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1.
Crit Rev Oncol Hematol ; 146: 102879, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32005411

RESUMEN

Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/líquido cefalorraquídeo , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN de Neoplasias/metabolismo , Glioma/líquido cefalorraquídeo , Biopsia Líquida/métodos , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , ADN de Neoplasias/genética , Genes Relacionados con las Neoplasias/genética , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Glioblastoma/patología , Glioma/genética , Glioma/patología , Humanos , Mutación , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Células Neoplásicas Circulantes/patología
2.
Medicine (Baltimore) ; 99(5): e19017, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000446

RESUMEN

O-(2-[F]fluoroethyl)-L-tyrosine positron-emission tomography/computed tomography (F-FET PET/CT) is well known in brain tumor management. Our study aimed to identify the prognostic value of F-FET PET/CT in high-grade gliomas (HGG) according the current 2016 World Health Organization (WHO) classification.Patients with histologically proven WHO 2016 HGG were prospectively included. A dynamic F-FET PET/CT was performed allowing to obtain 2 static PET frames (static frame 1: 20-40 minutes and static frame 2: 2-22 minutes). We analyzed static parameters (standard uptake value [SUV]max, SUVmean, SUVpeak, TBRmax, TBRmean, tumoral lesion glycolysis, and metabolic tumoral volume) for various isocontours (from 10% to 90%). PET parameters, clinical features, and molecular biomarkers were compared with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analysis.Twenty-nine patients were included (grade III n = 3, grade IV n = 26). Mean PFS and OS were, respectively, 8.8 and 13.9 months. According to univariate analysis, SUVmean, SUVpeak, TBRmax, and TBRmean were significantly correlated with OS. In static 1 analysis, TBRmax seemed to be the best OS prognostic parameter (P = .004). In static 2 analysis, TBRmean was the best parameter (P = .01). In static 1 analysis, only SUVpeak was significant (P = .05) for PFS. Good performance status (PS < 2; P < .0001) and extent of resection (P = .019) identified the subgroup of patients with the best OS. Only TBRmax (P = .026) and extent of resection (P = .025) remained significant parameters in multivariate analysis.Our data suggested that high TBRmax seemed to be the most significant OS independent prognostic factor in patients with newly diagnosed HGG.


Asunto(s)
Glioma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Medios de Contraste , Femenino , Glioma/patología , Glioma/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Prospectivos , Radiofármacos , Tasa de Supervivencia , Tirosina/análogos & derivados
3.
Adv Exp Med Biol ; 1225: 115-125, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030651

RESUMEN

Brain tumors are complex cellular ecosystems, composed of populations of both neoplastic and non-neoplastic cell types. While the contributions of the cancer cells in low-grade and high-grade gliomas have been extensively studied, there is comparatively less known about the contributions of the non-neoplastic cells in these tumors. As such, a large proportion of the non-neoplastic cells in gliomas are resident brain microglia, infiltrating circulating macrophages, and T lymphocytes. These immune system-like stromal cells are recruited into the evolving tumor through the elaboration of chemokines, and are reprogrammed to adopt new cellular identities critical for glioma formation, maintenance, and progression. In this manner, these populations of tumor-associated microglia and macrophages produce growth factors that support gliomagenesis and continued tumor growth. As we begin to characterize these immune cell contributions, future therapies might emerge as adjuvant approaches to glioma treatment.


Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Humanos , Macrófagos , Microglía/patología
4.
Medicine (Baltimore) ; 99(8): e19171, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080097

RESUMEN

Circular RNAs (circRNAs), a widespread type of noncoding RNA, are produced by reverse splicing with a circular loop structure. Circ_VCAN (hsa_circ_0073237) acts as a novel circRNA, although its roles in the progression and radioresistance of glioma remain unknown.Expressions of circ_VCAN and microRNA-1183 (miR-1183) were analyzed by quantitative real-time PCR, and the functions of circ_VCAN and irradiate in glioma cell proliferation, apoptosis, migration, and invasion were assessed using cell counting kit-8, flow cytometry, Wound healing, and Transwell assays. The interaction between circ_VCAN and miR-1183 was validated dual-luciferase reporter assay.Our results revealed that circ_VCAN was significantly upregulated in radioresistant glioma tissues compared with radiosensitive tissues, and that circ_VCAN expression was negatively correlated with miR-1183 expression in glioma tissues. We also determined that circ_VCAN expression was decreased and miR-1183 expression was increased in U87 and U251 cells after irradiation. Both knockdown of circ_VCAN and treatment with miR-1183 mimics inhibited proliferation, migration, and invasion, and accelerated apoptosis of the irradiated U87 and U251 cells. In addition, luciferase reporter assays revealed that circ_VCAN might function as a sponge for miR-1183. Finally, overexpression of circ_VCAN expedited carcinogenesis and reduced glioma radiosensitivity by regulating miR-1183.Circ_VCAN serves as a potential oncogene of glioma by regulating miR-1183, and plays an essential role in the radioresistance of glioma.


Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , MicroARNs/genética , Versicanos/genética , Apoptosis , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Carcinogénesis/genética , Carcinogénesis/efectos de la radiación , Movimiento Celular , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioma/patología , Glioma/radioterapia , Humanos , Regulación hacia Arriba/genética , Regulación hacia Arriba/efectos de la radiación
5.
Adv Exp Med Biol ; 1202: 203-222, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034715

RESUMEN

STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Transformación Celular Neoplásica , Humanos , Quinasas Janus/metabolismo , Fosforilación
6.
Adv Exp Med Biol ; 1202: 259-279, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034718

RESUMEN

Signal transduction pathways directly communicate and transform chromatin to change the epigenetic landscape and regulate gene expression. Chromatin acts as a dynamic platform of signal integration and storage. Histone modifications and alteration of chromatin structure play the main role in chromatin-based gene expression regulation. Alterations in genes coding for histone modifying enzymes and chromatin modifiers result in malfunction of proteins that regulate chromatin modification and remodeling. Such dysregulations culminate in profound changes in chromatin structure and distorted patterns of gene expression. Gliomagenesis is a multistep process, involving both genetic and epigenetic alterations. Recent applications of next generation sequencing have revealed that many chromatin regulation-related genes, including ATRX, ARID1A, SMARCA4, SMARCA2, SMARCC2, BAF155 and hSNF5 are mutated in gliomas. In this review we summarize newly identified mechanisms affecting expression or functions of selected histone modifying enzymes and chromatin modifiers in gliomas. We focus on selected examples of pathogenic mechanisms involving ATRX, histone methyltransferase G9a, histone acetylases/deacetylases and chromatin remodeling complexes SMARCA2/4. We discuss the impact of selected epigenetics alterations on glioma pathobiology, signaling and therapeutic responses. We assess the attempts of targeting defective pathways with new inhibitors.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Cromatina/metabolismo , Glioma/tratamiento farmacológico , Glioma/patología , Histonas/metabolismo , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/genética , Cromatina/genética , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Glioma/enzimología , Glioma/genética , Código de Histonas/efectos de los fármacos , Histonas/química , Humanos
7.
Adv Exp Med Biol ; 1202: 281-298, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034719

RESUMEN

In this chapter we describe the state of the art knowledge of the role played by myeloid cells in promoting and supporting the growth and the invasive properties of a deadly brain tumor, glioblastoma. We provide a review of the works describing the intercellular communication among glioma and associated microglia/macrophage cells (GAMs) using in vitro cellular models derived from mice, rats and human patients and in vivo animal models using syngeneic or xenogeneic experimental systems. Special emphasis will be given to 1) the timing alteration of brain microenvironment under the influence of glioma, 2) the bidirectional communication among tumor and GAMs, 3) possible approaches to interfere with or to guide these interactions, with the aim to identify molecular and cellular targets which could revert or delay the vicious cycle that favors tumor biology.


Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Macrófagos/patología , Microglía/patología , Microambiente Tumoral , Animales , Humanos
8.
Adv Exp Med Biol ; 1202: 13-33, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034707

RESUMEN

Purines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours.


Asunto(s)
Adenosina/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Transducción de Señal , Adenosina/análogos & derivados , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Transducción de Señal/efectos de los fármacos
9.
Adv Exp Med Biol ; 1202: 35-65, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034708

RESUMEN

The chapter is focused on the mechanism of action of metabotropic P2Y nucleotide receptors: P2Y1, P2Y2, P2Y12, P2Y14 and the ionotropic P2X7 receptor in glioma C6 cells. P2Y1 and P2Y12 both respond to ADP, but while P2Y1 links to PLC and elevates cytosolic Ca2+ concentration, P2Y12 negatively couples to adenylate cyclase, maintaining cAMP at low level. In glioma C6, these two P2Y receptors modulate activities of ERK1/2 and PI3K/Akt signaling and the effects depend on physiological conditions of the cells. During prolonged serum deprivation, cell growth is arrested, the expression of the P2Y1 receptor strongly decreases and P2Y12 becomes a major player responsible for ADP-evoked signal transduction. The P2Y12 receptor activates ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulates Akt activity, contributing to glioma invasiveness. In contrast, P2Y1 has an inhibitory effect on Akt pathway signaling. Furthermore, the P2X7 receptor, often responsible for apoptotic fate, is not involved in Ca2+elevation in C6 cells. The shift in nucleotide receptor expression from P2Y1 to P2Y12 during serum withdrawal, the cross talk between both receptors and the lack of P2X7 activity shows the precise self-regulating mechanism, enhancing survival and preserving the neoplastic features of C6 cells.


Asunto(s)
Glioma/metabolismo , Nucleótidos/metabolismo , Receptores Purinérgicos P2/metabolismo , Transducción de Señal , Adenosina Difosfato/metabolismo , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glioma/patología , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo
10.
Adv Exp Med Biol ; 1202: 67-86, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034709

RESUMEN

Calcium signaling is probably one of the evolutionary oldest and the most common way by which the signal can be transmitted from the cell environment to the cytoplasmic calcium binding effectors. Calcium signal is fast and due to diversity of calcium binding proteins it may have a very broad effect on cell behavior. Being a crucial player in neuronal transmission it is also very important for glia physiology. It is responsible for the cross-talk between neurons and astrocytes, for microglia activation and motility. Changes in calcium signaling are also crucial for the behavior of transformed glioma cells. The present chapter summarizes molecular mechanisms of calcium signal formation present in glial cells with a strong emphasis on extracellular nucleotide-evoked signaling pathways. Some aspects of glioma C6 signaling such as the cross-talk between P2Y1 and P2Y12 nucleotide receptors in calcium signal generation will be discussed in-depth, to show complexity of machinery engaged in formation of this signal. Moreover, possible mechanisms of modulation of the calcium signal in diverse environments there will be presented herein. Finally, the possible role of calcium signal in glioma motility is also discussed. This is a very important issue, since glioma cells, contrary to the vast majority of neoplastic cells, cannot spread in the body with the bloodstream and, at least in early stages of tumor development, may expand only by means of sheer motility.


Asunto(s)
Señalización del Calcio , Glioma/metabolismo , Receptores Purinérgicos P2Y/metabolismo , Animales , Calcio/metabolismo , Línea Celular Tumoral , Glioma/patología , Humanos , Nucleótidos/metabolismo
11.
Adv Exp Med Biol ; 1202: 87-108, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034710

RESUMEN

Among the pathological alterations that give tumor cells invasive potential, purinergic signaling is emerging as an important component. Studies performed in in vitro, in vivo and ex vivo glioma models indicate that alterations in the purinergic signaling are involved in the progression of these tumors. Gliomas have low expression of all E-NTPDases, when compared to astrocytes in culture. Nucleotides induce glioma proliferation and ATP, although potentially neurotoxic, does not evoke cytotoxic action on the majority of glioma cells in culture. The importance of extracellular ATP for glioma pathobiology was confirmed by the reduction in glioma tumor size by apyrase, which degrades extracellular ATP to AMP, and the striking increase in tumor size by over-expression of an ecto-enzyme that degrades ATP to ADP, suggesting the effect of extracellular ATP on the tumor growth depends on the nucleotide produced by its degradation. The participation of purinergic receptors on glioma progression, particularly P2X7, is involved in the resistance to ATP-induced cell death. Although more studies are necessary, the purinergic signaling, including ectonucleotidases and receptors, may be considered as future target for glioma pharmacological or gene therapy.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Progresión de la Enfermedad , Glioma/metabolismo , Glioma/patología , Receptores Purinérgicos/metabolismo , Transducción de Señal , Nucleótidos de Adenina/metabolismo , Animales , Humanos
12.
Adv Exp Med Biol ; 1202: 109-128, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034711

RESUMEN

This chapter describes signaling pathways, stimulated by the P2Y2 nucleotide receptor (P2Y2R), that regulate cellular processes dependent on actin cytoskeleton dynamics in glioma C6 cells. P2Y2R coupled with G-proteins, in response to ATP or UTP, regulates the level of iphosphatidylinositol-4,5-bisphosphate (PIP2) which modulates a variety of actin binding proteins and is involved in calcium response and activates Rac1 and RhoA proteins. The RhoA/ROCK signaling pathway plays an important role in contractile force generation needed for the assembly of stress fibers, focal adhesions and for tail retraction during cell migration. Blocking of this pathway by a specific Rho-kinase inhibitor induces changes in F-actin organization and cell shape and decreases the level of phosphorylated myosin II and cofilin. In glioma C6 cells these changes are reversed after UTP stimulation of P2Y2R. Signaling pathways responsible for this compensation are calcium signaling which regulates MLC kinase activation via calmodulin, and the Rac1/PAK/LIMK cascade. Stimulation of the Rac1 mediated pathway via Go proteins needs additional interaction between αvß5 integrins and P2Y2Rs. Calcium free medium, or growing of the cells in suspension, prevents Gαo activation by P2Y2 receptors. Rac1 activation is necessary for cofilin phosphorylation as well as integrin activation needed for focal complexes formation and stabilization of lamellipodium. Inhibition of positive Rac1 regulation prevents glioma C6 cells from recovery of control cell like morphology.


Asunto(s)
Citoesqueleto/metabolismo , Glioma/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Transducción de Señal , Actinas/metabolismo , Animales , Línea Celular Tumoral , Glioma/patología , Humanos , Nucleótidos/metabolismo , Fosforilación
13.
Adv Exp Med Biol ; 1202: 129-149, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034712

RESUMEN

Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Invasividad Neoplásica , Transducción de Señal , Animales , Movimiento Celular , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Integrinas/metabolismo
14.
Adv Exp Med Biol ; 1202: 151-178, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034713

RESUMEN

Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.


Asunto(s)
Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Glioma/enzimología , Glioma/patología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular , Proliferación Celular , Glioma/tratamiento farmacológico , Humanos , Fosforilación , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores
15.
Adv Exp Med Biol ; 1202: 179-201, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034714

RESUMEN

Transforming growth factor beta (TGF-ß) signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-ß acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-ß-activated kinase-1 (TAK1) is a component of TGF-ß signaling and activates mitogen-activated protein kinase (MAPK) cascades. Negative regulation of TGF-ß/Smad signaling may occur through the inhibitory Smad6/7. While genetic alterations in genes related to TGF-ß signaling are relatively rare in gliomas, the altered expression of those genes is a frequent event. The increased expression of TGF-ß1-3 correlates with a degree of malignancy of human gliomas. TGF-ß may contribute to tumor pathogenesis in many ways: by direct support of tumor growth, by maintaining self-renewal of glioma initiating stem cells and inhibiting anti-tumor immunity. Glioma initiating cells are dedifferentiated cells that retain many stem cell-like properties, play a role in tumor initiation and contribute to its recurrence. TGF-ß1,2 stimulate expression of the vascular endothelial growth factor as well as the plasminogen activator inhibitor and some metalloproteinases that are involved in vascular remodeling, angiogenesis and degradation of the extracellular matrix. Inhibitors of TGF-ß signaling reduce viability and invasion of gliomas in animal models and show a great promise as novel, potential anti-tumor therapeutics.


Asunto(s)
Glioma/metabolismo , Glioma/patología , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Carcinogénesis , Glioma/tratamiento farmacológico , Humanos , Fosforilación , Receptores de Factores de Crecimiento Transformadores beta/metabolismo
16.
Adv Exp Med Biol ; 1202: 223-241, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034716

RESUMEN

Cannabinoids are a group of structurally heterogeneous but pharmacologically related compounds, including plant-derived cannabinoids, synthetic substances and endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol. Cannabinoids elicit a wide range of central and peripheral effects mostly mediated through cannabinoid receptors. There are two types of specific Gi/o-protein-coupled receptors cloned so far, called CB1 and CB2, although an existence of additional cannabinoid-binding receptors has been suggested. CB1 and CB2 differ in their predicted amino acid sequence, tissue distribution, physiological role and signaling mechanisms. Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas. Cannabinoids exert anti-proliferative action in tumor cells. Induction of cell death by cannabinoid treatment relies on the generation of a pro-apoptotic sphingolipid ceramide and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation or apoptosis. Increased ceramide levels lead also to ER-stress and autophagy in drug-treated glioblastoma cells. Beyond blocking of tumor cells proliferation cannabinoids inhibit invasiveness, angiogenesis and the stem cell-like properties of glioma cells, showing profound activity in the complex tumor microenvironment. Advances in translational research on cannabinoid signaling led to clinical investigations on the use of cannabinoids in treatments of glioblastomas.


Asunto(s)
Cannabinoides/metabolismo , Glioma/metabolismo , Glioma/patología , Transducción de Señal , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Receptores de Cannabinoides/metabolismo , Microambiente Tumoral
17.
Nat Commun ; 11(1): 550, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992716

RESUMEN

Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that captures authentic cancer pathobiology. Orthotopic engraftment of the neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) results in formation of high-grade gliomas. Similar to patient-derived GBM, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, intra-tumor heterogeneity, and extrachromosomal DNA amplification. Re-engraftment of these primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. These cancer avatar models provide a platform for comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.


Asunto(s)
Ingeniería Genética , Glioblastoma/genética , Glioblastoma/patología , Células Madre Pluripotentes/patología , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Diferenciación Celular , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Genoma , Glioblastoma/metabolismo , Glioma/genética , Glioma/patología , Humanos , Ratones , Ratones SCID , Mutación , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Neurofibromina 1/genética , Fosfohidrolasa PTEN/genética , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/genética
18.
J Photochem Photobiol B ; 203: 111773, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31931385

RESUMEN

Glioma is the prime cause of cancer allied mortality in adolescent people and it accounts about 80% of all malignant tumours. Eugenol is a major bioactive constituent present in the essential oils with numerous pharmacological benefits including nueroprotective activity. The major drawback of eugenol is its extreme volatile property and oxygen sensitivity therefore we increased the efficacy of drug; eugenol by encapsulating with chitosan polymer. Eugenol loaded chitosan polymer (EuCs) was characterized using FTIR, XRD, SEM, HR-TEM analysis and the encapsulation, drug release efficacy was assessed at in vitro condition. The induction of autophagy and anticancer efficacy of EuCs on glioma cells was evaluated with rat C6 glioma cells using MTT assay, acridine orange staining, immunocytochemical analysis of NFκß protein expression and FLOW cytometric analysis. The anti-metastatic property of Eu-CS was assessed by immunoblotting and RT-PCR analysis of epithelial mesenchymal transition protein expression in EuCs treated rat C6 glioma cells. Our characterization analysis proves that EuCs possess essential physical and functional properties of copolymer to be utilized as a drug. Further the MTT analysis and AO staining confirms even in the presence of oncogenic inducer and autophagic inhibitors, EuCs exhibits apoptotic potency on rat C6 glioma cells. The result of immunocytochemical studies depicts the inhibition of NFκß protein expression and flow cytometry studies confirm apoptosis induction by EuCs. The inhibition of metastasis by EuCs was proven by the decrease in epithelial mesenchymal transition protein expression in Eu-Cs treated rat C6 glioma cells. Over all our results authentically confirms eugenol loaded chitosan nanopolymer persuasively induces apoptosis and inhibits metastasis in rat C6 glioma cells.


Asunto(s)
Antineoplásicos/química , Apoptosis/efectos de los fármacos , Quitosano/química , Eugenol/química , Metaloproteinasa 9 de la Matriz/metabolismo , Nanoestructuras/química , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Portadores de Fármacos/química , Eugenol/farmacología , Glioma/metabolismo , Glioma/patología , FN-kappa B/metabolismo , Ratas , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
19.
Cancer Sci ; 111(3): 891-906, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31943575

RESUMEN

Upstream ORF (uORF) is a translational initiation element located in the 5'UTR of eukaryotic mRNAs. Studies have found that uORFs play an important regulatory role in many diseases. Based on The Cancer Genome Atlas database, the results of our experiments and previous research evidence, we investigated transcription factor AP-4 (TFAP4) and its uORF, LIM and SH3 protein 1 (LASP1), long noncoding RNA 00520 (LINC00520), and microRNA (miR)-520f-3p as candidates involved in glioma malignancy, which is a poorly understood process. Both TFAP4-66aa-uORF and miR-520f-3p were downregulated, and TFAP4, LASP1, and LINC00520 were highly expressed in glioma tissues and cells. TFAP4-66aa-uORF or miR-520f-3p overexpression or TFAP4, LASP1, or LINC00520 knockdown inhibited glioma cell proliferation, migration, and invasion, but promoted apoptosis. TFAP4-66aa-uORF inhibited the translation of TFAP4 by binding to the TFAP4 mRNA. MicroRNA-520f-3p inhibited TFAP4 expression by binding to its 3'UTR. However, LINC00520 could promote the expression of TFAP4 by competitively binding to miR-520f-3p. In addition, TFAP4 transcriptionally activated LASP1 and LINC00520 expression by binding to their promoter regions, forming a positive feedback loop of TFAP4/LINC00520/miR-520f-3p. Our findings together indicated that TFAP4-66aa-uORF inhibited the TFAP4/LINC00520/miR-520f-3p feedback loop by directly inhibiting TFAP4 expression, subsequently leading to inhibition of glioma malignancy. This provides a basis for developing new therapeutic approaches for glioma treatment.


Asunto(s)
Movimiento Celular/genética , Proteínas de Unión al ADN/genética , Glioma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Proteínas de Unión al ARN/genética , Regiones no Traducidas 3'/genética , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas del Citoesqueleto/genética , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glioma/patología , Células HEK293 , Humanos , Proteínas con Dominio LIM/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
20.
World Neurosurg ; 135: e754-e764, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31901497

RESUMEN

OBJECTIVE: To assess the impact of intraoperative magnetic resonance imaging (iMRI), extent of resection (EOR), and other factors on overall survival (OS) and progression-free survival (PFS) for patients with newly diagnosed grade I gliomas. METHODS: A multicenter database was queried to identify patients with grade I gliomas. Retrospective analyses assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. RESULTS: A total of 284 patients underwent treatment for grade I gliomas, including 248 resections (205 with iMRI, 43 without), 23 biopsies, and 13 laser interstitial thermal therapy treatments. Log-rank analyses of Kaplan-Meier plots showed improved 5-year OS (P = 0.0107) and PFS (P = 0.0009) with increasing EOR, and a trend toward improved 5-year OS for patients with lower American Society of Anesthesiologists score (P = 0.0528). Greater EOR was associated with significantly increased 5-year PFS for pilocytic astrocytoma (P < 0.0001), but not for ganglioglioma (P = 0.10) or dysembryoplastic neuroepithelial tumor (P = 0.57). Temporal tumors (P = 0.04) and location of "other" (P = 0.04) were associated with improved PFS, and occipital/parietal tumors (P = 0.02) were associated with decreased PFS compared with all other locations. Additional tumor resection was performed after iMRI in 49.7% of cases using iMRI, which produced gross total resection in 64% of these additional resection cases. CONCLUSIONS: Patients with grade I gliomas have extended OS and PFS, which correlates positively with increasing EOR, especially for patients with pilocytic astrocytoma. iMRI may increase EOR, indicated by the rate of gross total resection after iMRI use but was not independently associated with increased OS or PFS.


Asunto(s)
Neoplasias Encefálicas/cirugía , Glioma/cirugía , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Niño , Preescolar , Femenino , Glioma/mortalidad , Glioma/patología , Humanos , Lactante , Cuidados Intraoperatorios , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/mortalidad , Factores de Riesgo , Resultado del Tratamiento , Adulto Joven
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