of neuron-glial networks and pronounced changes in the network characteristics. The observed negative effects of pz I–IV were aggravated under PDT. Considering the significant restructuring of the functional architectonics of neuron-glial networks that can lead to severe impairments in synaptic transmission and loss of brain functions, and the feasibility of direct application of PDT based on pz I–IV in the therapy of brain tumors is highly controversial. Nevertheless, the unique properties of pz I–IV retain a great prospect of their use in the therapy of tumors of another origin and cellular metabolism. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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16 pages, 2872 KiB

Open AccessFeature PaperArticle

GPER Agonist G-1 Disrupts Tubulin Dynamics and Potentiates Temozolomide to Impair Glioblastoma Cell Proliferation

by Alex Hirtz, Nolwenn Lebourdais, Fabien Rech, Yann Bailly, Athénaïs Vaginay, Malika Smaïl-Tabbone, Hélène Dubois-Pot-Schneider and Hélène Dumond

Cells 2021, 10(12), 3438; https://doi.org/10.3390/cells10123438 - 7 Dec 2021

Cited by 13 | Viewed by 2713

Abstract

Glioblastoma (GBM) is the most common brain tumor in adults, which is very aggressive, with a very poor prognosis that affects men twice as much as women, suggesting that female hormones (estrogen) play a protective role. With an in silico approach, we highlighted [...] Read more.

Glioblastoma (GBM) is the most common brain tumor in adults, which is very aggressive, with a very poor prognosis that affects men twice as much as women, suggesting that female hormones (estrogen) play a protective role. With an in silico approach, we highlighted that the expression of the membrane G-protein-coupled estrogen receptor (GPER) had an impact on GBM female patient survival. In this context, we explored for the first time the role of the GPER agonist G-1 on GBM cell proliferation. Our results suggested that G-1 exposure had a cytostatic effect, leading to reversible G2/M arrest, due to tubulin polymerization blockade during mitosis. However, the observed effect was independent of GPER. Interestingly, G-1 potentiated the efficacy of temozolomide, the current standard chemotherapy treatment, since the combination of both treatments led to prolonged mitotic arrest, even in a temozolomide less-sensitive cell line. In conclusion, our results suggested that G-1, in combination with standard chemotherapy, might be a promising way to limit the progression and aggressiveness of GBM. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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19 pages, 3585 KiB

Open AccessArticle

A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma

by Megan R. Reed, A. Geoffrey Lyle, Annick De Loose, Leena Maddukuri, Katrina Learned, Holly C. Beale, Ellen T. Kephart, Allison Cheney, Anouk van den Bout, Madison P. Lee, Kelsey N. Hundley, Ashley M. Smith, Teresa M. DesRochers, Cecile Rose T. Vibat, Murat Gokden, Sofie Salama, Christopher P. Wardell, Robert L. Eoff, Olena M. Vaske and Analiz Rodriguez

Cells 2021, 10(12), 3400; https://doi.org/10.3390/cells10123400 - 2 Dec 2021

Cited by 15 | Viewed by 6621

Abstract

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30–50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets [...] Read more.

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30–50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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12 pages, 1294 KiB

Open AccessArticle

PD-L1 Expression Fluctuates Concurrently with Cyclin D in Glioblastoma Cells

by Martina Tufano, Paolo D’Arrigo, Massimo D’Agostino, Carolina Giordano, Laura Marrone, Elena Cesaro, Maria Fiammetta Romano and Simona Romano

Cells 2021, 10(9), 2366; https://doi.org/10.3390/cells10092366 - 9 Sep 2021

Cited by 13 | Viewed by 2754

Abstract

Despite Glioblastoma (GBM) frequently expressing programmed cell death ligand-1 (PD-L1), treatment with anti-programmed cell death-1 (PD1) has not yielded brilliant results. Intratumor variability of PD-L1 can impact determination accuracy. A previous study on mouse embryonic fibroblasts (MEFs) reported a role for cyclin-D in [...] Read more.

Despite Glioblastoma (GBM) frequently expressing programmed cell death ligand-1 (PD-L1), treatment with anti-programmed cell death-1 (PD1) has not yielded brilliant results. Intratumor variability of PD-L1 can impact determination accuracy. A previous study on mouse embryonic fibroblasts (MEFs) reported a role for cyclin-D in control of PD-L1 expression. Because tumor-cell growth within a cancer is highly heterogeneous, we looked at whether PD-L1 and its cochaperone FKBP51s were influenced by cell proliferation, using U251 and SF767 GBM-cell-lines. PD-L1 was measured by Western blot, flow cytometry, confocal-microscopy, quantitative PCR (qPCR), CCND1 by qPCR, FKBP51s by Western blot and confocal-microscopy. Chromatin-Immunoprecipitation assay (xChIp) served to assess the DNA-binding of FKBP51 isoforms. In the course of cell culture, PD-L1 appeared to increase concomitantly to cyclin-D on G1/S transition, to decrease during exponential cell growth progressively. We calculated a correlation between CCND1 and PD-L1 gene expression levels. In the temporal window of PD-L1 and CCND1 peak, FKBP51s localized in ER. When cyclin-D declined, FKBP51s went nuclear. XChIp showed that FKBP51s binds CCND1 gene in a closed-chromatin configuration. Our finding suggests that the dynamism of PD-L1 expression in GBM follows cyclin-D fluctuation and raises the hypothesis that FKBP51s might participate in the events that govern cyclin-D oscillation. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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19 pages, 2286 KiB

Open AccessArticle

ERK Phosphorylation Regulates the Aml1/Runx1 Splice Variants and the TRP Channels Expression during the Differentiation of Glioma Stem Cell Lines

by Giorgio Santoni, Massimo Nabissi, Consuelo Amantini, Matteo Santoni, Lucia Ricci-Vitiani, Roberto Pallini, Federica Maggi and Maria Beatrice Morelli

Cells 2021, 10(8), 2052; https://doi.org/10.3390/cells10082052 - 10 Aug 2021

Cited by 7 | Viewed by 3123

Abstract

The identification of cancer stem cells in brain tumors paved the way for new therapeutic approaches. Recently, a role for the transcriptional factor Runx1/Aml1 and the downstream ion channel genes in brain cancer development and progression has been suggested. This study aimed to [...] Read more.

The identification of cancer stem cells in brain tumors paved the way for new therapeutic approaches. Recently, a role for the transcriptional factor Runx1/Aml1 and the downstream ion channel genes in brain cancer development and progression has been suggested. This study aimed to explore the expression and the role of Runx1/Aml1, its Aml1b and Aml1c splice variants and the downstream TRPA1 and TRPV1 ion channels in undifferentiated and day-14 differentiated neural stem cells (NSCs and D-NSCs) and glioblastoma stem cells (GSCs and D-GSCs) lines with different proneural (PN) or mesenchymal (MES) phenotype. Gene and protein expression were evaluated by qRT-PCR, cytofluorimetric, western blot and confocal microscopy analyses. Moreover, by western blot, we observed that ERK phosphorylation enhances the Aml1b and Aml1c protein expression during glioma differentiation. Furthermore, the agonists of TRPA1 and TRPV1 channels stimulated apoptosis/necrosis in GSCs and D-GSCs as evaluated by Annexin V and PI staining and cytofluorimetric analysis. Finally, by qRT-PCR, the modulation of Wnt/β catenin, FGF, and TGFβ/SMAD signaling pathways in PN- and MES-GSCs was reported. Overall, our results provide new evidence regarding Runx1/Aml1 isoform overexpression and modulation in TRP channel expression during gliomagenesis, thus offering new directions for glioblastoma therapy. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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Review

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11 pages, 2335 KiB

Open AccessReview

Cancer Stem Cell-Associated Immune Microenvironment in Recurrent Glioblastomas

by Yoshitaka Murota, Kouichi Tabu and Tetsuya Taga

Cells 2022, 11(13), 2054; https://doi.org/10.3390/cells11132054 - 28 Jun 2022

Cited by 9 | Viewed by 2618

Abstract

Glioblastoma multiforme (GBM) is the most incurable tumor (due to the difficulty in complete surgical resection and the resistance to conventional chemo/radiotherapies) that displays a high relapse frequency. Cancer stem cells (CSCs) have been considered as a promising target responsible for therapy resistance [...] Read more.

Glioblastoma multiforme (GBM) is the most incurable tumor (due to the difficulty in complete surgical resection and the resistance to conventional chemo/radiotherapies) that displays a high relapse frequency. Cancer stem cells (CSCs) have been considered as a promising target responsible for therapy resistance and cancer recurrence. CSCs are known to organize a self-advantageous microenvironment (niche) for their maintenance and expansion. Therefore, understanding how the microenvironment is reconstructed by the remaining CSCs after conventional treatments and how it eventually causes recurrence should be essential to inhibit cancer recurrence. However, the number of studies focusing on recurrence is limited, particularly those related to tumor immune microenvironment, while numerous data have been obtained from primary resected samples. Here, we summarize recent investigations on the immune microenvironment from the viewpoint of recurrent GBM (rGBM). Based on the recurrence-associated immune cell composition reported so far, we will discuss how CSCs manipulate host immunity and create the special microenvironment for themselves to regrow. An integrated understanding of the interactions between CSCs and host immune cells at the recurrent phase will lead us to develop innovative therapies and diagnoses to achieve GBM eradication. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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18 pages, 1081 KiB

Open AccessReview

Applications of CRISPR-Cas9 Technology to Genome Editing in Glioblastoma Multiforme

by Nadia Al-Sammarraie and Swapan K. Ray

Cells 2021, 10(9), 2342; https://doi.org/10.3390/cells10092342 - 7 Sep 2021

Cited by 17 | Viewed by 5316

Abstract

Glioblastoma multiforme (GBM) is an aggressive malignancy of the brain and spinal cord with a poor life expectancy. The low survivability of GBM patients can be attributed, in part, to its heterogeneity and the presence of multiple genetic alterations causing rapid tumor growth [...] Read more.

Glioblastoma multiforme (GBM) is an aggressive malignancy of the brain and spinal cord with a poor life expectancy. The low survivability of GBM patients can be attributed, in part, to its heterogeneity and the presence of multiple genetic alterations causing rapid tumor growth and resistance to conventional therapy. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) nuclease 9 (CRISPR-Cas9) system is a cost-effective and reliable gene editing technology, which is widely used in cancer research. It leads to novel discoveries of various oncogenes that regulate autophagy, angiogenesis, and invasion and play important role in pathogenesis of various malignancies, including GBM. In this review article, we first describe the principle and methods of delivery of CRISPR-Cas9 genome editing. Second, we summarize the current knowledge and major applications of CRISPR-Cas9 to identifying and modifying the genetic regulators of the hallmark of GBM. Lastly, we elucidate the major limitations of current CRISPR-Cas9 technology in the GBM field and the future perspectives. CRISPR-Cas9 genome editing aids in identifying novel coding and non-coding transcriptional regulators of the hallmarks of GBM particularly in vitro, while work using in vivo systems requires further investigation. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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Other

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9 pages, 661 KiB

Open AccessCommentary

Strategic Development of an Immunotoxin for the Treatment of Glioblastoma and Other Tumours Expressing the Calcitonin Receptor

by Pragya Gupta, David L. Hare and Peter J. Wookey

Cells 2021, 10(9), 2347; https://doi.org/10.3390/cells10092347 - 8 Sep 2021

Cited by 1 | Viewed by 2337

Abstract

New strategies aimed at treatment of glioblastoma are frequently proposed to overcome poor prognosis. Recently, research has focused on glioma stem cells (GSCs), some quiescent, which drive expansion of glioblastoma and provide the complexity and heterogeneity of the tumour hierarchy. Targeting quiescent GSCs [...] Read more.

New strategies aimed at treatment of glioblastoma are frequently proposed to overcome poor prognosis. Recently, research has focused on glioma stem cells (GSCs), some quiescent, which drive expansion of glioblastoma and provide the complexity and heterogeneity of the tumour hierarchy. Targeting quiescent GSCs is beyond the capability of conventional drugs such as temozolomide. Here, we discuss the proposal that the calcitonin receptor (CT Receptor), expressed in 76–86% of patient biopsies, is expressed by both malignant glioma cells and GSCs. Forty-two percent (42%) of high-grade glioma (HGG; representative of GSCs) cell lines available from one source express CT Receptor protein in cell culture. The pharmacological calcitonin (CT)-response profiles of four of the HGG cell lines were reported, suggesting mutational/splicing inactivation. Alternative splicing, commonly associated with cancer cells, could result in the predominant expression of the insert-positive isoform and explain the atypical pharmacology exhibited by CT non-responders. A role for the CT Receptor as a putative tumour suppressor and/or oncoprotein is discussed. Both CT responders and non-responders were sensitive to immunotoxins based on an anti-CT Receptor antibody conjugated to ribosomal-inactivating proteins. Sensitivity was increased by several logs with the triterpene glycoside SO1861, an endosomal escape enhancer. Under these conditions, the immunotoxins were 250–300 times more potent than an equivalent antibody conjugated with monomethyl auristatin E. Further refinements for improving the penetration of solid tumours are discussed. With this knowledge, a potential strategy for effective targeting of CSCs expressing this receptor is proposed for the treatment of GBM. Full article

(This article belongs to the Special Issue Glioblastoma Cell: From Molecular Target to Innovative Therapy)

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