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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 August 2020) | Viewed by 74439

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Special Issue Editors

Prof. Dr. Alessandro Frati

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Neurosurgery Division, Human Neurosciences Department, Sapienza University, 00135 Rome, Italy
Interests: gliobastoma; intrinsic brain tumors; spinal intramedullary tumors; eloquent area neurosurgery
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Francesco Fornai

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Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56124 Pisa, Italy
Interests: neuroanatomy; neuroscience; neurodegeneration; methamphetamine; autophagy; movement disorders; substances of abuse; morphology; ultrastructure
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Prof. Dr. Maurizio Salvati

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Department of Neurosurgery, University of Tor Vergata, Rome, Italy
Interests: neuro-oncology; spine surgery; functional neurosurgery; vascular neurosurgery
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Prof. Dr. Antonio Santoro

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Department of Neurosurgery, Neuromed, IRCCS, Sapienza University of Rome, Pozzilli, Italy
Interests: brain aneurysms; intrinsic brain tumors; spinal intramedullary tumors; eloquent area neurosurgery; skull base neurosurgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last decade, great improvements in the understanding of the molecular basis of both primary and metastatic brain tumors have brought critical improvement and a subsequent dramatic impact on their clinical management. Compelling evidence has demonstrated the critical role played by the molecular pattern of brain tumors on the final oncologic prognosis. With regard to intrinsic brain tumors (IBT), further developments have outlined the role of factors such as focal hypoxia, the VEGF signaling system, mitochondrial metabolism, and intracellular and transmembrane G-protein coupled receptors in the mitotic drive of neoplastic cells. Furthermore, the mechanism determining the migration along the fibers of the white matter tracts have provided in-depth explanations of the invasiveness of IBTs. With regard to brain metastases (BM), outstanding proof has shed a light over a potential role of adhesion molecules, reactive species of oxygen, and even lymphatic extracranial cells over the intracranial diffusion of the disease.

Therefore, it is our pleasure to invite investigators to contribute to this Special Issue with original research articles as well as review and meta-analysis articles aimed at promoting the diffusion of the current knowledge of the molecular basis of neuro-oncological practice. We are particularly interested in articles describing new insights into pathophysiological mechanisms, conveying potentially useful insights to achieve original diagnostic and therapeutic approaches.

Potential topics include but are not limited to the following:

Molecular insights of glioblastoma and intrinsic brain tumor pathogenesis;
Molecular insights concerning brain metastases pathogenesis and their diffusion inside the intracranial compartment;
Clinical and surgical translations of the latest pathophysiological findings;
Molecular prognostic factors in glioblastoma and intrinsic brain tumors;
Molecular prognostic factors in brain metastases;
Novel research approaches in primary or metastatic brain tumor investigations;
Nutraceuticals and brain tumors;
Autophagy related to the biology of gliomas.

Prof. Dr. Alessandro Frati
Prof. Dr. Francesco Fornai
Prof. Dr. Maurizio Salvati
Prof. Dr. Antonio Santoro
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Glioblastoma
Intrinsic brain tumor pathogenesis
Low-grade gliomas
Spinal intramedullary tumors
Brain metastases
Molecular pathogenesis of primary brain tumors
Molecular pathogenesis of brain metastases

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Published Papers (13 papers)

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Research

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16 pages, 3954 KiB

Open AccessArticle

The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

by Anna Maria Lucianò, Elisa Perciballi, Mario Fiore, Donatella Del Bufalo and Ada Maria Tata

Int. J. Mol. Sci. 2020, 21(22), 8433; https://doi.org/10.3390/ijms21228433 - 10 Nov 2020

Cited by 9 | Viewed by 2199

Abstract

One of the major limits of chemotherapy is depending on the ability of the cancer cells to elude and adapt to different drugs. Recently, we demonstrated how the activation of the M2 muscarinic receptor could impair neuroblastoma cell proliferation. In the present paper, we investigate the possible effects mediated by the preferential M2 receptor agonist arecaidine propargyl ester (APE) on drug resistance in two neuroblastoma cell lines, SK-N-BE and SK-N-BE(2C), a sub-clone presenting drug resistance. In both cell lines, we compare the expression of the M2 receptor and the effects mediated by the M2 agonist APE on cell cycle, demonstrating a decreased percentage of cells in S phase and an accumulation of SK-N-BE cells in G1 phase, while the APE treatment of SK-N-BE(2C) cells induced a block in G2/M phase. The withdrawal of the M2 agonist from the medium shows that only the SK-N-BE(2C) cells are able to rescue cell proliferation. Further, we demonstrate that the co-treatment of low doses of APE with doxorubicin or cisplatin significantly counteracts cell proliferation when compared with the single treatment. Analysis of the expression of ATP-binding cassette (ABC) efflux pumps demonstrates the ability of the M2 agonist to downregulate their expression and that this negative modulation may be dependent on N-MYC decreased expression induced by the M2 agonist. Our data demonstrate that the combined effect of low doses of conventional drugs and the M2 agonist may represent a new promising therapeutic approach in neuroblastoma treatment, in light of its significant impact on drug resistance and the possible reduction in the side effects caused by high doses of chemotherapy drugs. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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18 pages, 2591 KiB

Open AccessArticle

Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

by Andrea Balogh, Lilla Reiniger, Szabolcs Hetey, Peter Kiraly, Eszter Toth, Katalin Karaszi, Kata Juhasz, Zsolt Gelencser, Agnes Zvara, Andras Szilagyi, Laszlo G. Puskas, Janos Matko, Zoltan Papp, Ilona Kovalszky, Csaba Juhasz and Nandor Gabor Than

Int. J. Mol. Sci. 2020, 21(16), 5762; https://doi.org/10.3390/ijms21165762 - 11 Aug 2020

Cited by 6 | Viewed by 3674

Abstract

Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein subfamily, is predominantly expressed in the brain and placenta in humans. Recently, we unveiled that ZNF554 regulates trophoblast invasion during placentation and its decreased expression leads to the early pathogenesis of preeclampsia. Since ZNF proteins are immensely implicated in the development of several tumors including malignant tumors of the brain, here we explored the pathological role of ZNF554 in gliomas. We examined the expression of ZNF554 at mRNA and protein levels in normal brain and gliomas, and then we searched for genome-wide transcriptomic changes in U87 glioblastoma cells transiently overexpressing ZNF554. Immunohistochemistry of brain tissues in our cohort (n = 62) and analysis of large TCGA RNA-Seq data (n = 687) of control, oligodendroglioma, and astrocytoma tissues both revealed decreased expression of ZNF554 towards higher glioma grades. Furthermore, low ZNF554 expression was associated with shorter survival of grade III and IV astrocytoma patients. Overexpression of ZNF554 in U87 cells resulted in differential expression, mostly downregulation of 899 genes. The “PI3K-Akt signaling pathway”, known to be activated during glioma development, was the most impacted among 116 dysregulated pathways. Most affected pathways were cancer-related and/or immune-related. Congruently, cell proliferation was decreased and cell cycle was arrested in ZNF554-transfected glioma cells. These data collectively suggest that ZNF554 is a potential tumor suppressor and its decreased expression may lead to the loss of oncogene suppression, activation of tumor pathways, and shorter survival of patients with malignant glioma. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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20 pages, 6388 KiB

Open AccessArticle

CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment

by Metka Novak, Miha Koprivnikar Krajnc, Barbara Hrastar, Barbara Breznik, Bernarda Majc, Mateja Mlinar, Ana Rotter, Andrej Porčnik, Jernej Mlakar, Katja Stare, Richard G. Pestell and Tamara Lah Turnšek

Int. J. Mol. Sci. 2020, 21(12), 4199; https://doi.org/10.3390/ijms21124199 - 12 Jun 2020

Cited by 45 | Viewed by 4813

Abstract

The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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22 pages, 5796 KiB

Open AccessArticle

Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression

by Marco Papale, Mariachiara Buccarelli, Cristiana Mollinari, Matteo A. Russo, Roberto Pallini, Lucia Ricci-Vitiani and Marco Tafani

Int. J. Mol. Sci. 2020, 21(8), 2660; https://doi.org/10.3390/ijms21082660 - 11 Apr 2020

Cited by 38 | Viewed by 4854

Abstract

Tumor hypoxic microenvironment causes hypoxia inducible factor 1 alpha (HIF-1α) activation and necrosis with alarmins release. Importantly, HIF-1α also controls the expression of alarmin receptors in tumor cells that can bind to and be activated by alarmins. Human tumor tissues possess 1–2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of tumors. Our hypothesis is that hypoxic CSCs express alarmin receptors that can bind alarmins released during necrosis, an event favoring CSCs migration. To investigate this aspect, glioblastoma stem-like cell (GSC) lines were kept under hypoxia to determine the expression of hypoxic markers as well as receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1α inhibition by digoxin or acriflavine prevented the response of GSCs to hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that hypoxia is important not only for GSCs maintenance but also for guiding their response to external necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by glioblastoma stem cells (GSCs). Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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14 pages, 2973 KiB

Open AccessArticle

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

by Ilaria Cristofaro, Chiara Limongi, Paola Piscopo, Alessio Crestini, Claudia Guerriero, Mario Fiore, Luciano Conti, Annamaria Confaloni and Ada Maria Tata

Int. J. Mol. Sci. 2020, 21(5), 1700; https://doi.org/10.3390/ijms21051700 - 2 Mar 2020

Cited by 7 | Viewed by 3908

Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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9 pages, 2638 KiB

Open AccessArticle

Chemoradiotherapy Increases Intratumor Heterogeneity of HPSE Expression in the Relapsed Glioblastoma Tumors

by Anastasia V. Suhovskih, Galina M. Kazanskaya, Alexander M. Volkov, Alexandra Y. Tsidulko, Svetlana V. Aidagulova and Elvira V. Grigorieva

Int. J. Mol. Sci. 2020, 21(4), 1301; https://doi.org/10.3390/ijms21041301 - 14 Feb 2020

Cited by 6 | Viewed by 2502

Abstract

Adjuvant chemoradiotherapy is a standard treatment option for glioblastoma multiforme (GBM). Despite intensive care, recurrent tumors developed during the first year are fatal for the patients. Possibly contributing to this effect, among other causes, is that therapy induces changes of polysaccharide heparan sulfate (HS) chains in the cancer cells and/or tumor microenvironment. The aim of this study was to perform a comparative analysis of heparanase (HPSE) expression and HS content in different normal and GBM brain tissues. Immunohistochemical analysis revealed a significant decrease of HPSE protein content in the tumor (12-15-fold) and paratumorous (2.5-3-fold) GBM tissues compared with normal brain tissue, both in cellular and extracellular compartments. The relapsed GBM tumors demonstrated significantly higher intertumor and/or intratumor heterogeneity of HPSE and HS content and distribution compared with the matched primary ones (from the same patient) (n = 8), although overall expression levels did not show significant differences, suggesting local deterioration of HPSE expression with reference to the control system or by the treatment. Double immunofluorescence staining of various glioblastoma cell lines (U87, U343, LN18, LN71, T406) demonstrated a complex pattern of HPSE expression and HS content with a tendency towards a negative association of these parameters. Taken together, the results demonstrate the increase of intratumor heterogeneity of HPSE protein in relapsed GBM tumors and suggest misbalance of HPSE expression regulation by the adjuvant anti-GBM chemoradiotherapy. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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Review

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14 pages, 1051 KiB

Open AccessReview

The Pharmacology of Xenobiotics after Intracerebro Spinal Fluid Administration: Implications for the Treatment of Brain Tumors

by Justine Paris, Eurydice Angeli and Guilhem Bousquet

Int. J. Mol. Sci. 2021, 22(3), 1281; https://doi.org/10.3390/ijms22031281 - 28 Jan 2021

Cited by 5 | Viewed by 2937

Abstract

The incidence of brain metastasis has been increasing for 10 years, with poor prognosis, unlike the improvement in survival for extracranial tumor localizations. Since recent advances in molecular biology and the development of specific molecular targets, knowledge of the brain distribution of drugs has become a pharmaceutical challenge. Most anticancer drugs fail to cross the blood–brain barrier. In order to get around this problem and penetrate the brain parenchyma, the use of intrathecal administration has been developed, but the mechanisms governing drug distribution from the cerebrospinal fluid to the brain parenchyma are poorly understood. Thus, in this review we discuss the pharmacokinetics of drugs after intrathecal administration, their penetration of the brain parenchyma and the different systems causing their efflux from the brain to the blood. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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23 pages, 2161 KiB

Open AccessReview

The Added Value of Diagnostic and Theranostic PET Imaging for the Treatment of CNS Tumors

by Ilanah J. Pruis, Guus A. M. S. van Dongen and Sophie E. M. Veldhuijzen van Zanten

Int. J. Mol. Sci. 2020, 21(3), 1029; https://doi.org/10.3390/ijms21031029 - 4 Feb 2020

Cited by 25 | Viewed by 5727

Abstract

This review highlights the added value of PET imaging in Central Nervous System (CNS) tumors, which is a tool that has rapidly evolved from a merely diagnostic setting to multimodal molecular diagnostics and the guidance of targeted therapy. PET is the method of choice for studying target expression and target binding behind the assumedly intact blood–brain barrier. Today, a variety of diagnostic PET tracers can be used for the primary staging of CNS tumors and to determine the effect of therapy. Additionally, theranostic PET tracers are increasingly used in the context of pharmaceutical and radiopharmaceutical drug development and application. In this approach, a single targeted drug is used for PET diagnosis, upon the coupling of a PET radionuclide, as well as for targeted (nuclide) therapy. Theranostic PET tracers have the potential to serve as a non-invasive whole body navigator in the selection of the most effective drug candidates and their most optimal dose and administration route, together with the potential to serve as a predictive biomarker in the selection of patients who are most likely to benefit from treatment. PET imaging supports the transition from trial and error medicine to predictive, preventive, and personalized medicine, hopefully leading to improved quality of life for patients and more cost-effective care. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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24 pages, 2727 KiB

Open AccessReview

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

by Alessandro Gambella, Rebecca Senetta, Giammarco Collemi, Stefano Gabriele Vallero, Matteo Monticelli, Fabio Cofano, Pietro Zeppa, Diego Garbossa, Alessia Pellerino, Roberta Rudà, Riccardo Soffietti, Franca Fagioli, Mauro Papotti, Paola Cassoni and Luca Bertero

Int. J. Mol. Sci. 2020, 21(3), 753; https://doi.org/10.3390/ijms21030753 - 23 Jan 2020

Cited by 64 | Viewed by 8689

Abstract

The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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17 pages, 6097 KiB

Open AccessReview

Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers

by Antonietta Arcella, Fiona Limanaqi, Rosangela Ferese, Francesca Biagioni, Maria Antonietta Oliva, Marianna Storto, Mirco Fanelli, Stefano Gambardella and Francesco Fornai

Int. J. Mol. Sci. 2020, 21(2), 685; https://doi.org/10.3390/ijms21020685 - 20 Jan 2020

Cited by 25 | Viewed by 12749

Abstract

Recently, several studies focused on the genetics of gliomas. This allowed identifying several germline loci that contribute to individual risk for tumor development, as well as various somatic mutations that are key for disease classification. Unfortunately, none of the germline loci clearly confers increased risk per se. Contrariwise, somatic mutations identified within the glioma tissue define tumor genotype, thus representing valid diagnostic and prognostic markers. Thus, genetic features can be used in glioma classification and guided therapy. Such copious genomic variabilities are screened routinely in glioma diagnosis. In detail, Sanger sequencing or pyrosequencing, fluorescence in-situ hybridization, and microsatellite analyses were added to immunohistochemistry as diagnostic markers. Recently, Next Generation Sequencing was set-up as an all-in-one diagnostic tool aimed at detecting both DNA copy number variations and mutations in gliomas. This approach is widely used also to detect circulating tumor DNA within cerebrospinal fluid from patients affected by primary brain tumors. Such an approach is providing an alternative cost-effective strategy to genotype all gliomas, which allows avoiding surgical tissue collection and repeated tumor biopsies. This review summarizes available molecular features that represent solid tools for the genetic diagnosis of gliomas at present or in the next future. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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17 pages, 1121 KiB

Open AccessReview

How to Make Anticancer Drugs Cross the Blood–Brain Barrier to Treat Brain Metastases

by Eurydice Angeli, Thuy T. Nguyen, Anne Janin and Guilhem Bousquet

Int. J. Mol. Sci. 2020, 21(1), 22; https://doi.org/10.3390/ijms21010022 - 18 Dec 2019

Cited by 58 | Viewed by 6377

Abstract

The incidence of brain metastases has increased in the last 10 years. However, the survival of patients with brain metastases remains poor and challenging in daily practice in medical oncology. One of the mechanisms suggested for the persistence of a high incidence of brain metastases is the failure to cross the blood–brain barrier of most chemotherapeutic agents, including the more recent targeted therapies. Therefore, new pharmacological approaches are needed to optimize the efficacy of anticancer drug protocols. In this article, we present recent findings in molecular data on brain metastases. We then discuss published data from pharmacological studies on the crossing of the blood–brain barrier by anticancer agents. We go on to discuss future developments to facilitate drug penetration across the blood–brain barrier for the treatment of brain metastases among cancer patients, using physical methods or physiological transporters. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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15 pages, 1650 KiB

Open AccessReview

Prion Protein in Glioblastoma Multiforme

by Larisa Ryskalin, Carla L. Busceti, Francesca Biagioni, Fiona Limanaqi, Pietro Familiari, Alessandro Frati and Francesco Fornai

Int. J. Mol. Sci. 2019, 20(20), 5107; https://doi.org/10.3390/ijms20205107 - 15 Oct 2019

Cited by 24 | Viewed by 7249

Abstract

The cellular prion protein (PrPc) is an evolutionarily conserved cell surface protein encoded by the PRNP gene. PrPc is ubiquitously expressed within nearly all mammalian cells, though most abundantly within the CNS. Besides being implicated in the pathogenesis and transmission of prion diseases, recent studies have demonstrated that PrPc contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPc over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, breast cancer, gastric cancer, and primary brain tumors, mostly glioblastoma multiforme (GBM). Thus, PrPc is emerging as a key in maintaining glioblastoma cancer stem cells’ (GSCs) phenotype, thereby strongly affecting GBM infiltration and relapse. In fact, PrPc contributes to GSCs niche’s maintenance by modulating GSCs’ stem cell-like properties while restraining them from differentiation. This is the first review that discusses the role of PrPc in GBM. The manuscript focuses on how PrPc may act on GSCs to modify their expression and translational profile while making the micro-environment surrounding the GSCs niche more favorable to GBM growth and infiltration. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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21 pages, 1478 KiB

Open AccessReview

The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies

by Larisa Ryskalin, Anderson Gaglione, Fiona Limanaqi, Francesca Biagioni, Pietro Familiari, Alessandro Frati, Vincenzo Esposito and Francesco Fornai

Int. J. Mol. Sci. 2019, 20(15), 3824; https://doi.org/10.3390/ijms20153824 - 5 Aug 2019

Cited by 54 | Viewed by 7576

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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