RESUMEN
Historical records as far back as 3000 BCE show that oral and head and neck cancer was a disease process well known to Egyptian physicians. Luminaries such as Hippocrates, Galen, Pott, and Virchow were instrumental in shaping our understanding of the etiology and pathogenesis of cancer. During the 20th century, evidence-based medicine catalyzed the development of rigorous science-based diagnostic and treatment protocols. The use of surgery, therapeutic radiation, and chemotherapy as single-treatment agents or in combination with one another gradually emerged as the preferred approach to cancer therapy. The recognition of tobacco, alcohol, and human papillomavirus as etiological agents in oral and head and neck cancer prompted the development of new diagnostic aids and treatment strategies to mitigate cancer progression. More in-depth mechanistic insights into the multistep process of oral and head and neck cancer were made possible by the use of the hamster buccal pouch and mouse models. New technologies, such as the sequencing of the human genome, metabolomics, and proteomics, have provided the foundation for what we today call precision medicine. The future success of tailored medical treatment for cancer patients will depend on the discovery of new druggable targets with improved therapeutic efficacy. As the precision and sensitivity of existing tools for prevention and risk assessment improve, greater accuracy will be achieved in predicting health outcomes.
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Neoplasias de Cabeza y Cuello , Animales , Protocolos Clínicos , Humanos , Ratones , Factores de RiesgoRESUMEN
BACKGROUND: Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. PATIENTS AND METHODS: Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. RESULTS: Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001). CONCLUSIONS: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. CLINICAL TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02258659.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/mortalidad , Neoplasias Orofaríngeas/terapia , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Cetuximab/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Paclitaxel/administración & dosificación , Infecciones por Papillomavirus/virología , Pronóstico , Tasa de SupervivenciaRESUMEN
PURPOSE: Patients with an upper brachial plexus lesion can suffer from dysfunction, joint deformities and instability of the shoulder. The goal of this study was to determine pain, shoulder function, patient satisfaction and muscle strength in shoulder arthrodesis in patients with an upper brachial plexus lesion more than 15 years after surgery. METHODS: We retrospectively studied 12 patients with a brachial plexus lesion of mean age 46 years (27-61). At a mean of 19.8 years (15.4-30.3) after shoulder arthrodesis, patient-reported outcome measures (PROMs), range of motion (e.g., active and passive), patient satisfaction, strength of the affected and non-affected side (e.g., maximum isometric strength in Newton in forward and retroflexion, ab- and adduction, internal and external rotation) and position of fusion were obtained. PROMS consisted of the Visual Analogue Scale (VAS; 0-100, 0 being painless) for pain and the Disabilities of the Arm, Shoulder and Hand Score (DASH; 0-100, 0 being the best score) for function. RESULTS: At latest follow-up, the median VAS pain score was 49 (0-96) and 0 for, respectively, the affected and unaffected side. The DASH was 15 (8-46), meaning a reasonable to good function of the upper extremity. Active and passive retroflexion was significantly different (p = 0.028). All subjects stated that in the same situation they would undergo a shoulder arthrodesis again. The unaffected side was significantly stronger in every direction. Arthrodesis showed position of fusion of 31° (12-70) abduction, 20° (10-50) forward flexion and 22° (- 14 to 58) internal rotation. The unaffected side was significantly (p ≤ 0.05) stronger in every movement direction. CONCLUSION: At a mean of 20 years after shoulder arthrodesis, patients with an upper brachial plexus lesion are still satisfied with a good to moderate functional improvement. LEVEL OF EVIDENCE III: A retrospective cohort study.
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Artrodesis , Neuropatías del Plexo Braquial/cirugía , Articulación del Hombro/cirugía , Adulto , Artralgia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Proyectos Piloto , Rango del Movimiento Articular , Recuperación de la Función , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: An expert panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the Center for Evidence-Based Dentistry conducted a systematic review and formulated clinical recommendations to inform primary care clinicians about the potential use of adjuncts as triage tools for the evaluation of lesions, including potentially malignant disorders (PMDs), in the oral cavity. TYPES OF STUDIES REVIEWED: This is an update of the ADA's 2010 recommendations on the early diagnosis of PMDs and oral squamous cell carcinoma. The authors conducted a systematic search of the literature in MEDLINE and Embase via Ovid and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials and diagnostic test accuracy studies. The authors used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty in the evidence and to move from the evidence to the decisions. RESULTS: The panel formulated 1 good practice statement and 6 clinical recommendations that concluded that no available adjuncts demonstrated sufficient diagnostic test accuracy to support their routine use as triage tools during the evaluation of lesions in the oral cavity. For patients seeking care for suspicious lesions, immediate performance of a biopsy or referral to a specialist remains the single most important recommendation for clinical practice. In exceptional cases, when patients decline a biopsy or live in rural areas with limited access to care, the panel suggested that cytologic testing may be used to initiate the diagnostic process until a biopsy can be performed (conditional recommendation, low-quality evidence). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The authors urge clinicians to remain alert and take diligent action when they identify a PMD. The authors emphasize the need for counseling because patients may delay diagnosis because of anxiety and denial.(AU)
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Humanos , Biopsia/métodos , Neoplasias de la Boca/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Boca/patología , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/patologíaRESUMEN
BACKGROUND: Transition of care from pediatric to adult services is a complex process. Factors influencing the success of health care transition of adolescents with chronic neurological disorders are poorly understood. METHODS: Young adults with chronic neurological disorders who had been cared for in an Interdisciplinary Pediatric Center participated in this study. Using the Patient Satisfaction Questionnaire Short-form (PSQ-18) we investigated whether satisfaction of these patients with their medical care in adult services was depending on the severity and complexity of their condition. They were assigned to a group of severely disabled patients (group 1; intellectual disability or learning disability plus motor handicap or degree of disability≥80, n=11) or a group 2 of patients with milder impairment (N=39). We used descriptive and t-statistics to compare both groups. RESULTS: Patients of group 1 reported slightly lower satisfaction with their present medical care in adult services (M=3.25; 95%-KI=[2.96-3.55]) compared to patients of group 2 (M=3.59; 95%.KI=[3.37-3.81]; p=0.084). Satisfaction with transition was significantly lower in group 1 (M=2.65; 95% KI=[2.29-3.01]) than in group 2 (M=3.11; 95% KI=[2.89-3.33], p=0.045). The difference of mean values of 0.46 reflects a moderate effect size (Hedges' g=0.68). CONCLUSION: Health care transition of adolescent patients with chronic neurological disorders is significantly more successful in patients with minor impairment compared to patients with severe complex neurological conditions.
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Enfermedades del Sistema Nervioso/terapia , Transición a la Atención de Adultos , Adolescente , Enfermedad Crónica , Comorbilidad , Personas con Discapacidad , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/terapia , Comunicación Interdisciplinaria , Colaboración Intersectorial , Discapacidades para el Aprendizaje/diagnóstico , Discapacidades para el Aprendizaje/terapia , Trastornos Motores/diagnóstico , Trastornos Motores/terapia , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/psicología , Satisfacción del Paciente , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. METHODS: Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. RESULTS: Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. CONCLUSION: Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma.
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Apoptosis/efectos de los fármacos , Apoptosis/genética , Genes bcl-2 , Glucocorticoides/farmacología , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Animales , Asma/genética , Asma/inmunología , Asma/metabolismo , Asma/patología , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Resistencia a Medicamentos/genética , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunofenotipificación , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Recent progress in genetic testing has facilitated obtaining an etiologic diagnosis in children with developmental delay/intellectual disability (DD/ID) or multiple congenital anomalies (MCA) or both. Little is known about the benefits of diagnostic elucidation for affected families. We studied the impact of a genetic diagnosis on parental quality of life (QoL) using a validated semiquantitative questionnaire in families with a disabled child investigated by array-based comparative genomic hybridization (aCGH). We received completed questionnaires from 95 mothers and 76 fathers of 99 families. We used multivariate analysis for adjustment of potential confounders. Taken all 99 families together, maternal QoL score (percentile rank scale 51.05) was significantly lower than fathers' QoL (61.83, p = 0.01). Maternal QoL score was 20.17 [95% CI (5.49; 34.82)] percentile rank scales higher in mothers of children with diagnostic (n = 34) aCGH as opposed to mothers of children with inconclusive (n = 65) aCGH (Hedges' g = 0.71). Comparison of these QoL scores with retrospectively recalled QoL before aCGH revealed an increase of maternal QoL after diagnostic clarification. Our results indicate a benefit for maternal QoL if a genetic test, here aCGH, succeeds to clarify the etiologic diagnosis in a disabled child.
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Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Padres , Calidad de Vida , Adulto , Niño , Hibridación Genómica Comparativa , Factores de Confusión Epidemiológicos , Demografía , Femenino , Humanos , MasculinoRESUMEN
The major goals of Kawasaki disease (KD) therapy are to reduce inflammation and prevent thrombosis in the coronary arteries (CA), but some children do not respond to currently available non-specific therapies. New treatments have been difficult to develop because the molecular pathogenesis is unknown. In order to identify dysregulated gene expression in KD CA, we performed high-throughput RNA sequencing on KD and control CA, validated potentially dysregulated genes by real-time reverse transcription-polymerase chain reaction (RT-PCR) and localized protein expression by immunohistochemistry. Signalling lymphocyte activation molecule CD84 was up-regulated 16-fold (P < 0·01) in acute KD CA (within 2 months of onset) and 32-fold (P < 0·01) in chronic CA (5 months to years after onset). CD84 was localized to inflammatory cells in KD tissues. Genes associated with cellular proliferation, motility and survival were also up-regulated in KD CA, and immune activation molecules MX2 and SP140 were up-regulated in chronic KD. CD84, which facilitates immune responses and stabilizes platelet aggregates, is markedly up-regulated in KD CA in patients with acute and chronic arterial disease. We provide the first molecular evidence of dysregulated inflammatory responses persisting for months to years in CA significantly damaged by KD.
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Antígenos CD/metabolismo , Antígenos Nucleares/metabolismo , Plaquetas/inmunología , Síndrome Mucocutáneo Linfonodular/inmunología , Proteínas de Resistencia a Mixovirus/metabolismo , Factores de Transcripción/metabolismo , Calcificación Vascular/inmunología , Enfermedad Aguda , Antígenos CD/genética , Antígenos Nucleares/genética , Procesos de Crecimiento Celular/genética , Movimiento Celular/genética , Supervivencia Celular/genética , Enfermedad Crónica , Vasos Coronarios/patología , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/genética , Proteínas de Resistencia a Mixovirus/genética , Agregación Plaquetaria/genética , ARN Mensajero/análisis , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Factores de Transcripción/genética , Regulación hacia Arriba , Calcificación Vascular/sangre , Calcificación Vascular/genéticaRESUMEN
BACKGROUND: Cancer is a multifactorial disease composed of cells that show somatic mutations and epigenetic changes. The aim of this study was to investigate the expression of proteins involved in the development and maintenance of epithelia, cell cycle regulation, and apoptosis in human oral squamous cell carcinoma (OSCC) tissue samples. METHODS: A tissue microarray containing 65 primary human OSCC specimens was immunolabeled for bcl-2, survivin, epidermal growth factor receptor (EGFR), p21, p53, p63, and cleaved caspase-3. RESULTS: Samples were scored for percentage of positively stained tumor cells and staining intensity. A total immunostaining score was also calculated, using the product of percentage and intensity scores. All specimens showed high scores, > 75%, for p63 and survivin, and 75.4% of the specimens also presented high EGFR expression. All cases showed p53-positive cells. p21 showed a diffuse staining pattern. The percentage of cells positive for cleaved caspase-3 and bcl-2 was low. CONCLUSIONS: The high frequency of tumor cells expressing p63 and survivin highlights the role of these proteins in the malignant transformation of oral epithelium. Collectively, our results suggest that p63 and survivin may constitute attractive targets for cancer therapy in patients with OSCC.
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Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Proteínas de la Membrana/biosíntesis , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/metabolismo , Anciano , Anciano de 80 o más Años , Proteínas Reguladoras de la Apoptosis , Femenino , Humanos , Masculino , Persona de Mediana Edad , SurvivinRESUMEN
BACKGROUND: Oral cavity and in particular oral tongue cancers occur with a rising incidence in younger patients often lacking the typical risk factors of tobacco use, alcohol use, and human papilloma virus (HPV) infection. Their prognosis when treated with chemoradiation has not been well studied and responsible risk factors remain elusive. A viral etiology (other than HPV) has been hypothesized. METHODS: First we analyzed outcomes from 748 head and neck cancer patients with locoregionally advanced stage tumors treated with curative-intent chemoradiation by anatomic site. Second, we analyzed seven oral tongue (OT) tumors from young, non-smokers/non-drinkers for the presence of viral mRNA using short-read massively-parallel sequencing (RNA-Seq) in combination with a newly-developed digital subtraction method followed by viral screening and discovery algorithms. For positive controls we used an HPV16-positive HNC cell line, a cervical cancer, and an EBV-LMP2A transgene lymphoma. RESULTS: Younger patients with oral cavity tumors had worse outcomes compared to non-oral cavity patients. Surprisingly none of the seven oral tongue cancers showed significant presence of viral transcripts. In positive controls the expected viral material was identified. CONCLUSION: Oral cavity tumors in younger patients have a poor prognosis and do not appear to be caused by a transcriptionally active oncovirus.
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Neoplasias de la Boca/patología , ARN Viral/análisis , Adulto , Algoritmos , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Masculino , Neoplasias de la Boca/virología , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Pronóstico , Análisis de SupervivenciaRESUMEN
Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. The phenotypic features of patients with clinically significant CNV were compared with those without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.
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Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo , Discapacidad Intelectual , Adolescente , Niño , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/fisiopatología , Femenino , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Microcefalia/genética , Microcefalia/fisiopatología , Fenotipo , Estudios RetrospectivosRESUMEN
BACKGROUND: AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). METHODS: TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. RESULTS: Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. CONCLUSIONS: TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , ADN/administración & dosificación , Neoplasias de Cabeza y Cuello/terapia , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Quimioradioterapia , ADN/genética , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorouracilo/administración & dosificación , Terapia Genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Hidroxiurea/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada , Retratamiento , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis whose expression suppresses tumor growth in vivo. Like many angiogenesis-related genes, TSP-1 expression is tightly controlled by various mechanisms, but there is little data regarding the contribution of post-transcriptional processing to this regulation. NOL7 is a novel tumor suppressor that induces an antiangiogenic phenotype and suppresses tumor growth, in part through upregulation of TSP-1. Here we demonstrate that NOL7 is an mRNA-binding protein that must localize to the nucleoplasm to exert its antiangiogenic and tumor suppressive effects. There, it associates with the RNA-processing machinery and specifically interacts with TSP-1 mRNA through its 3'UTR. Reintroduction of NOL7 into SiHa cells increases luciferase expression through interaction with the TSP-1 3'UTR at both the mRNA and protein levels. NOL7 also increases endogenous TSP-1 mRNA half-life. Further, NOL7 post-transcriptional stabilization is observed in a subset of angiogenesis-related mRNAs, suggesting that the stabilization of TSP-1 may be part of a larger novel mechanism. These data demonstrate that NOL7 significantly alters TSP-1 expression and may be a master regulator that coordinates the post-transcriptional expression of key signaling factors critical for the regulation of the angiogenic phenotype.
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Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/metabolismo , Procesamiento Postranscripcional del ARN , Trombospondina 1/genética , Proteínas Supresoras de Tumor/metabolismo , Regiones no Traducidas 3' , Animales , Línea Celular , Núcleo Celular/metabolismo , Proliferación Celular , Femenino , Humanos , Ratones , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Fenotipo , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribonucleoproteínas/metabolismo , Trombospondina 1/metabolismoRESUMEN
Squamous cell carcinoma (SCC) of the oral and oropharyngeal region is the sixth most common malignancy in the world today. Despite numerous advances in treatment, long-term survival from this disease remains poor. Early detection can decrease both morbidity and mortality associated with this neoplasm. However, screening for potentially malignant disease is typically confounded by difficulty in discriminating between reactive/inflammatory lesions vs those lesions that are premalignant in nature. Furthermore, the histologic diagnosis of dysplasia can be subjective and is thus prone to a considerable range of interpretation. Similarly, no definitive, validated criteria exist for predicting which dysplastic lesions are most likely to progress to cancer over time. Given this state of science, the presence of dysplasia can only be used to indicate that an oral lesion may have an increased risk of malignant transformation. Molecular biomarkers capable of identifying the subset of lesions likely to progress to cancer are required to eliminate this clinical diagnostic dilemma. The purpose of this review is to assess the current state of knowledge regarding genetic/epigenetic alterations observed in oral mucosal premalignancy. In addition, recommendations for future research studies directed at defining the predictive capacity of specific biomarkers in this modeling are presented.
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Epigénesis Genética/genética , Neoplasias de la Boca/genética , Lesiones Precancerosas/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Transformación Celular Neoplásica/genética , Investigación Dental/tendencias , Epigenómica/tendencias , Predicción , HumanosRESUMEN
Vascular endothelial growth factor (VEGF) signaling is critical for tumor angiogenesis. However, therapies based on inhibition of VEGF receptors (VEGFRs) have shown modest results for patients with cancer. Surprisingly little is known about mechanisms underlying the regulation of VEGFR1 and VEGFR2 expression, the main targets of these drugs. Here, analysis of tissue microarrays revealed an inversely reciprocal pattern of VEGFR regulation in the endothelium of human squamous-cell carcinomas (high VEGFR1, low VEGFR2), as compared with the endothelium of control tissues (low VEGFR1, high VEGFR2). Mechanistic studies demonstrated that VEGF signals through the Akt/ERK pathway to inhibit constitutive ubiquitination and induce rapid VEGFR1 accumulation in endothelial cells. Surprisingly, VEGFR1 is primarily localized in the nucleus of endothelial cells. In contrast, VEGF signals through the JNK/c-Jun pathway to induce endocytosis, nuclear translocation, and downregulation of VEGFR2 via ubiquitination. VEGFR1 signaling is required for endothelial-cell survival, while VEGFR2 regulates capillary tube formation. Notably, the antiangiogenic effect of bevacizumab (anti-VEGF antibody) requires normalization of VEGFR1 and VEGFR2 levels in human squamous-cell carcinomas vascularized with human blood vessels in immunodeficient mice. Collectively, this work demonstrates that VEGF-induced angiogenesis requires inverse regulation of VEGFR1 and VEGFR2 in tumor-associated endothelial cells.
Asunto(s)
Neovascularización Patológica/metabolismo , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales Humanizados , Apoptosis/fisiología , Bevacizumab , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Células Endoteliales/citología , Células Endoteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Análisis por Micromatrices , Fosfatidilinositol 3-Quinasas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitina/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, agents that inhibit angiogenesis have important therapeutic implications in numerous malignancies. We examined the effects of methylnaltrexone (MNTX), a peripheral mu opioid receptor antagonist, on agonist-induced human EC proliferation and migration, two key components in angiogenesis. Using human dermal microvascular EC, we observed that morphine sulfate (MS), the active metabolite, morphine-6-glucuronide (M6G), DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkaphalin) and VEGF induced migration which were inhibited by pretreatment with MNTX at therapeutically relevant concentration (0.1 microM). The biologically inactive metabolite morphine-3-glucuronide (M3G) did not affect EC migration. We next examined the mechanism(s) by which MNTX inhibits opioid and VEGF-induced angiogenesis using human pulmonary microvascular EC. MS and DAMGO induced Src activation which was required for VEGF receptor transactivation and opioid-induced EC proliferation and migration. MNTX inhibited MS, DAMGO and VEGF induced tyrosine phosphorylation (transactivation) of VEGF receptors 1 and 2. Furthermore, MS, DAMGO and VEGF induced RhoA activation which was inhibited by MNTX or VEGF receptor tyrosine kinase inhibition. Finally, MNTX or silencing RhoA expression (siRNA) blocked MS, DAMGO and VEGF-induced EC proliferation and migration. Taken together, these results indicate that MNTX inhibits opioid-induced EC proliferation and migration via inhibition of VEGF receptor phosphorylation/transactivation with subsequent inhibition of RhoA activation. These results suggest that MNTX inhibition of angiogenesis can be a useful therapeutic intervention for cancer treatment.
Asunto(s)
Naltrexona/análogos & derivados , Neoplasias/tratamiento farmacológico , Neovascularización Patológica , Péptidos Opioides/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Proliferación Celular , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Humanos , Pulmón/irrigación sanguínea , Pulmón/patología , Morfina/farmacología , Derivados de la Morfina/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Compuestos de Amonio Cuaternario/farmacología , Activación TranscripcionalRESUMEN
Cervical cancer is associated with human papilloma virus infection. However, this infection is insufficient to induce transformation and progression. Loss of heterozygosity analyses suggest the presence of a tumor suppressor gene (TSG) on chromosome 6p21.3-p25. Here we report the cloning NOL7, its mapping to chromosome band 6p23, and localization of the protein to the nucleolus. Fluorescence in situ hybridization analysis demonstrated an allelic loss of an NOL7 in cultured tumor cells and human tumor samples. Transfection of NOL7 into cervical carcinoma cells inhibited their growth in mouse xenografts, confirming its in vivo tumor suppressor activity. The induction of tumor dormancy correlated with an angiogenic switch caused by a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These data suggest that NOL7 may function as a TSG in part by modulating the expression of the angiogenic phenotype.
Asunto(s)
Nucléolo Celular/química , Genes Supresores de Tumor , Neovascularización Patológica/prevención & control , Neoplasias del Cuello Uterino/genética , Animales , Línea Celular Tumoral , Mapeo Cromosómico , Cromosomas Humanos Par 6 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Trombospondina 1/genética , Neoplasias del Cuello Uterino/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BRK is a non-receptor tyrosine kinase whose functional role is poorly understood. Although it is an epithelial specific kinase, its expression appears to be tissue specific. To date, little is known about BRK expression in human oral epithelium. We investigated expression of BRK in human oral squamous cell carcinomas (OSCC) and normal oral epithelium (NOE) using immunohistochemistry, laser confocal microscopy and Western blotting. The subcellular localization of BRK was identified by confocal microscopy and Western blotting of nuclear and cytoplasmic extracts from these cells. The results indicate that NOE express higher levels of BRK compared with OSCC cells. In NOE and moderately differentiated OSCC cells, BRK was localized in the nucleus and cytoplasm. However, in poorly differentiated OSCC cells, BRK was localized in perinuclear regions. These results suggest that BRK expression differs in normal and OSCC which may reflect a possible functional involvement in OSCC.