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Special Issue "Molecular Biology of Brain Tumors"

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 (31 December 2019).

Special Issue Editors

Prof. Dr. Alessandro Frati
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Guest Editor
Università degli Studi di Roma La Sapienza, Rome, Italy
Interests: gliobastoma; intrinsic brain tumors; spinal intramedullary tumors; eloquent area neurosurgery
Prof. Dr. Maurizio Salvati
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Guest Editor
Università degli Studi di Roma La Sapienza, Rome, Italy
Interests: gliobastoma; brain metastsis; intrinsic brain tumors; spinal intramedullary tumors; eloquent area neurosurgery
Prof. Dr. Antonio Santoro
E-Mail
Guest Editor
Università degli Studi di Roma La Sapienza, Rome, Italy
Interests: brain aneurysms; intrinsic brain tumors; spinal intramedullary tumors; eloquent area neurosurgery; skull base neurosurgery

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

Manuscript Submission Information

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 papers will be 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

Published Papers (7 papers)

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Research

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Open AccessArticle
Chemoradiotherapy Increases Intratumor Heterogeneity of HPSE Expression in the Relapsed Glioblastoma Tumors
Int. J. Mol. Sci. 2020, 21(4), 1301; https://doi.org/10.3390/ijms21041301 (registering DOI) - 14 Feb 2020
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 [...] Read more.
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)

Review

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Open AccessReview
The Added Value of Diagnostic and Theranostic PET Imaging for the Treatment of CNS Tumors
Int. J. Mol. Sci. 2020, 21(3), 1029; https://doi.org/10.3390/ijms21031029 - 04 Feb 2020
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 [...] Read more.
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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Open AccessReview
NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target
Int. J. Mol. Sci. 2020, 21(3), 753; https://doi.org/10.3390/ijms21030753 - 23 Jan 2020
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 [...] Read more.
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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Open AccessReview
Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers
Int. J. Mol. Sci. 2020, 21(2), 685; https://doi.org/10.3390/ijms21020685 - 20 Jan 2020
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 [...] Read more.
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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Open AccessReview
How to Make Anticancer Drugs Cross the Blood–Brain Barrier to Treat Brain Metastases
Int. J. Mol. Sci. 2020, 21(1), 22; https://doi.org/10.3390/ijms21010022 - 18 Dec 2019
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 [...] Read more.
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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Open AccessReview
Prion Protein in Glioblastoma Multiforme
Int. J. Mol. Sci. 2019, 20(20), 5107; https://doi.org/10.3390/ijms20205107 - 15 Oct 2019
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, [...] Read more.
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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Open AccessReview
The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies
Int. J. Mol. Sci. 2019, 20(15), 3824; https://doi.org/10.3390/ijms20153824 - 05 Aug 2019
Cited by 5
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 [...] Read more.
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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