International Journal of Molecular Sciences

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16 pages, 1996 KiB

Open AccessArticle

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

by Carmen J. Zamora-Sánchez, Aylin Del Moral-Morales, Ana M. Hernández-Vega, Valeria Hansberg-Pastor, Ivan Salido-Guadarrama, Mauricio Rodríguez-Dorantes and Ignacio Camacho-Arroyo

Int. J. Mol. Sci. 2018, 19(3), 864; https://doi.org/10.3390/ijms19030864 - 15 Mar 2018

Cited by 9 | Viewed by 3717

Abstract

Glioblastomas (GBM) are the most frequent and aggressive brain tumors. In these malignancies, progesterone (P4) promotes proliferation, migration, and invasion. The P4 metabolite allopregnanolone (3α-THP) similarly promotes cell proliferation in the U87 human GBM cell line. Here, we evaluated global changes in gene [...] Read more.

Glioblastomas (GBM) are the most frequent and aggressive brain tumors. In these malignancies, progesterone (P4) promotes proliferation, migration, and invasion. The P4 metabolite allopregnanolone (3α-THP) similarly promotes cell proliferation in the U87 human GBM cell line. Here, we evaluated global changes in gene expression of U87 cells treated with 3α-THP, P4, and the 5α-reductase inhibitor, finasteride (F). 3α-THP modified the expression of 137 genes, while F changed 90. Besides, both steroids regulated the expression of 69 genes. After performing an over-representation analysis of gene ontology terms, we selected 10 genes whose products are cytoskeleton components, transcription factors, and proteins involved in the maintenance of DNA stability and replication to validate their expression changes by RT-qPCR. 3α-THP up-regulated six genes, two of them were also up-regulated by F. Two genes were up-regulated by P4 alone, however, such an effect was blocked by F when cells were treated with both steroids. The remaining genes were regulated by the combined treatments of 3α-THP + F or P4 + F. An in-silico analysis revealed that promoters of the six up-regulated genes by 3α-THP possess cyclic adenosine monophosphate (cAMP) responsive elements along with CCAAT/Enhancer binding protein alpha (CEBPα) binding sites. These findings suggest that P4 and 3α-THP regulate different sets of genes that participate in the growth of GBMs. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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13 pages, 2335 KiB

Open AccessArticle

CircSMARCA5 Inhibits Migration of Glioblastoma Multiforme Cells by Regulating a Molecular Axis Involving Splicing Factors SRSF1/SRSF3/PTB

by Davide Barbagallo, Angela Caponnetto, Matilde Cirnigliaro, Duilia Brex, Cristina Barbagallo, Floriana D’Angeli, Antonio Morrone, Rosario Caltabiano, Giuseppe Maria Barbagallo, Marco Ragusa, Cinzia Di Pietro, Thomas Birkballe Hansen and Michele Purrello

Int. J. Mol. Sci. 2018, 19(2), 480; https://doi.org/10.3390/ijms19020480 - 6 Feb 2018

Cited by 154 | Viewed by 8838

Abstract

Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM) pathogenesis, we assayed the expression of twelve circRNAs, physiologically [...] Read more.

Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM) pathogenesis, we assayed the expression of twelve circRNAs, physiologically enriched in several regions of the brain, through real-time PCR in a cohort of fifty-six GBM patient biopsies and seven normal brain parenchymas. We focused on hsa_circ_0001445 (circSMARCA5): it was significantly downregulated in GBM biopsies as compared to normal brain tissues (p-value < 0.00001, student’s t-test), contrary to its linear isoform counterpart that did not show any differential expression (p-value = 0.694, student’s t-test). Analysis of a public dataset revealed a negative correlation between the expression of circSMARCA5 and glioma’s histological grade, suggesting its potential negative role in the progression to malignancy. Overexpressing circSMARCA5 in U87MG cells significantly decreased their migration, but not their proliferation rate. In silico scanning of circSMARCA5 sequence revealed an enrichment in binding motifs for several RNA binding proteins (RBPs), specifically involved in splicing. Among them, serine and arginine rich splicing factor 1 (SRSF1), a splicing factor known to be a positive controller of cell migration and known to be overexpressed in GBM, was predicted to bind circSMARCA5 by three different prediction tools. Direct interaction between circSMARCA5 and SRSF1 is supported by enhanced UV crosslinking and immunoprecipitation (eCLIP) data for SRSF1 in K562 cells from Encyclopedia of DNA Elements (ENCODE). Consistently, U87MG overexpressing circSMARCA5 showed an increased expression of serine and arginine rich splicing factor 3 (SRSF3) RNA isoform containing exon 4, normally skipped in a SRSF1-dependent manner, resulting in a non-productive non-sense mediated decay (NMD) substrate. Interestingly, SRSF3 is known to interplay with two other splicing factors, polypyrimidine tract binding protein 1 (PTBP1) and polypyrimidine tract binding protein 2 (PTBP2), that positively regulate glioma cells migration. Collectively, our data show circSMARCA5 as a promising druggable tumor suppressor in GBM and suggest that it may exert its function by tethering the RBP SRSF1. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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14 pages, 3374 KiB

Open AccessArticle

Differential Characterization of Temozolomide-Resistant Human Glioma Cells

by Sheng-Wei Lai, Bor-Ren Huang, Yu-Shu Liu, Hsiao-Yun Lin, Chun-Chuan Chen, Cheng-Fang Tsai, Dah-Yuu Lu and Chingju Lin

Int. J. Mol. Sci. 2018, 19(1), 127; https://doi.org/10.3390/ijms19010127 - 2 Jan 2018

Cited by 28 | Viewed by 5597

Abstract

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. Temozolomide (TMZ) has been considered to be one of the most effective chemotherapeutic agents to prolong the survival of patients with glioblastoma. Many [...] Read more.

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. Temozolomide (TMZ) has been considered to be one of the most effective chemotherapeutic agents to prolong the survival of patients with glioblastoma. Many glioma cells develop drug-resistance against TMZ that is mediated by increasing O-6-methylguanine-DNA methyltransferase (MGMT) levels. The expression of connexin 43 was increased in the resistant U251 subline compared with the parental U251 cells. The expression of epithelial–mesenchymal transition (EMT)-associated regulators, including vimentin, N-cadherin, and β-catenin, was reduced in the resistant U251 subline. In addition, the resistant U251 subline exhibited decreased cell migratory activity and monocyte adhesion ability compared to the parental U251 cells. Furthermore, the resistant U251 subline also expressed lower levels of vascular cell adhesion molecule (VCAM)-1 after treatment with recombinant tumor necrosis factor (TNF)-α. These findings suggest differential characteristics in the drug-resistant GBM from the parental glioma cells. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Open AccessArticle

Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs)

by Giuseppina Catanzaro, Claudia Sabato, Michele Russo, Alessandro Rosa, Luana Abballe, Zein Mersini Besharat, Agnese Po, Evelina Miele, Diana Bellavia, Martina Chiacchiarini, Marco Gessi, Giovanna Peruzzi, Maddalena Napolitano, Manila Antonelli, Angela Mastronuzzi, Felice Giangaspero, Franco Locatelli, Isabella Screpanti, Alessandra Vacca and Elisabetta Ferretti

Int. J. Mol. Sci. 2017, 18(12), 2742; https://doi.org/10.3390/ijms18122742 - 17 Dec 2017

Cited by 22 | Viewed by 4394

Abstract

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This [...] Read more.

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Open AccessArticle

The Invasive Region of Glioblastoma Defined by 5ALA Guided Surgery Has an Altered Cancer Stem Cell Marker Profile Compared to Central Tumour

by Stuart J. Smith, Mohammed Diksin, Saachi Chhaya, Shwetha Sairam, Maria A. Estevez-Cebrero and Ruman Rahman

Int. J. Mol. Sci. 2017, 18(11), 2452; https://doi.org/10.3390/ijms18112452 - 18 Nov 2017

Cited by 39 | Viewed by 5877

Abstract

Glioblastoma, a WHO grade IV astrocytoma, is a highly aggressive and heterogeneous tumour that infiltrates deeply into surrounding brain parenchyma, making complete surgical resection impossible. Despite chemo-radiotherapy, the residual cell population within brain parenchyma post-surgery causes inevitable recurrence. Previously, the tumour core has [...] Read more.

Glioblastoma, a WHO grade IV astrocytoma, is a highly aggressive and heterogeneous tumour that infiltrates deeply into surrounding brain parenchyma, making complete surgical resection impossible. Despite chemo-radiotherapy, the residual cell population within brain parenchyma post-surgery causes inevitable recurrence. Previously, the tumour core has been the focus of research and the basis for targeted therapeutic regimes, which have failed to improve survival in clinical trials. Here, we focus on the invasive margin as defined by the region with 5-aminolevulinic acid (5ALA) (GliolanTM) fluorescence at surgery beyond the T1 enhancing region on magnetic resonance imaging (MRI). This area is hypothesized to constitute unique microenvironmental pressures, and consequently be molecularly distinct to tumour core and enhancing rim regions. We conducted hematoxylin and eosin (H&E), array real time polymerase chain reaction (PCR), and immunohistochemistry staining on various intra-tumour regions of glioblastoma to determine molecular heterogeneity between regions. We analyzed 73 tumour samples from 21 patients and compared cellular density, cell proliferation, and the degree of vascularity. There is a statistically significant difference between the core, invasive margin and other regions for cell density (p < 0.001), cell proliferation (p = 0.029), and vascularity (p = 0.007). Aldehyde dehydrogenase 1 (ALDH1) and Nestin immunohistochemistry were used as a measure of stem-like properties, showing significantly decreased Nestin expression (p < 0.0001) in the invasive margin. Array PCR of the core, rim, and invasive regions showed significantly increased fibroblast growth factor (FGF) and ALDH1 expression in the invasive zone, with elevated hypoxia inducing factor 1-alpha (HIF1α) in the rim region, adjacent to the hypoxic core. The influence of varying microenvironments in the intra-tumour regions is a major key to understanding intra-tumour heterogeneity. This study confirms the distinct molecular composition of the heterogeneous invasive margin and cautions against purported therapy strategies that target candidate glioblastoma stem-like genes that are predominantly expressed in the tumour core. Full characterization of tumour cells in the invasive margin is critical, as these cells may more closely resemble the residual cell population responsible for tumour recurrence. Their unique nature should be considered when developing targeted agents for residual glioblastoma multiforme (GBM). Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Open AccessArticle

The Na, K-ATPase β-Subunit Isoforms Expression in Glioblastoma Multiforme: Moonlighting Roles

by Deborah Rotoli, Mariana-Mayela Cejas, María-del-Carmen Maeso, Natalia-Dolores Pérez-Rodríguez, Manuel Morales, Julio Ávila, Ali Mobasheri and Pablo Martín-Vasallo

Int. J. Mol. Sci. 2017, 18(11), 2369; https://doi.org/10.3390/ijms18112369 - 8 Nov 2017

Cited by 15 | Viewed by 5370

Abstract

Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of [...] Read more.

Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of the β-subunit of Na, K-ATPase have been implicated in regulating cellular dynamics, particularly during cancer progression. The aim of this study was to determine the Na, K-ATPase β subunit isoform subcellular expression patterns in all cell types responsible for microenvironment heterogeneity of GBM using immunohistochemical analysis. All three isoforms, β1, β2/AMOG (Adhesion Molecule On Glia) and β3, were found to be expressed in GBM samples. Generally, β1 isoform was not expressed by astrocytes, in both primary and secondary GBM, although other cell types (endothelial cells, pericytes, telocytes, macrophages) did express this isoform. β2/AMOG and β3 positive expression was observed in the cytoplasm, membrane and nuclear envelope of astrocytes and GFAP (Glial Fibrillary Acidic Protein) negative cells. Interestingly, differences in isoforms expression have been observed between primary and secondary GBM: in secondary GBM, β2 isoform expression in astrocytes was lower than that observed in primary GBM, while the expression of the β3 subunit was more intense. These changes in β subunit isoforms expression in GBM could be related to a different ionic handling, to a different relationship between astrocyte and neuron (β2/AMOG) and to changes in the moonlighting roles of Na, K-ATPase β subunits as adaptor proteins and transcription factors. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Open AccessArticle

Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation

by Victor S. Ushakov, Alexandra Y. Tsidulko, Gabin De La Bourdonnaye, Galina M. Kazanskaya, Alexander M. Volkov, Roman S. Kiselev, Vyacheslav V. Kobozev, Diana V. Kostromskaya, Alexey S. Gaytan, Alexei L. Krivoshapkin, Svetlana V. Aidagulova and Elvira V. Grigorieva

Int. J. Mol. Sci. 2017, 18(11), 2301; https://doi.org/10.3390/ijms18112301 - 1 Nov 2017

Cited by 28 | Viewed by 4795

Abstract

Heparan sulfate (HS) is an important component of the extracellular matrix and cell surface, which plays a key role in cell–cell and cell–matrix interactions. Functional activity of HS directly depends on its structure, which determined by a complex system of HS biosynthetic enzymes. [...] Read more.

Heparan sulfate (HS) is an important component of the extracellular matrix and cell surface, which plays a key role in cell–cell and cell–matrix interactions. Functional activity of HS directly depends on its structure, which determined by a complex system of HS biosynthetic enzymes. During malignant transformation, the system can undergo significant changes, but for glioma, HS biosynthesis has not been studied in detail. In this study, we performed a comparative analysis of the HS biosynthetic system in human gliomas of different grades. RT-PCR analysis showed that the overall transcriptional activity of the main HS biosynthesis-involved genes (EXT1, EXT2, NDST1, NDST2, GLCE, HS2ST1, HS3ST1, HS3ST2, HS6ST1, HS6ST2, SULF1, SULF2, HPSE) was decreased by 1.5–2-fold in Grade II-III glioma (p < 0.01) and by 3-fold in Grade IV glioma (glioblastoma multiforme, GBM) (p < 0.05), as compared with the para-tumourous tissue. The inhibition was mainly due to the elongation (a decrease in EXT1/2 expression by 3–4-fold) and 6-O-sulfation steps (a decrease in 6OST1/2 expression by 2–5-fold) of the HS biosynthesis. Heparanase (HPSE) expression was identified in 50% of GBM tumours by immunostaining, and was characterised by a high intratumoural heterogeneity of the presence of the HPSE protein. The detected disorganisation of the HS biosynthetic system in gliomas might be a potential molecular mechanism for the changes of HS structure and content in tumour microenvironments, contributing to the invasion of glioma cells and the development of the disease. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Open AccessArticle

The Impact of Non-Lethal Single-Dose Radiation on Tumor Invasion and Cytoskeletal Properties

by Tim Hohmann, Urszula Grabiec, Carolin Vogel, Chalid Ghadban, Stephan Ensminger, Matthias Bache, Dirk Vordermark and Faramarz Dehghani

Int. J. Mol. Sci. 2017, 18(9), 2001; https://doi.org/10.3390/ijms18092001 - 18 Sep 2017

Cited by 11 | Viewed by 5655

Abstract

Irradiation is the standard therapy for glioblastoma multiforme. Glioblastoma are highly resistant to radiotherapy and the underlying mechanisms remain unclear. To better understand the biological effects of irradiation on glioblastoma cells, we tested whether nonlethal irradiation influences the invasiveness, cell stiffness, and actin [...] Read more.

Irradiation is the standard therapy for glioblastoma multiforme. Glioblastoma are highly resistant to radiotherapy and the underlying mechanisms remain unclear. To better understand the biological effects of irradiation on glioblastoma cells, we tested whether nonlethal irradiation influences the invasiveness, cell stiffness, and actin cytoskeleton properties. Two different glioblastoma cell lines were irradiated with 2 Gy and changes in mechanical and migratory properties and alterations in the actin structure were measured. The invasiveness of cell lines was determined using a co-culture model with organotypic hippocampal slice cultures. Irradiation led to changes in motility and a less invasive phenotype in both investigated cell lines that were associated with an increase in a ”generalized stiffness” and changes in the actin structure. In this study we demonstrate that irradiation can induce changes in the actin cytoskeleton and motility, which probably results in reduced invasiveness of glioblastoma cell lines. Furthermore, “generalized stiffness” was shown to be a profound marker of the invasiveness of a tumor cell population in our model. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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CD15s/CD62E Interaction Mediates the Adhesion of Non-Small Cell Lung Cancer Cells on Brain Endothelial Cells: Implications for Cerebral Metastasis

by Samah A. Jassam, Zaynah Maherally, James R. Smith, Keyoumars Ashkan, Federico Roncaroli, Helen L. Fillmore and Geoffrey J. Pilkington

Int. J. Mol. Sci. 2017, 18(7), 1474; https://doi.org/10.3390/ijms18071474 - 10 Jul 2017

Cited by 23 | Viewed by 7876

Abstract

Expression of the cell adhesion molecule (CAM), Sialyl Lewis X (CD15s) correlates with cancer metastasis, while expression of E-selectin (CD62E) is stimulated by TNF-α. CD15s/CD62E interaction plays a key role in the homing process of circulating leukocytes. We investigated the heterophilic interaction of [...] Read more.

Expression of the cell adhesion molecule (CAM), Sialyl Lewis X (CD15s) correlates with cancer metastasis, while expression of E-selectin (CD62E) is stimulated by TNF-α. CD15s/CD62E interaction plays a key role in the homing process of circulating leukocytes. We investigated the heterophilic interaction of CD15s and CD62E in brain metastasis-related cancer cell adhesion. CD15s and CD62E were characterised in human brain endothelium (hCMEC/D3), primary non-small cell lung cancer (NSCLC) (COR-L105 and A549) and metastatic NSCLC (SEBTA-001 and NCI-H1299) using immunocytochemistry, Western blotting, flow cytometry and immunohistochemistry in human brain tissue sections. TNF-α (25 pg/mL) stimulated extracellular expression of CD62E while adhesion assays, under both static and physiological flow live-cell conditions, explored the effect of CD15s-mAb immunoblocking on adhesion of cancer cell–brain endothelium. CD15s was faintly expressed on hCMEC/D3, while high levels were observed on primary NSCLC cells with expression highest on metastatic NSCLC cells (p < 0.001). CD62E was highly expressed on hCMEC/D3 cells activated with TNF-α, with lower levels on primary and metastatic NSCLC cells. CD15s and CD62E were expressed on lung metastatic brain biopsies. CD15s/CD62E interaction was localised at adhesion sites of cancer cell–brain endothelium. CD15s immunoblocking significantly decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (p < 0.001), highlighting the role of CD15s–CD62E interaction in brain metastasis. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Review

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24 pages, 17252 KiB

Open AccessReview

Migration/Invasion of Malignant Gliomas and Implications for Therapeutic Treatment

by Ching-Ann Liu, Chia-Yu Chang, Kuo-Wei Hsueh, Hong-Lin Su, Tzyy-Wen Chiou, Shinn-Zong Lin and Horng-Jyh Harn

Int. J. Mol. Sci. 2018, 19(4), 1115; https://doi.org/10.3390/ijms19041115 - 8 Apr 2018

Cited by 83 | Viewed by 7452

Abstract

Malignant tumors of the central nervous system (CNS) are among cancers with the poorest prognosis, indicated by their association with tumors of high-level morbidity and mortality. Gliomas, the most common primary CNS tumors that arise from neuroglial stem or progenitor cells, have estimated [...] Read more.

Malignant tumors of the central nervous system (CNS) are among cancers with the poorest prognosis, indicated by their association with tumors of high-level morbidity and mortality. Gliomas, the most common primary CNS tumors that arise from neuroglial stem or progenitor cells, have estimated annual incidence of 6.6 per 100,000 individuals in the USA, and 3.5 per 100,000 individuals in Taiwan. Tumor invasion and metastasis are the major contributors to the deaths in cancer patients. Therapeutic goals including cancer stem cells (CSC), phenotypic shifts, EZH2/AXL/TGF-β axis activation, miRNAs and exosomes are relevant to GBM metastasis to develop novel targeted therapeutics for GBM and other brain cancers. Herein, we highlight tumor metastasis in our understanding of gliomas, and illustrate novel exosome therapeutic approaches in glioma, thereby paving the way towards innovative therapies in neuro-oncology. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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20 pages, 1590 KiB

Open AccessReview

When Immune Cells Turn Bad—Tumor-Associated Microglia/Macrophages in Glioma

by Saskia Roesch, Carmen Rapp, Steffen Dettling and Christel Herold-Mende

Int. J. Mol. Sci. 2018, 19(2), 436; https://doi.org/10.3390/ijms19020436 - 1 Feb 2018

Cited by 229 | Viewed by 15003

Abstract

As a substantial part of the brain tumor microenvironment (TME), glioma-associated microglia/macrophages (GAMs) have an emerging role in tumor progression and in controlling anti-tumor immune responses. We review challenges and improvements of cell models and highlight the contribution of this highly plastic cell [...] Read more.

As a substantial part of the brain tumor microenvironment (TME), glioma-associated microglia/macrophages (GAMs) have an emerging role in tumor progression and in controlling anti-tumor immune responses. We review challenges and improvements of cell models and highlight the contribution of this highly plastic cell population to an immunosuppressive TME, besides their well-known functional role regarding glioma cell invasion and angiogenesis. Finally, we summarize first therapeutic interventions to target GAMs and their effect on the immunobiology of gliomas, focusing on their interaction with T cells. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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32 pages, 1000 KiB

Open AccessReview

Role of Microenvironment in Glioma Invasion: What We Learned from In Vitro Models

by Ivana Manini, Federica Caponnetto, Anna Bartolini, Tamara Ius, Laura Mariuzzi, Carla Di Loreto, Antonio Paolo Beltrami and Daniela Cesselli

Int. J. Mol. Sci. 2018, 19(1), 147; https://doi.org/10.3390/ijms19010147 - 4 Jan 2018

Cited by 91 | Viewed by 10518

Abstract

The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a [...] Read more.

The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a crucial step. Since in vitro models represent an over-simplification of the in vivo system, in these years it has been attempted to increase the level of complexity of in vitro assays to create models that could better mimic the behaviour of the cells in vivo. These levels of complexity involved: 1. The dimension of the system, moving from two-dimensional to three-dimensional models; 2. The use of microfluidic systems; 3. The use of mixed cultures of tumour cells and cells of the tumour micro-environment in order to mimic the complex cross-talk between tumour cells and their micro-environment; 4. And the source of cells used in an attempt to move from commercial lines to patient-based models. In this review, we will summarize the evidence obtained exploring these different levels of complexity and highlighting advantages and limitations of each system used. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Molecular Determinants of Malignant Brain Cancers: From Intracellular Alterations to Invasion Mediated by Extracellular Vesicles

by Gabriella Schiera, Carlo Maria Di Liegro and Italia Di Liegro

Int. J. Mol. Sci. 2017, 18(12), 2774; https://doi.org/10.3390/ijms18122774 - 20 Dec 2017

Cited by 20 | Viewed by 6834

Abstract

Malignant glioma cells invade the surrounding brain parenchyma, by migrating along the blood vessels, thus promoting cancer growth. The biological bases of these activities are grounded in profound alterations of the metabolism and the structural organization of the cells, which consequently acquire the [...] Read more.

Malignant glioma cells invade the surrounding brain parenchyma, by migrating along the blood vessels, thus promoting cancer growth. The biological bases of these activities are grounded in profound alterations of the metabolism and the structural organization of the cells, which consequently acquire the ability to modify the surrounding microenvironment, by altering the extracellular matrix and affecting the properties of the other cells present in the brain, such as normal glial-, endothelial- and immune-cells. Most of the effects on the surrounding environment are probably exerted through the release of a variety of extracellular vesicles (EVs), which contain many different classes of molecules, from genetic material to defined species of lipids and enzymes. EV-associated molecules can be either released into the extracellular matrix (ECM) and/or transferred to neighboring cells: as a consequence, both deep modifications of the recipient cell phenotype and digestion of ECM components are obtained, thus causing cancer propagation, as well as a general brain dysfunction. In this review, we first analyze the main intracellular and extracellular transformations required for glioma cell invasion into the brain parenchyma; then we discuss how these events may be attributed, at least in part, to EVs that, like the pawns of a dramatic chess game with cancer, open the way to the tumor cells themselves. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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Molecular and Genetic Determinants of Glioma Cell Invasion

by Kenta Masui, Yoichiro Kato, Tatsuo Sawada, Paul S. Mischel and Noriyuki Shibata

Int. J. Mol. Sci. 2017, 18(12), 2609; https://doi.org/10.3390/ijms18122609 - 4 Dec 2017

Cited by 26 | Viewed by 6327

Abstract

A diffusely invasive nature is a major obstacle in treating a malignant brain tumor, “diffuse glioma”, which prevents neurooncologists from surgically removing the tumor cells even in combination with chemotherapy and radiation. Recently updated classification of diffuse gliomas based on distinct genetic and [...] Read more.

A diffusely invasive nature is a major obstacle in treating a malignant brain tumor, “diffuse glioma”, which prevents neurooncologists from surgically removing the tumor cells even in combination with chemotherapy and radiation. Recently updated classification of diffuse gliomas based on distinct genetic and epigenetic features has culminated in a multilayered diagnostic approach to combine histologic phenotypes and molecular genotypes in an integrated diagnosis. However, it is still a work in progress to decipher how the genetic aberrations contribute to the aggressive nature of gliomas including their highly invasive capacity. Here we depict a set of recent discoveries involving molecular genetic determinants of the infiltrating nature of glioma cells, especially focusing on genetic mutations in receptor tyrosine kinase pathways and metabolic reprogramming downstream of common cancer mutations. The specific biology of glioma cell invasion provides an opportunity to explore the genotype-phenotype correlation in cancer and develop novel glioma-specific therapeutic strategies for this devastating disease. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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The Molecular and Phenotypic Basis of the Glioma Invasive Perivascular Niche

by Mohammed Diksin, Stuart J. Smith and Ruman Rahman

Int. J. Mol. Sci. 2017, 18(11), 2342; https://doi.org/10.3390/ijms18112342 - 6 Nov 2017

Cited by 37 | Viewed by 6696

Abstract

Gliomas are devastating brain cancers that have poor prognostic outcomes for their patients. Short overall patient survival is due to a lack of durable, efficacious treatment options. Such therapeutic difficulties exist, in part, due to several glioma survival adaptations and mechanisms, which allow [...] Read more.

Gliomas are devastating brain cancers that have poor prognostic outcomes for their patients. Short overall patient survival is due to a lack of durable, efficacious treatment options. Such therapeutic difficulties exist, in part, due to several glioma survival adaptations and mechanisms, which allow glioma cells to repurpose paracrine signalling pathways and ion channels within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from anti-cancer defence mechanisms. Ultimately, this culminates in glioma repopulation and migration at distances beyond the original tumour site, which is a considerable obstacle for effective treatment. After an era of failed phase II trials targeting individual signalling pathways, coupled to our increasing knowledge of glioma sub-clonal divergence, combinatorial therapeutic approaches which target multiple molecular pathways and mechanisms will be necessary for better treatment outcomes in treating malignant gliomas. Furthermore, next-generation therapy which focuses on infiltrative tumour phenotypes and disruption of the vascular and perivascular microenvironments harbouring residual disease cells offers optimism for the localised control of malignant gliomas. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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EGFR and EGFRvIII Promote Angiogenesis and Cell Invasion in Glioblastoma: Combination Therapies for an Effective Treatment

by Stefanie Keller and Mirko H. H. Schmidt

Int. J. Mol. Sci. 2017, 18(6), 1295; https://doi.org/10.3390/ijms18061295 - 18 Jun 2017

Cited by 94 | Viewed by 9787

Abstract

Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related [...] Read more.

Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM) through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways. This review describes the role of EGFR and EGFRvIII in those mechanisms which might offer new combined therapeutic approaches targeting EGFR or EGFRvIII together with drug treatments against proteases of the ECM or downstream signaling to increase the inhibitory effects of mono-therapies. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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