International Journal of Molecular Sciences

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12 pages, 3416 KiB

Open AccessArticle

Generation of Glioblastoma Patient-Derived Intracranial Xenografts for Preclinical Studies

by Amber E. Kerstetter-Fogle, Peggy L. R. Harris, Susann M. Brady-Kalnay and Andrew E. Sloan

Int. J. Mol. Sci. 2020, 21(14), 5113; https://doi.org/10.3390/ijms21145113 - 20 Jul 2020

Cited by 13 | Viewed by 3656

Abstract

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapeutic options for GBM have remained the same for over a decade with no significant improvement. Many therapies that are successful in culture have failed in patients, likely due to the [...] Read more.

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapeutic options for GBM have remained the same for over a decade with no significant improvement. Many therapies that are successful in culture have failed in patients, likely due to the complex microenvironment in the brain, which has yet to be reproduced in any culture model. Furthermore, the high passage number of cultured cells and clonal selection fail to recapitulate the molecular and genomic signatures of GBM. We have established orthotopic patient-derived xenografts (PDX) from 37 GBM patients with human GBM. Of the 69 patient samples analyzed, we were successful in passaging 37 lines three or more generations (53.6%). After phenotypic characterization of the xenografted tumor tissue, two different growth patterns emerged highly invasive or localized. The phenotype was dependent on malignancy and previous treatment of the patient from which the xenograft was derived. Physiologically, mice exhibited symptoms more quickly with each subsequent passage, particularly in the localized tumors. Study of these physiologically relevant human xenografts in mice will enable therapeutic screenings in a microenvironment that more closely resembles GBM and may allow development of individualized patient models which may eventually be used for simulating treatment. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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14 pages, 4140 KiB

Open AccessArticle

Proteomic Analysis of the Breast Cancer Brain Metastasis Microenvironment

by Priyakshi Kalita-de Croft, Jasmin Straube, Malcolm Lim, Fares Al-Ejeh, Sunil R. Lakhani and Jodi M. Saunus

Int. J. Mol. Sci. 2019, 20(10), 2524; https://doi.org/10.3390/ijms20102524 - 22 May 2019

Cited by 17 | Viewed by 5034

Abstract

Patients with brain-metastatic breast cancer face a bleak prognosis marked by morbidity and premature death. A deeper understanding of molecular interactions in the metastatic brain tumour microenvironment may inform the development of new therapeutic strategies. In this study, triple-negative MDA-MB-231 breast cancer cells [...] Read more.

Patients with brain-metastatic breast cancer face a bleak prognosis marked by morbidity and premature death. A deeper understanding of molecular interactions in the metastatic brain tumour microenvironment may inform the development of new therapeutic strategies. In this study, triple-negative MDA-MB-231 breast cancer cells or PBS (modelling traumatic brain injury) were stereotactically injected into the cerebral cortex of NOD/SCID mice to model metastatic colonization. Brain cells were isolated from five tumour-associated samples and five controls (pooled uninvolved and injured tissue) by immunoaffinity chromatography, and proteomic profiles were compared using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) discovery platform. Ontology and cell type biomarker enrichment analysis of the 125 differentially abundant proteins (p < 0.05) showed the changes largely represent cellular components involved in metabolic reprogramming and cell migration (min q = 4.59 × 10⁻⁵), with high-throughput PubMed text mining indicating they have been most frequently studied in the contexts of mitochondrial dysfunction, oxidative stress and autophagy. Analysis of mouse brain cell type-specific biomarkers suggested the changes were paralleled by increased proportions of microglia, mural cells and interneurons. Finally, we orthogonally validated three of the proteins in an independent xenograft cohort, and investigated their expression in craniotomy specimens from triple-negative metastatic breast cancer patients, using a combination of standard and fluorescent multiplex immunohistochemistry. This included 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), which is integral for gluconeogenic valine catabolism in the brain, and was strongly induced in both graft-associated brain tissue (13.5-fold by SWATH-MS; p = 7.2 × 10⁻⁴), and areas of tumour-associated, reactive gliosis in human clinical samples. HIBCH was also induced in the tumour compartment, with expression frequently localized to margins and haemorrhagic areas. These observations raise the possibility that catabolism of valine is an effective adaptation in metastatic cells able to access it, and that intermediates or products could be transferred from tumour-associated glia. Overall, our findings indicate that metabolic reprogramming dominates the proteomic landscape of graft-associated brain tissue in the intracranial MDA-MB-231 xenograft model. Brain-derived metabolic provisions could represent an exploitable dependency in breast cancer brain metastases. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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15 pages, 5429 KiB

Open AccessArticle

A PTPmu Biomarker is Associated with Increased Survival in Gliomas

by Mette L. Johansen, Jason Vincent, Haley Gittleman, Sonya E. L. Craig, Marta Couce, Andrew E. Sloan, Jill S. Barnholtz-Sloan and Susann M. Brady-Kalnay

Int. J. Mol. Sci. 2019, 20(10), 2372; https://doi.org/10.3390/ijms20102372 - 14 May 2019

Cited by 4 | Viewed by 3044

Abstract

An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a [...] Read more.

An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a wide range in overall survival, from months for the worst cases of glioblastoma (GBM) to years for lower grade astrocytic and oligodendroglial tumors. We previously identified a change in the cell adhesion molecule PTPmu in brain tumors that results in the generation of proteolytic fragments. We developed agents to detect this cell surface-associated biomarker of the tumor microenvironment. In the current study, we evaluated the PTPmu biomarker in tissue microarrays and individual tumor samples of adolescent and young adult (n = 25) and adult (n = 69) glioma populations using a fluorescent histochemical reagent, SBK4-TR, that recognizes the PTPmu biomarker. We correlated staining with clinical data and found that high levels of the PTPmu biomarker correlate with increased survival of glioma patients, including those with GBM. Patients with high PTPmu live for 48 months on average, whereas PTPmu low patients live only 22 months. PTPmu high staining indicates a doubling of patient survival. Use of the agent to detect the PTPmu biomarker would allow differentiation of glioma patients with distinct survival outcomes and would complement current molecular approaches used in glioma prognosis. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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20 pages, 2374 KiB

Open AccessArticle

Are There Thresholds in Glioblastoma Cell Death Responses Triggered by Temozolomide?

by Yang He and Bernd Kaina

Int. J. Mol. Sci. 2019, 20(7), 1562; https://doi.org/10.3390/ijms20071562 - 28 Mar 2019

Cited by 42 | Viewed by 5020

Abstract

Temozolomide (TMZ) is an alkylating agent used in the treatment of high-grade malignant glioma, notably glioblastoma multiforme, the most aggressive form of brain cancer. The drug induces a dozen DNA methylation adducts, including O⁶-methylguanine (O⁶MeG), which is the [...] Read more.

Temozolomide (TMZ) is an alkylating agent used in the treatment of high-grade malignant glioma, notably glioblastoma multiforme, the most aggressive form of brain cancer. The drug induces a dozen DNA methylation adducts, including O⁶-methylguanine (O⁶MeG), which is the most toxic primary DNA lesion as it causes the formation of DNA double-strand breaks (DSBs) that trigger apoptosis. In p53 wild-type cells, TMZ activates p-p53ser15 and p-p53ser46, which have opposing dual functions regulating survival and death, respectively. Since the use of TMZ in a therapeutic setting is limited because of its side effects, the question arises as to the existence of threshold doses that activate the death pathway and start apoptosis. To determine whether there is a threshold for the TMZ-induced DNA damage response and exploring the factors regulating the switch between p53 dependent survival and death, the glioblastoma lines LN-229 (deficient in MGMT) and LN-229MGMT (stably transfected with MGMT) were exposed to different doses of TMZ. p53 protein expression and phosphorylation levels of p-p53ser15 and p-p53ser46 were determined by Western blotting. Also, apoptosis, senescence and autophagy levels were checked after different doses of TMZ. The results show that pro-survival p-p53ser15 and pro-death p-p53ser46 were induced by O⁶MeG in a specific dose- and time-dependent manner. p-p53ser15 was an early response while p-p53ser46 was activated at later times following treatment. Unexpectedly, the dose-response curves for total p53, p-p53ser15 and p-p53ser46 were linear, without an obvious threshold. O⁶MeG induces apoptosis late after treatment as a linear function of TMZ dose. This was observed for both p53 proficient LN-229 and p53 lacking LN-308 cells. A linear dose-response after TMZ was also observed for senescence and autophagy as well as γH2AX, an indicator of DSBs that are considered to be the downstream trigger of apoptosis, senescence and autophagy. LN-229MGMT cells were highly resistant to all measured endpoints because of repair of the critical primary lesion. Although LN-308 were less responsive than LN-229 to TMZ, they displayed the same TMZ-induced DSB level. The observed linear dose-responses are not compatible with the view that low DNA damage level evokes survival while high damage level activates death functions. The data bear important therapeutic implications as they indicate that even low doses of TMZ may elicit a cytotoxic response. However, since O⁶MeG triggers apoptosis, senescence and autophagy in the same dose range, it is likely that the accumulation of senescent cells in the population counteracts the killing effect of the anticancer drug. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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14 pages, 6269 KiB

Open AccessArticle

Identification of a Prognostic Hypoxia-Associated Gene Set in IDH-Mutant Glioma

by Philip Dao Trong, Saskia Rösch, Heimo Mairbäurl, Stefan Pusch, Andreas Unterberg, Christel Herold-Mende and Rolf Warta

Int. J. Mol. Sci. 2018, 19(10), 2903; https://doi.org/10.3390/ijms19102903 - 25 Sep 2018

Cited by 24 | Viewed by 4923

Abstract

Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1^mut) GSCs, biology under hypoxic conditions has [...] Read more.

Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1^mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1^wt) GSCs. We therefore grew well-characterized IDH1^mut (n = 4) and IDH1^wt (n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1^wt than in IDH1^mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1^mut and IDH1^wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1^mut GSCs a hypoxia-related survival score (HRS-score) of five genes (LYVE1, FAM162A, WNT6, OTP, PLOD1) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1^mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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13 pages, 2103 KiB

Open AccessArticle

Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

by Bodo Haas, Lena Schütte, Maria Wos-Maganga, Sandra Weickhardt, Marco Timmer and Niels Eckstein

Int. J. Mol. Sci. 2018, 19(10), 2874; https://doi.org/10.3390/ijms19102874 - 21 Sep 2018

Cited by 18 | Viewed by 4570

Abstract

Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic [...] Read more.

Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl-disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of β-catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively. In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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19 pages, 6829 KiB

Open AccessArticle

Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

by Paola Palumbo, Francesca Lombardi, Giuseppe Siragusa, Soheila Raysi Dehcordi, Sabino Luzzi, AnnaMaria Cimini, Maria Grazia Cifone and Benedetta Cinque

Int. J. Mol. Sci. 2018, 19(9), 2801; https://doi.org/10.3390/ijms19092801 - 17 Sep 2018

Cited by 56 | Viewed by 4776

Abstract

Aberrant nitric oxide synthase 2 (NOS2) expression has been suggested as an interesting therapeutic target that is being implicated as a component of the molecular profile of several human malignant tumors, including glioblastoma, which is the most aggressive brain tumor with limited therapeutic [...] Read more.

Aberrant nitric oxide synthase 2 (NOS2) expression has been suggested as an interesting therapeutic target that is being implicated as a component of the molecular profile of several human malignant tumors, including glioblastoma, which is the most aggressive brain tumor with limited therapeutic options and poor prognosis. The aim of the present work was to evaluate the effect of 1400W, a specific NOS2 inhibitor, on human glioma cells in terms of clonogenic potential, proliferation, migration rate, and neurosphere generation ability. NOS2 expression was determined by Western blotting. Nitric oxide (NO) production was measured through nitrite level determination. The trypan blue exclusion test and the plate colony formation assay were performed to evaluate cell proliferation and clonogenic potential. Cell proliferation and migration ability was assessed by the in vitro wound-healing assay. Neurosphere generation in a specific stemcell medium was investigated. NOS2 was confirmed to be expressed in both the glioma cell line and a human glioma primary culture, and overexpressed in relative derived neurospheres. Experiments that aimed to evaluate the influence of 1400W on U-87 MG, T98G (glioblastoma cell lines) and primary glioma cells sustained the crucial role played by NOS2 in proliferation, colony formation, migration, and neurosphere generation, thus supporting the emerging relevance of a NOS2/NO system as a prognostic factor for glioma malignancy and recurrence. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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13 pages, 3404 KiB

Open AccessArticle

Gene Suppression of Transketolase-Like Protein 1 (TKTL1) Sensitizes Glioma Cells to Hypoxia and Ionizing Radiation

by Sonja Heller, Gabriele D. Maurer, Christina Wanka, Ute Hofmann, Anna-Luisa Luger, Ines Bruns, Joachim P. Steinbach and Johannes Rieger

Int. J. Mol. Sci. 2018, 19(8), 2168; https://doi.org/10.3390/ijms19082168 - 25 Jul 2018

Cited by 15 | Viewed by 5412

Abstract

In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the [...] Read more.

In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the present in vitro study using LNT-229 glioma cells, we analyzed the impact of TKTL1 gene suppression on basic metabolic parameters and on survival following oxygen restriction and ionizing radiation. TKTL1 was induced by hypoxia and by hypoxia-inducible factor-1α (HIF-1α). Knockdown of TKTL1 via shRNA increased the cells’ demand for glucose, decreased flux through the PPP and promoted cell death under hypoxic conditions. Following irradiation, suppression of TKTL1 expression resulted in elevated levels of reactive oxygen species (ROS) and reduced clonogenic survival. In summary, our results indicate a role of TKTL1 in the adaptation of tumor cells to oxygen deprivation and in the acquisition of radioresistance. Further studies are necessary to examine whether strategies that antagonize TKTL1 function will be able to restore the sensitivity of glioma cells towards irradiation and antiangiogenic therapies in the more complex in vivo environment. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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12 pages, 1528 KiB

Open AccessArticle

Circulating Cell-Free DNA as a Prognostic and Molecular Marker for Patients with Brain Tumors under Perillyl Alcohol-Based Therapy

by Giselle Faria, Emanuelle Silva, Clovis Da Fonseca and Thereza Quirico-Santos

Int. J. Mol. Sci. 2018, 19(6), 1610; https://doi.org/10.3390/ijms19061610 - 30 May 2018

Cited by 26 | Viewed by 5126

Abstract

Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to [...] Read more.

Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors. The cohort included 130 healthy subjects arranged as control-paired groups and patients at terminal stages with glioblastoma (GBM, n = 122) or brain metastasis (BM, n = 55) from stage IV adenocarcinomas. Serum cfDNA was isolated and quantified by fluorimetry. Compared with the controls (40 ng/mL), patients with brain tumors before ITN-POH treatment had increased (p < 0.0001) cfDNA median levels: GBM (286 ng/mL) and BM (588 ng/mL). ITN-POH treatment was significantly correlated (rho = −0.225; p = 0.024) with survival of >6 months at a concentration of 599 ± 221 ng/mL and of <6 months at 1626 ± 505 ng/mL, but a sharp and abrupt increase of cfDNA and tumor recurrence occurred after ITN-POH discontinuation. Patients under continuous ITN-POH treatment and checked with brain magnetic resonance imaging (MRI) compatible with complete response had cfDNA levels similar to the controls. cfDNA may be used as a noninvasive prognostic and molecular marker for POH-based therapy in brain tumors and as an accurate screening tool for the early detection of tumor progression. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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Review

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24 pages, 2159 KiB

Open AccessReview

Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

by Malcolm Lim, Simon Puttick, Zachary H. Houston, Kristofer J. Thurecht, Priyakshi Kalita-de Croft, Stephen Mahler, Stephen E. Rose, Rosalind L. Jeffree, Roberta Mazzieri, Riccardo Dolcetti, Sunil R. Lakhani and Jodi M. Saunus

Int. J. Mol. Sci. 2019, 20(6), 1280; https://doi.org/10.3390/ijms20061280 - 14 Mar 2019

Cited by 20 | Viewed by 5959

Abstract

Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the [...] Read more.

Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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21 pages, 2043 KiB

Open AccessReview

Targeting Telomerase and ATRX/DAXX Inducing Tumor Senescence and Apoptosis in the Malignant Glioma

by Hueng-Chuen Fan, Chuan-Mu Chen, Ching-Shiang Chi, Jeng-Dau Tsai, Kuo-Liang Chiang, Yu-Kang Chang, Shinn-Zong Lin and Horng-Jyh Harn

Int. J. Mol. Sci. 2019, 20(1), 200; https://doi.org/10.3390/ijms20010200 - 8 Jan 2019

Cited by 34 | Viewed by 7275

Abstract

Glioblastoma multiforme (GBM) is a type of brain tumor that is notorious for its aggressiveness and invasiveness, and the complete removal of GBM is still not possible, even with advanced diagnostic strategies and extensive therapeutic plans. Its dismal prognosis and short survival time [...] Read more.

Glioblastoma multiforme (GBM) is a type of brain tumor that is notorious for its aggressiveness and invasiveness, and the complete removal of GBM is still not possible, even with advanced diagnostic strategies and extensive therapeutic plans. Its dismal prognosis and short survival time after diagnosis make it a crucial public health issue. Understanding the molecular mechanisms underlying GBM may inspire novel and effective treatments against this type of cancer. At a molecular level, almost all tumor cells exhibit telomerase activity (TA), which is a major means by which they achieve immortalization. Further studies show that promoter mutations are associated with increased TA and stable telomere length. Moreover, some tumors and immortalized cells maintain their telomeres with a telomerase-independent mechanism termed the “alternative lengthening of telomeres” (ALT), which relates to the mutations of the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), the death-domain associated protein (DAXX) and H3.3. By means of the mutations of the telomerase reverse transcriptase (TERT) promoter and ATRX/DAXX, cancers can immortalize and escape cell senescence and apoptosis. In this article, we review the evidence for triggering GBM cell death by targeting telomerase and the ALT pathway, with an extra focus on a plant-derived compound, butylidene phthalide (BP), which may be a promising novel anticancer compound with good potential for clinical applications. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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21 pages, 1105 KiB

Open AccessReview

Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development

by Thomas C. Chen, Clovis O. Da Fonseca and Axel H. Schönthal

Int. J. Mol. Sci. 2018, 19(12), 3905; https://doi.org/10.3390/ijms19123905 - 6 Dec 2018

Cited by 69 | Viewed by 9176

Abstract

Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal [...] Read more.

Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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23 pages, 6880 KiB

Open AccessReview

Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

by Martina Da Ros, Veronica De Gregorio, Anna Lisa Iorio, Laura Giunti, Milena Guidi, Maurizio De Martino, Lorenzo Genitori and Iacopo Sardi

Int. J. Mol. Sci. 2018, 19(10), 2879; https://doi.org/10.3390/ijms19102879 - 22 Sep 2018

Cited by 160 | Viewed by 9704

Abstract

For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes [...] Read more.

For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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13 pages, 232 KiB

Open AccessReview

Drug Repurposing of Metabolic Agents in Malignant Glioma

by Corinna Seliger and Peter Hau

Int. J. Mol. Sci. 2018, 19(9), 2768; https://doi.org/10.3390/ijms19092768 - 14 Sep 2018

Cited by 31 | Viewed by 5435

Abstract

Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient’s metabolism [...] Read more.

Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient’s metabolism may also influence glioma metabolism. In this review, we outline definitions and methods for drug repurposing. Furthermore, we give insights into important candidates for a metabolic drug repurposing, namely metformin, statins, non-steroidal anti-inflammatory drugs, disulfiram and lonidamine. Advantages and pitfalls of drug repurposing will finally be discussed. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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20 pages, 2671 KiB

Open AccessReview

The Significance of Chondroitin Sulfate Proteoglycan 4 (CSPG4) in Human Gliomas

by Davide Schiffer, Marta Mellai, Renzo Boldorini, Ilaria Bisogno, Silvia Grifoni, Cristiano Corona, Luca Bertero, Paola Cassoni, Cristina Casalone and Laura Annovazzi

Int. J. Mol. Sci. 2018, 19(9), 2724; https://doi.org/10.3390/ijms19092724 - 12 Sep 2018

Cited by 34 | Viewed by 7968

Abstract

Neuron glial antigen 2 (NG2) is a chondroitin sulphate proteoglycan 4 (CSPG4) that occurs in developing and adult central nervous systems (CNSs) as a marker of oligodendrocyte precursor cells (OPCs) together with platelet-derived growth factor receptor α (PDGFRα). It behaves variably in different [...] Read more.

Neuron glial antigen 2 (NG2) is a chondroitin sulphate proteoglycan 4 (CSPG4) that occurs in developing and adult central nervous systems (CNSs) as a marker of oligodendrocyte precursor cells (OPCs) together with platelet-derived growth factor receptor α (PDGFRα). It behaves variably in different pathological conditions, and is possibly involved in the origin and progression of human gliomas. In the latter, NG2/CSPG4 induces cell proliferation and migration, is highly expressed in pericytes, and plays a role in neoangiogenesis. NG2/CSPG4 expression has been demonstrated in oligodendrogliomas, astrocytomas, and glioblastomas (GB), and it correlates with malignancy. In rat tumors transplacentally induced by N-ethyl-N-nitrosourea (ENU), NG2/CSPG4 expression correlates with PDGFRα, Olig2, Sox10, and Nkx2.2, and with new vessel formation. In this review, we attempt to summarize the normal and pathogenic functions of NG2/CSPG4, as well as its potential as a therapeutic target. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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20 pages, 687 KiB

Open AccessReview

Exosomal Chaperones and miRNAs in Gliomagenesis: State-of-Art and Theranostics Perspectives

by Celeste Caruso Bavisotto, Francesca Graziano, Francesca Rappa, Antonella Marino Gammazza, Mariantonia Logozzi, Stefano Fais, Rosario Maugeri, Fabio Bucchieri, Everly Conway de Macario, Alberto J. L. Macario, Francesco Cappello, Domenico G. Iacopino and Claudia Campanella

Int. J. Mol. Sci. 2018, 19(9), 2626; https://doi.org/10.3390/ijms19092626 - 5 Sep 2018

Cited by 37 | Viewed by 4767

Abstract

Gliomas have poor prognosis no matter the treatment applied, remaining an unmet clinical need. As background for a substantial change in this situation, this review will focus on the following points: (i) the steady progress in establishing the role of molecular chaperones in [...] Read more.

Gliomas have poor prognosis no matter the treatment applied, remaining an unmet clinical need. As background for a substantial change in this situation, this review will focus on the following points: (i) the steady progress in establishing the role of molecular chaperones in carcinogenesis; (ii) the recent advances in the knowledge of miRNAs in regulating gene expression, including genes involved in carcinogenesis and genes encoding chaperones; and (iii) the findings about exosomes and their cargo released by tumor cells. We would like to trigger a discussion about the involvement of exosomal chaperones and miRNAs in gliomagenesis. Chaperones may be either targets for therapy, due to their tumor-promoting activity, or therapeutic agents, due to their antitumor growth activity. Thus, chaperones may well represent a Janus-faced approach against tumors. This review focuses on extracellular chaperones as part of exosomes’ cargo, because of their potential as a new tool for the diagnosis and management of gliomas. Moreover, since exosomes transport chaperones and miRNAs (the latter possibly related to chaperone gene expression in the recipient cell), and probably deliver their cargo in the recipient cells, a new area of investigation is now open, which is bound to generate significant advances in the understanding and treatment of gliomas. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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14 pages, 765 KiB

Open AccessReview

Therapeutic Immunization against Glioblastoma

by Virgil E. J. C. Schijns, Chrystel Pretto, Anna M. Strik, Rianne Gloudemans-Rijkers, Laurent Devillers, Denis Pierre, Jinah Chung, Manisha Dandekar, Jose A. Carrillo, Xiao-Tang Kong, Beverly D. Fu, Frank P. K. Hsu, Florence M. Hofman, Thomas C. Chen, Raphael Zidovetzki, Daniela A. Bota and Apostolos Stathopoulos

Int. J. Mol. Sci. 2018, 19(9), 2540; https://doi.org/10.3390/ijms19092540 - 27 Aug 2018

Cited by 14 | Viewed by 6013

Abstract

Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, [...] Read more.

Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient’s immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation. Full article

(This article belongs to the Special Issue Intracranial Malignancies: Molecular Insights and Therapeutic Advances)

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