RESUMO
Tapentadol (TAP) and oxycodone/naloxone (OXN) potentially offer an improved opioid tolerability. However, real-world studies in chronic non-cancer pain (CNCP) remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. An observational study was developed with ambulatory test cases under TAP (n = 194) or OXN (n = 175) prescription with controls (prescribed with other opioids (control), n = 216) CNCP patients. Pain intensity and relief, quality of life, morphine equivalent daily doses (MEDD), concomitant analgesic drugs, adverse events (AEs), hospital frequentation and genetic variants of OPRM1 (rs1799971, A118G) and COMT (rs4680, G472A) genes, were analysed. Test CNCP cases evidenced a significantly higher pain relief predictable due to pain intensity and quality of life (R2 = 0.3), in front of controls. Here, OXN achieved the greatest pain relief under a 28% higher MEDD, 8-13% higher use of pregabalin and duloxetine, and 23% more prescription change due to pain, compared to TAP. Whilst, TAP yielded a better tolerability due the lower number of 4 [0-6] AEs/patient, in front of OXN. Furthermore, OXN COMT-AA homozygotes evidenced higher rates of erythema and vomiting, especially in females. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. Further research is necessary to clarify the potential influence of COMT and sex on OXN side-effects.
Assuntos
Dor do Câncer , Dor Crônica , Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Constipação Intestinal/tratamento farmacológico , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Humanos , Morfina/efeitos adversos , Naloxona/efeitos adversos , Oxicodona/efeitos adversos , Testes Farmacogenômicos , Qualidade de Vida , TapentadolRESUMO
The prevalence of personality disorders (PDs) and sexual dysfunction in chronic pain patients is higher than in general population. Our main objective was to analyse the influence of PD in patients with erectile dysfunction and chronic non-cancer pain and their response to andrological treatment. One-hundred one patients were included along 30 months. Pain intensity, quality of life, sexual life quality, anxiety and depression were analysed together with opioid dose. Erectile functioning was measured with the International Index of Erectile Function (IIEF) and PDs with Millon Clinical Multiaxial Inventory (MCMI-III). The mean age was 57 ± 12 years old, with moderate to severe pain, 70% were sexually active and presented moderate to severe ED. PDs were very frequent (31%, cut-off 85 and 84% cut-off 75 scores) mostly anxiety, compulsive, though disorder, somatoform and narcissistic. Self-defeating feature presence was significantly correlated (r = -0.4, 95% CI = -0.605 to -0.145, p = 0.002) with a more severe baseline ED and narcissistic, and a better response to andrological treatment (p = 0.010, d = 1.082). Patients with dysthymia features required significantly higher opioid doses vs. control (238 vs. 102 mg/day, respectively). These findings underline the importance of diagnosing PDs to rigorously treat patients with chronic pain and ED.
Assuntos
Dor Crônica , Disfunção Erétil , Idoso , Analgésicos Opioides/uso terapêutico , Dor Crônica/complicações , Disfunção Erétil/complicações , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Personalidade , Transtornos da Personalidade/complicações , Transtornos da Personalidade/epidemiologia , Estudos Prospectivos , Qualidade de VidaRESUMO
Safety data in chronic non-cancer pain (CNCP) with long-term opioid therapy has been poorly studied and can be differently influenced by gender. Furthermore, pharmacogenetics (PGx) could possibly be used to tailor pain medication based on the individual's genetic background. The aim was to assess whether PGx applied to a pharmacovigilance system could help to improve a patient's security profile. A pharmacovigilance data recording system was conducted over 24 months, including genotyping of OPRM1 variants (opioid receptor, A118G) and COMT (enzyme that degrades catecholamines such as norepinephrine, G1947A). Pain intensity (visual analogue scale, VAS), morphine equivalent daily dose (MEDD), adverse events (AEs) and suspected adverse drug reactions (ADRs) were recorded and analysed by gender. The Ethics Committee approved the study and data were analysed with R 3.6.0 software. A total of 748 patients were recruited in the study (67% female, VAS 62 ± 29 mm, MEDD 119 ± 114 mg/day) reporting a median of 6 (3.5-9) AEs/patient. Women presented more nausea, headaches, insomnia, loss of appetite, weight change, depression and dizziness than men. Analysis by genotype demonstrated that PGx influenced the prevalence of vomiting and depression in men, dizziness in women and sexual dysfunction in both. Physicians notified 150 ADRs mostly in females (79%) related to nervous system disorders. PGx applied to a pharmacovigilance recording system provides important information to achieve a better knowledge about AEs in CNCP pharmacological therapy. OPRM1 and COMT polymorphisms were associated with AEs in CNCP patients that differed according to gender.
Assuntos
Analgésicos Opioides/efeitos adversos , Dor Crônica/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Manejo da Dor/métodos , Farmacogenética/métodos , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Dor Crônica/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Polimorfismo de Nucleotídeo Único/genética , Espanha/epidemiologiaRESUMO
BACKGROUND: The experience of chronic non-cancer pain (CNCP) is one of the most common reasons individuals seek medical attention. Patients with CNCP frequently experience concomitant sleep-related problems. OBJECTIVES: The aim was to evaluate sleep problems in opioid naïve CNCP patients, before and after opioid titration, analyzing the influence of OPRM1 gene variants. STUDY DESIGN: A prospective, cohort, observational study. SETTING: This study was performed at the Pain Unit of the Alicante University General Hospital. METHODS: Pain and Medical Outcomes Study Sleep questionnaire (MOS-Sleep) were assessed at baseline and 3 months after opioid titration in 231 opioid naïve CNCP patients. Sleep data was compared with a matched-control group (n = 64). Morphine equivalent daily doses, adverse events, and drugs prescribed for pain were also registered. OPRM1 polymorphism rs1799971 was analyzed by RT-PCR. Ethics Committee approved the study and results were analyzed by R software. RESULTS: After 3 months of opioid titration, patients with CNCP (63 ± 14 years, 64% female, VAS 74 ± 17 mm) significantly decreased pain intensity, anxiety and depression, and increased quality of life. Sleep problems were significantly more frequent in females (P = 0.002). Age, quality of life, anxiety, and depression all influenced sleep disturbances and problems indices, which were significantly different from the control group. Furthermore, the OPRM1 118-GG genotype was also associated with significantly lower sleep adequacy, and more sleep problems. LIMITATIONS: Total number of subjects studied was relatively small and most patients were on other non-opioid centrally-acting medications. CONCLUSIONS: Opioids decreased CNCP severity, improving patients' psychological areas, and quality of life. However, patients with OPRM1 118-GG genotype indicated an increase in sleep problems and worsening sleep pattern while taking opioids. KEY WORDS: OPRM1, pharmacogenetics, MOS-Sleep, opioids, chronic noncancer pain, sleep related problems, sleep problem index SLP-6 and SLP-9.
Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Receptores Opioides mu/genética , Sono/efeitos dos fármacos , Sono/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de VidaRESUMO
BACKGROUND: Safety data from long-term opioid therapy in the real world has been poorly studied in chronic non-cancer pain (CNCP). The aim was to design a pharmacovigilance data recording system and assess whether participation in this recording system improves pain management, enhancing patient's health status. METHODS: A pharmacovigilance data recording system was conducted during 24 months. Data were self-reported by patients (pain, adverse events [AEs] and healthcare resources use) and physicians (morphine equivalent daily dose [MEDD] prescribed and suspected adverse drug reaction [ADRs]). Outcomes from patients with (case) or without (controls) suspected ADRs and cases follow-up were also compared with Spanish Pharmacovigilance System data. RESULTS: A total of 753 patients were recruited in 897 visits. Fentanyl and tramadol were the most prescribed opioids, 89% with concomitant drugs, pregabalin being the one with the most potential drug interactions. Cases presented significantly higher pain intensity (VAS 67 ± 26 vs 59 ± 30 mm, P < 0.05), number of AEs (8 ± 6 vs 5 ± 3 AEs/patient, P < 0.01), polypharmacy related to pain (65% vs 34%, P < 0.01) and MEDD (139 ± 130 vs 106 ± 99 mg/d, P < 0.01) than controls. Furthermore, cases presented significant higher changes in pharmacological pain therapy due to pain, unplanned emergency visits and hospital admission than controls. Physicians notified 168 suspected ADRs mostly related to neurological or psychiatric events and 8% of them were previously unknown. CONCLUSIONS: This data recording system provided important information to achieve a better control of CNCP pharmacological pain therapy, improving patient's health status and reducing costs to the Health System.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Analgésicos Opioides/efeitos adversos , Dor Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Feminino , Fentanila/efeitos adversos , Fentanila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Manejo da Dor , Farmacovigilância , Médicos , Estudos Retrospectivos , Autorrelato , Tramadol/efeitos adversos , Tramadol/uso terapêuticoRESUMO
OBJECTIVES: To investigate whether endothelial nitric oxide synthase (eNOS) T786C, 4VNTR and G894â¯T gene polymorphisms could mediate in andrological treatment response in Spaniards. SUBJECT PATIENTS/METHODS: The study participants were Spaniard males with erectile dysfunction (ED) and chronic pain (nâ¯=â¯105) recruited at the Pain Unit. eNOS polymorphisms were genotyped by quantitative polymerase chain reaction using Taqman specific probes. Statistical analyses were carried out using R-3.2.4 software. RESULTS: A total of 69 patients required andrological treatment and 76% of them improved ED upon iPED5 (20%), testosterone (35%) or iPDE5/testosterone treatment (45%); being significantly better in T786C-CC patients. Multivariate regression analysis indicated that age, opioid daily dose and carriage of T786C-C allele influenced the risk and ED severity in Spaniard chronic pain patients. CONCLUSION: T786C polymorphism at eNOS locus appeared to be a major contributor in the variable erectile function iPDE5/testosterone response in Spaniards.
RESUMO
Screening for opioid use disorder should be considered in chronic non-cancer pain (CNCP) patients with long-term use of opioids. The aim of our study was to assess the effectiveness of an individualized treatment plan (ITP) for prescription opioid dependence that included screening of pharmacogenetic markers. An observational prospective study was performed using prescription opioid-dependent CNCP outpatients (n = 88). Patients were divided into nonresponders, responders, or high responders according to their response to the ITP. Genotyping of OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), and ARRB2 (C8622T) was performed by real-time PCR. Our ITP achieved a significant reduction of the morphine equivalent daily dose (MEDD) in 64% of responders, including 33% of high responders. Nonopioid medication or buprenorphine use was significantly higher at final versus basal visit. 118-AA OPRM1 patients required significantly lower MEDD at basal and final visits. Our ITP showed effectiveness and security in reducing MEDD in opioid-dependent patients, with good conversion to buprenorphine that was more pronounced in 118-AA OPRM1 patients.
Assuntos
Analgésicos Opioides/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Receptores Opioides mu/genética , Adulto , Idoso , Buprenorfina/uso terapêutico , Dor Crônica/tratamento farmacológico , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/genética , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
The present study was designed to investigate the functional status of ß2 adrenoceptors (ß2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The ß2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte ß2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13±4 mmHg, CHILD 7±2 and MELD 11±4 scores), OA patients (n=30, 84% KellgrenLawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 109 to 104 mM), and ß2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. ß2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the ß2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the ß2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.
Assuntos
Genótipo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Osteoartrite/etiologia , Osteoartrite/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores , Estudos de Casos e Controles , Doença Crônica , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/metabolismo , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnósticoRESUMO
BACKGROUND: Video-assisted thoracic surgery (VATS) emerged as a minimally invasive surgery for diseases in the field of thoracic surgery. We herein reviewed our experience on thoracoscopic lobectomy for early lung cancer and evaluated Health System use. METHODS: A cost-effectiveness study was performed comparing VATS vs. open thoracic surgery (OPEN) for lung cancer patients. Demographic data, tumor localization, dynamic pulmonary function tests [forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusion capacity (DLCO) and maximal oxygen uptake (VO2max)], surgical approach, postoperative details, and complications were recorded and analyzed. RESULTS: One hundred seventeen patients underwent lung resection by VATS (n=42, 36%; age: 63±9 years old, 57% males) or OPEN (n=75, 64%; age: 61±11 years old, 73% males). Pulmonary function tests decreased just after surgery with a parallel increasing tendency during first 12 months. VATS group tended to recover FEV1 and FVC quicker with significantly less clinical and post-surgical complications (31% vs. 53%, P=0.015). Costs including surgery and associated hospital stay, complications and costs in the 12 months after surgery were significantly lower for VATS (P<0.05). CONCLUSIONS: The VATS approach surgery allowed earlier recovery at a lower cost than OPEN with a better cost-effectiveness profile.
RESUMO
BACKGROUND: Opioids are an effective treatment for chronic non-malignant pain (CNP). Long-term use risks and side effects such as opioid-induced androgen deficiency (OPIAD) exist. This could be measured by saliva testosterone (Sal-T). OBJECTIVES: To evaluate OPIAD in long-term opioid use in CNP patients. METHODS: A cross-sectional study included CNP male outpatients under opioid treatment. Total-Testosterone (Total-T), Free-Testosterone (Free-T), Bio-Testosterone (Bio-T) and Sal-T were measured. Correlations were calculated by Spearman's rho (SPSS 20). RESULTS: From 2012 to 2014, 134 from 249 (54%) consecutive male outpatients reported erectile dysfunction (ED), 37% of them related to opioids and 19% evidenced OPIAD. A total of 120 subjects (94 cases and 26 matched-controls) were included. A significantly lower luteinizing hormone, Total-T and Free-T were found, as well as, a significant correlation between Sal-T and Total-T (r = 0.234, p = 0.039), Bio-T (r = 0.241, p = 0.039), IIEF (r = 0.363, p = 0.003) and HAD-anxiety (r = -0.414, p = 0.012) in OPIAD patients. Sal-T levels were significantly lower in patients with severe-moderate ED versus mild ED (p = 0.045) and in patients with severe ED versus moderate-mild ED (p = 0.036). CONCLUSIONS: These data demonstrate the high prevalence of ED in long-term use of opioids, part of this is associated to OPIAD, which can be tested by Sal-T as a non-invasive approach.
Assuntos
Analgésicos Opioides/efeitos adversos , Androgênios/deficiência , Dor Crônica/tratamento farmacológico , Disfunção Erétil/induzido quimicamente , Saliva/química , Testosterona/deficiência , Idoso , Analgésicos Opioides/administração & dosagem , Estudos de Casos e Controles , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Inquéritos e QuestionáriosRESUMO
UNLABELLED: In advanced cancer, including glioblastoma, the TGFß pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFß activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFß can induce TGFß2, generating an autocrine loop leading to aberrantly high levels of TGFß2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFß2 by TGFß. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFß to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFß2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFß2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFß2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFß treatments and a therapeutic target in glioblastoma. SIGNIFICANCE: TGFß is considered a promising therapeutic target, and several clinical trials using TGFß inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFß2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFß therapies.
Assuntos
Comunicação Autócrina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glioblastoma/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Animais , Sequência de Bases , Modelos Animais de Doenças , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Dados de Sequência Molecular , Motivos de Nucleotídeos , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Ativação Transcricional , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/química , Fator de Crescimento Transformador beta2/genéticaRESUMO
Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.
RESUMO
Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Astrócitos/citologia , Astrócitos/fisiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Mutantes , Camundongos Nus , PTEN Fosfo-Hidrolase/genética , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transplante Heterólogo , Células Tumorais Cultivadas , Tirosina/metabolismoRESUMO
While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14(ARF), and p16(INK4A)), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14(ARF) and p16(INK4A) did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14(ARF) and p16(INK4A), in which other alterations (mutations, homozygous deletions) are prevalent.
RESUMO
Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
Assuntos
Neoplasias Encefálicas/metabolismo , Receptores ErbB/metabolismo , Proteínas de Ligação ao GTP/biossíntese , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Receptores ErbB/genética , Proteínas de Ligação ao GTP/genética , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Metaloproteinase 1 da Matriz/biossíntese , Metaloproteinase 1 da Matriz/genética , Camundongos , Camundongos Nus , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Estrutura Terciária de Proteína , Transplante HeterólogoRESUMO
Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Comunicação Celular , Modelos Animais de Doenças , Receptores ErbB/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Camundongos , Mutação , Células-Tronco Neoplásicas/patologiaRESUMO
Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.
Assuntos
Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/fisiopatologia , Mutação/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/fisiologia , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Glioblastoma/genética , Glioma/fisiopatologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Ligantes , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Regulação para CimaRESUMO
Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.
Assuntos
Receptores ErbB/metabolismo , Glioblastoma/enzimologia , Glioblastoma/terapia , Estresse Oxidativo , Inibidores de Poli(ADP-Ribose) Polimerases , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Glioblastoma/genética , Humanos , Tolerância a Radiação , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
Although cancer is rare in children, primary brain tumors constitute the most frequent location of solid tumors in childhood. Primitive neuroectodermal tumors (PNET) of the central nervous system can be divided into infratentorial PNET or medulloblastoma (MB), and supratentorial (sPNET) tumors. Although MB and sPNET are histologically similar, clinical evolution differs, sPNET being more aggressive than MB. Some studies have suggested that MB and sPNET present different molecular genetic aberrations. The RASSF1A (Ras Association Domain Family Protein 1) gene, located at 3p21.3, is highly methylated in multiple primary tumor samples, including neuroblastoma. In order to define whether there are genetic differences in the methylation frequency of RASSF1A between MB and sPNET, we analyzed 32 PNET paraffin-embedded samples (23 MB and 9 sPNET) by methylation specific polymerase chain reaction (MSP). We also analyzed RASSF1A expression by reverse transcription polymerase chain reaction in five PNET cell lines. All PNET cell lines showed lack of RASSF1A expression that was correlated with RASSF1A promoter hypermethylation. RASSF1A methylation was detected in 19 of 21 MB cases (91%) and in five of six sPNET samples (83%). Although the methylation frequency found in MB was slightly higher than in sPNET, no statistical differences were found for the RASSF1A hypermethylation frequency (P > 0.05) presented at MB versus sPNET. Therefore, the inactivation of the RASSF1A gene seems to be an important step in the tumorigenesis of PNET of the central nervous sytem. More studies should be performed in order to determine genetic differences between MB and sPNET.
Assuntos
Neoplasias Cerebelares/genética , Meduloblastoma/genética , Tumores Neuroectodérmicos Primitivos/genética , Regiões Promotoras Genéticas , Neoplasias Supratentoriais/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Various genomic alterations have been detected in glioblastoma. Chromosome 7p, with the epidermal growth factor receptor locus, together with chromosome 10q, with the phosphatase and tensin homologue deleted in chromosome 10 and deleted in malignant brain tumors-1 loci, and chromosome 9p, with the cyclin-dependent kinase inhibitor 2A locus, are among the most frequently damaged chromosomal regions in glioblastoma. In this study, we evaluated the genetic status of 32 glioblastomas by comparative genomic hybridization; the sensitivity of comparative genomic hybridization versus differential polymerase chain reaction to detect deletions at the phosphatase and tensin homologue deleted in chromosome 10, deleted in malignant brain tumors-1, and cyclin-dependent kinase inhibitor 2A loci and amplifications at the cyclin-dependent kinase 4 locus; the frequency of genetic lesions (gain or loss) at 16 different selected loci (including oncogenes, tumor-suppressor genes, and proliferation markers) mapping on 13 different chromosomes; and the possible existence of a statistical association between any pair of molecular markers studied, to subdivide the glioblastoma entity molecularly. Comparative genomic hybridization showed that the most frequent region of gain was chromosome 7p, whereas the most frequent losses occurred on chromosomes 10q and 13q. The only statistically significant association was found for 7p gain and 10q loss.