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1.
Int J Mol Sci ; 22(2)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477674

RESUMO

Diffuse gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. Because of their locally aggressive behaviour and the fact that they cannot be cured by current therapies, they represent one of the most devastating cancers. The present review summarises recent advances in our understanding of glioma development and progression by use of various in vitro and in vivo models, as well as more complex techniques including cultures of 3D organoids and organotypic slices. We discuss the progress that has been made in understanding glioma heterogeneity, alteration in gene expression and DNA methylation, as well as advances in various in silico models. Lastly current treatment options and future clinical trials, which aim to improve early diagnosis and disease monitoring, are also discussed.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA/genética , Glioma/genética , Adulto , Animais , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Glioma/epidemiologia , Glioma/patologia , Humanos
2.
J Pathol ; 242(2): 178-192, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28299802

RESUMO

The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal , Receptores Notch/genética , Transdução de Sinais , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Células Epiteliais/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Biológicos , Fenótipo , Prognóstico , Receptores Notch/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo
3.
Future Oncol ; 9(12): 1923-35, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24295421

RESUMO

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Somatic mutations in genes encoding IDH1 and IDH2 were first identified in glioma and subsequently in acute myeloid leukemia and other solid tumors. These heterozygous point mutations occur at the arginine residue of the enzyme's active site and cause both loss of normal enzyme function and gain of function, causing reduction of α-KG to D-2-hydroxyglutarate, which accumulates. D-2-hydroxyglutarate may act as an oncometabolite through the inhibition of various α-KG-dependent enzymes, stimulating angiogenesis, histone modifications and aberrant DNA methylation. Possibly, IDH mutations may also cause oncogenic effects through dysregulation of the tricarboxylic acid cycle, or by increasing susceptibility to oxidative stress. Clinically, IDH mutations may be useful diagnostic, prognostic and predictive biomarkers, and it is anticipated that a better understanding of the pathogenesis of IDH mutations will enable IDH-directed therapies to be developed in the future.


Assuntos
Carcinogênese/genética , Isocitrato Desidrogenase/genética , Neoplasias/terapia , Biomarcadores Tumorais/genética , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/genética , Neoplasias/patologia , Estresse Oxidativo/genética , Prognóstico
4.
Cancers (Basel) ; 15(11)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37296846

RESUMO

Altered metabolism is a common feature of many cancers and, in some cases, is a consequence of mutation in metabolic genes, such as the ones involved in the TCA cycle. Isocitrate dehydrogenase (IDH) is mutated in many gliomas and other cancers. Physiologically, IDH converts isocitrate to α-ketoglutarate (α-KG), but when mutated, IDH reduces α-KG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at elevated levels in IDH mutant tumours, and in the last decade, a massive effort has been made to develop small inhibitors targeting mutant IDH. In this review, we summarise the current knowledge about the cellular and molecular consequences of IDH mutations and the therapeutic approaches developed to target IDH mutant tumours, focusing on gliomas.

5.
Biochim Biophys Acta ; 1807(11): 1432-43, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21771581

RESUMO

The SDHA, SDHB, SDHC, SDHD genes encode the four subunits of succinate dehydrogenase (SDH; mitochondrial complex II), a mitochondrial enzyme involved in two essential energy-producing metabolic processes of the cell, the Krebs cycle and the electron transport chain. Germline loss-of-function mutations in any of the SDH genes or assembly factor (SDHAF2) cause hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC) through a mechanism which is largely unknown. Owing to the central function of SDH in cellular energy metabolism it is important to understand its role in tumor suppression. Here is reported an overview of genetics, clinical and molecular progress recently performed in understanding the basis of HPGL/PCC tumorigenesis.


Assuntos
Isoenzimas/genética , Mutação , Neoplasias/enzimologia , Neoplasias/genética , Succinato Desidrogenase/genética , Animais , Genes Supressores de Tumor , Humanos , Isoenzimas/química , Mitocôndrias/enzimologia , Subunidades Proteicas/química , Subunidades Proteicas/genética , Succinato Desidrogenase/química
6.
J Pathol ; 225(1): 4-11, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21630274

RESUMO

Germline mutations in the FH gene encoding the Krebs cycle enzyme fumarate hydratase predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. FH-deficient cells and tissues accumulate high levels of fumarate, which may act as an oncometabolite and contribute to tumourigenesis. A recently proposed role for fumarate in the covalent modification of cysteine residues to S-(2-succinyl) cysteine (2SC) (termed protein succination) prompted us to assess 2SC levels in our existing models of HLRCC. Herein, using a previously characterized antibody against 2SC, we show that genetic ablation of FH causes high levels of protein succination. We next hypothesized that immunohistochemistry for 2SC would serve as a metabolic biomarker for the in situ detection of FH-deficient tissues. Robust detection of 2SC was observed in Fh1 (murine FH)-deficient renal cysts and in a retrospective series of HLRCC tumours (n = 16) with established FH mutations. Importantly, 2SC was undetectable in normal tissues (n = 200) and tumour types not associated with HLRCC (n = 1342). In a prospective evaluation of cases referred for genetic testing for HLRCC, the presence of 2SC-modified proteins (2SCP) correctly predicted genetic alterations in FH in every case. In two series of unselected type II papillary renal cancer (PRCC), prospectively analysed by 2SCP staining followed by genetic analysis, the biomarker accurately identified previously unsuspected FH mutations (2/33 and 1/36). The investigation of whether metabolites in other tumour types produce protein modification signature(s) that can be assayed using similar strategies will be of interest in future studies of cancer.


Assuntos
Carcinoma de Células Renais/diagnóstico , Fumarato Hidratase/deficiência , Neoplasias Renais/diagnóstico , Leiomiomatose/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Adulto , Idoso , Animais , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Modelos Animais de Doenças , Feminino , Fumarato Hidratase/genética , Fumarato Hidratase/metabolismo , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/genética , Leiomiomatose/genética , Perda de Heterozigosidade , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Estudos Prospectivos , Sensibilidade e Especificidade , Ácido Succínico/metabolismo
7.
Proc Natl Acad Sci U S A ; 106(18): 7420-5, 2009 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-19383788

RESUMO

Estrogen receptor alpha (ERalpha) and E-cadherin are primary markers of luminal epithelial breast cancer cells with E-cadherin being a main caretaker of the epithelial phenotype. E-cadherin repression is needed for cancer cells to acquire motile and invasive properties, and it is known that in ER-positive breast cancer cells, estrogen down-regulate E-cadherin gene transcription. We report here that ERalpha is bound to the E-cadherin promoter in both the presence and the complete absence of estrogen, suggesting an unexpected role for unliganded ERalpha in E-cadherin transcription. Indeed, our data reveal that activation by unliganded ERalpha and repression by estrogen-activated ERalpha require direct binding to a half-estrogen response element within the E-cadherin promoter and exchange from associated coactivators to corepressors. Therefore, these results suggest a pivotal role for unliganded ERalpha in controlling a fundamental caretaker of the epithelial phenotype in breast cancer cells. Here, we show that ERalpha-positive breast cancer T47D cells transduced with the sfRON kinase undergo a full epithelial-mesenchymal conversion and lose E-cadherin and ERalpha expression. Our data show that, although the E-cadherin gene becomes hypermethylated and heterochromatic, kinase inhibitors can restore E-cadherin expression, together with an epithelial morphology in an ERalpha-dependent fashion. Similarly, transfection of ERalpha, in the absence of ligands, was sufficient to restore E-cadherin transcription in both sfRON-T47D and other ERalpha-, E-cadherin-negative cells. Therefore, our results suggest a novel role for the ERalpha that plays the dual role of ligand-independent activator and ligand-dependent repressor of E-cadherin in breast cancer cells.


Assuntos
Neoplasias da Mama/patologia , Caderinas/genética , Células Epiteliais/patologia , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Sequência de Aminoácidos , Antígenos CD , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Humanos , Ligantes , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Transcrição Gênica
8.
Nat Commun ; 13(1): 4785, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35970853

RESUMO

Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Resistencia a Medicamentos Antineoplásicos/genética , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Piridinas/uso terapêutico
9.
FASEB J ; 24(8): 2680-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20354140

RESUMO

Loss of the fumarate hydratase (FH) tumor suppressor gene results in the development of benign tumors that rarely, but regrettably, progress to very aggressive cancers. Using mouse embryo fibroblasts (MEFs) to model transformation, we found that fh knockdown results in increased expression of the met oncogene-encoded tyrosine kinase receptor through hypoxia-inducible factor (hif) stabilization. MET-increased expression was alone able to stabilize hif, thus establishing a feed forward loop that might enforce tumor progression. The fh-defective MEFs showed increased motility and protection from apoptosis. Motility, but not survival, relied on hif-1alpha and was greatly enhanced by MET ligand hepatocyte growth factor. Met cooperated with a weakly oncogenic ras in making MEFs transformed and tumorigenic, as shown by in vitro and in vivo assays. Loss of fh was not equally effective by itself but enhanced the transformed and tumorigenic phenotype induced by ras and MET. Consistently, the rescue of fumarase expression abrogated the motogenic and transformed phenotype of fh-defective MEFs. In conclusion, the data suggest that the progression of tumors where FH is lost might be boosted by activation of the MET oncogene, which is able to drive cell-autonomous tumor progression and is a strong candidate for targeted therapy.


Assuntos
Transformação Celular Neoplásica , Fumarato Hidratase/fisiologia , Neoplasias/etiologia , Proteínas Proto-Oncogênicas c-met/fisiologia , Animais , Células Cultivadas , Fibroblastos , Fumarato Hidratase/deficiência , Fumarato Hidratase/genética , Fator de Crescimento de Hepatócito/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Camundongos , Proteínas Supressoras de Tumor/genética
10.
Commun Biol ; 3(1): 247, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433536

RESUMO

Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes and identifying new diagnostic, prognostic, and therapeutic targets. Comprehensive and robust analysis of primary metabolic pathways in cells, tissues and bio-fluids, remains technically challenging. We report on the development and validation of a highly reproducible and robust untargeted method using anion-exchange tandem mass spectrometry (IC-MS) that enables analysis of 431 metabolites, providing detailed coverage of central carbon metabolism. We apply the method in an untargeted, discovery-driven workflow to investigate the metabolic effects of isocitrate dehydrogenase 1 (IDH1) mutations in glioblastoma cells. IC-MS provides comprehensive coverage of central metabolic pathways revealing significant elevation of 2-hydroxyglutarate and depletion of 2-oxoglutarate. Further analysis of the data reveals depletion in additional metabolites including previously unrecognised changes in lysine and tryptophan metabolism.


Assuntos
Cromatografia por Troca Iônica , Glutaratos/metabolismo , Isocitrato Desidrogenase/genética , Ácidos Cetoglutáricos/metabolismo , Mutação , Espectrometria de Massas em Tandem , Linhagem Celular Tumoral , Glioblastoma , Humanos , Redes e Vias Metabólicas
11.
Clin Cancer Res ; 25(2): 629-640, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322876

RESUMO

PURPOSE: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed. RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC. CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.


Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Proteínas Imediatamente Precoces/sangue , Proteínas Serina-Treonina Quinases/sangue , Animais , Biomarcadores Tumorais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Modelos Animais de Doenças , Feminino , Expressão Gênica , Genes Reporter , Humanos , Proteínas Imediatamente Precoces/genética , Camundongos , Gradação de Tumores , Metástase Neoplásica , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro , Ratos , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Clin Cancer Res ; 13(7): 2191-8, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17404103

RESUMO

PURPOSE: Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance. We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics. EXPERIMENTAL DESIGN: Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses. RESULTS: In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own. CONCLUSIONS: These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Terapia Genética/métodos , Fator de Crescimento de Hepatócito/genética , Neoplasias Ovarianas/tratamento farmacológico , Animais , Apoptose , Western Blotting , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Feminino , Citometria de Fluxo , Vetores Genéticos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Técnicas In Vitro , Lentivirus/genética , Camundongos , Neoplasias Ovarianas/metabolismo , Paclitaxel/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transgenes
13.
Prog Neurobiol ; 170: 37-52, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29654835

RESUMO

The adult subventricular zone (SVZ) stem cell niche has proven vital for discovering neurodevelopmental mechanisms and holds great potential in medicine for neurodegenerative diseases. Yet the SVZ holds a dark side - it can become tumorigenic. Glioblastomas can arise from the SVZ via cancer stem cells (CSCs). Glioblastoma and other brain cancers often have dismal prognoses since they are resistant to treatment. In this review we argue that the SVZ is susceptible to cancer because it contains stem cells, migratory progenitors and unusual inflammation. Theoretically, SVZ stem cells can convert to CSCs more readily than can postmitotic neural cells. Additionally, the robust long-distance migration of SVZ progenitors can be subverted upon tumorigenesis to an infiltrative phenotype. There is evidence that the SVZ, even in health, exhibits chronic low-grade cellular and molecular inflammation. Its inflammatory response to brain injuries and disease differs from that of other brain regions. We hypothesize that the SVZ inflammatory environment can predispose cells to novel mutations and exacerbate cancer phenotypes. This can be studied in animal models in which human mutations related to cancer are knocked into the SVZ to induce tumorigenesis and the CSC immune interactions that precede full-blown cancer. Importantly inflammation can be pharmacologically modulated providing an avenue to brain cancer management and treatment. The SVZ is accessible by virtue of its location surrounding the lateral ventricles and CSCs in the SVZ can be targeted with a variety of pharmacotherapies. Thus, the SVZ can yield aggressive tumors but can be targeted via several strategies.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Inflamação/fisiopatologia , Nicho de Células-Tronco/imunologia , Animais , Humanos , Ventrículos Laterais
14.
Cell Rep ; 22(12): 3107-3114, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29562167

RESUMO

Since the discovery of mutations in isocitrate dehydrogenase 1 (IDH1) in gliomas and other tumors, significant efforts have been made to gain a deeper understanding of the consequences of this oncogenic mutation. One aspect of the neomorphic function of the IDH1 R132H enzyme that has received less attention is the perturbation of cellular redox homeostasis. Here, we describe a biosynthetic pathway exhibited by cells expressing mutant IDH1. By virtue of a change in cellular redox homeostasis, IDH1-mutated cells synthesize excess glutamine-derived proline through enhanced activity of pyrroline 5-carboxylate reductase 1 (PYCR1), coupled to NADH oxidation. Enhanced proline biosynthesis partially uncouples the electron transport chain from tricarboxylic acid (TCA) cycle activity through the maintenance of a lower NADH/NAD+ ratio and subsequent reduction in oxygen consumption. Thus, we have uncovered a mechanism by which tumor cell survival may be promoted in conditions associated with perturbed redox homeostasis, as occurs in IDH1-mutated glioma.


Assuntos
Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mitocôndrias/metabolismo , Mutação , Prolina/biossíntese , Pirrolina Carboxilato Redutases/metabolismo , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico , Técnicas de Silenciamento de Genes , Glutamina/metabolismo , Homeostase , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Oligodendroglioma , Oxirredução , Pirrolina Carboxilato Redutases/genética , delta-1-Pirrolina-5-Carboxilato Redutase
15.
Cancer Res ; 64(15): 5154-61, 2004 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-15289319

RESUMO

RON is a tyrosine kinase receptor that triggers scattering of normal cells and invasive growth of cancer cells on ligand binding. We identified a short RON mRNA, which is expressed in human lung, ovary, tissues of the gastrointestinal tract, and also in several human cancers, including ovarian carcinomas and cell lines from pancreatic carcinomas and leukemias. This transcript encodes a truncated protein (short-form RON; sf-RON), lacking most of the RON receptor extracellular domain but retaining the whole transmembrane and intracellular domains. Sf-RON shows strong intrinsic tyrosine kinase activity and is constitutively phosphorylated. Epithelial cells transduced with sf-RON display an aggressive phenotype; they shift to a nonepithelial morphology, are unable to form aggregates, grow faster in monolayer cultures, show anchorage-independent growth, and become motile. We show that in these cells, E-cadherin expression is lost through a dominant transcriptional repression pathway likely mediated by the transcriptional factor SLUG. Altogether, these data show that expression of a naturally occurring, constitutively active truncated RON kinase results in loss of epithelial phenotype and aggressive behavior and, thus, it might contribute to tumor progression.


Assuntos
Caderinas/metabolismo , Adesão Celular , Neoplasias/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Supressão Genética , Transcrição Gênica , Caderinas/genética , Divisão Celular , Movimento Celular , Ensaio de Desvio de Mobilidade Eletroforética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Luciferases/metabolismo , Neoplasias/genética , Neoplasias/patologia , Fosforilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas
16.
Cancer Cell ; 30(4): 578-594, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27693047

RESUMO

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/biossíntese , Ventrículos Laterais/enzimologia , Células-Tronco Neoplásicas/enzimologia , Nicho de Células-Tronco , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA , Glioma/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Ventrículos Laterais/patologia , Camundongos , Camundongos Transgênicos , Mutação , Células-Tronco Neoplásicas/patologia , Transcriptoma
17.
Future Sci OA ; 1(3)2015.
Artigo em Inglês | MEDLINE | ID: mdl-26948489

RESUMO

AIMS: Somatic mutations in IDH1 and IDH2 are described in glioblastomas (GBMs). Mutant IDH1 and IDH2 reduce α-KG to D-2HG which accumulates, and is proposed to promote tumorigenesis. HOT catalyzes the conversion of γ-hydroxybutyrate to succinic semialdehyde in a reaction that produces D-2HG. Since increased HOT enzyme activity could lead to an accumulation of D-2HG, coupled with the fact that only a minority of GBMs carry IDH1/2 mutations and 2HG accumulation has recently been described in IDH wild-type tumors, we analyzed a set of GBM samples for mutations in the HOT gene. MATERIALS & METHODS: We screened 42 human GBM samples for mutations in HOT. RESULTS: No mutations in HOT were identified in the 42 GBM samples screened. CONCLUSION: Mutations in the coding regions of HOT do not occur at an appreciable frequency in GBM.

18.
Nat Med ; 21(1): 62-70, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25419707

RESUMO

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Nicho de Células-Tronco/genética , Animais , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Mutação , Receptores Acoplados a Proteínas G/genética
19.
Nat Commun ; 6: 6336, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25790038

RESUMO

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos/ultraestrutura , Neoplasias Renais/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/química , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Exoma , Éxons , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Filogenia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
20.
Nat Genet ; 44(4): 420-5, S1-2, 2012 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-22406644

RESUMO

Although genome-wide association studies (GWAS) have identified the existence of numerous population-based cancer susceptibility loci, mechanistic insights remain limited, particularly for intergenic polymorphisms. Here, we show that polymorphism at a remote intergenic region on chromosome 11q13.3, recently identified as a susceptibility locus for renal cell carcinoma, modulates the binding and function of hypoxia-inducible factor (HIF) at a previously unrecognized transcriptional enhancer of CCND1 (encoding cyclin D1) that is specific for renal cancers characterized by inactivation of the von Hippel-Lindau tumor suppressor (pVHL). The protective haplotype impairs binding of HIF-2, resulting in an allelic imbalance in cyclin D1 expression, thus affecting a link between hypoxia pathways and cell cycle control.


Assuntos
Ciclina D1/genética , Elementos Facilitadores Genéticos , Variação Genética , Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/genética , Pontos de Checagem do Ciclo Celular/genética , Hipóxia Celular , Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Ciclina D1/biossíntese , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Neoplasias Renais/metabolismo , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
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