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BACKGROUND: Although hematogenous spread of osteosarcoma is well known, the imaging findings of cardiovascular involvement by osteosarcoma are seldom reported and can be difficult to recognize. The enhanced resolution of modern CT and MRI scanners may lead to better detection of cardiovascular involvement. OBJECTIVE: To describe the key imaging findings and clinical behavior of cardiovascular involvement by osteosarcoma. MATERIALS AND METHODS: We retrospectively reviewed the imaging findings and clinical characteristics of 20 patients with cardiovascular involvement by osteosarcoma identified by two pediatric radiologists from a review of imaging studies at our institution from 2007 to 2013. RESULTS: At initial diagnosis, the median age of the patients was 15.1 years (range 4.8-24.6 years), and 7 (35%) patients had detectable metastases. Median time to detection of cardiovascular metastases was 1.8 years (range 0-7.3 years). Sixteen patients died of disease; 4 have survived a median of 7.4 years since initial diagnosis. The sites of cardiovascular involvement were the systemic veins draining the primary and metastatic osteosarcoma, pulmonary arteries, pulmonary veins draining the pulmonary metastases, and heart. A dilated and mineralized terminal pulmonary arteriole is an early sign of metastatic osteosarcoma in the lung. Unfamiliarity with the imaging features resulted in under-recognition and misinterpretation of intravascular tumor thrombus as bland thrombus. CONCLUSION: Knowledge of imaging findings in the era of modern imaging modalities has enhanced our ability to detect cardiovascular involvement and lung metastases early and avoid misinterpreting tumor thrombus in draining systemic veins or pulmonary arteries as bland thrombus.
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Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/secundario , Osteosarcoma/diagnóstico , Osteosarcoma/secundario , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/secundario , Adolescente , Neoplasias Óseas/diagnóstico , Niño , Preescolar , Diagnóstico por Imagen/métodos , Femenino , Humanos , Masculino , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
The pediatric bone sarcomas osteosarcoma and Ewing sarcoma represent a tremendous challenge for the clinician. Though less common than acute lymphoblastic leukemia or brain tumors, these aggressive cancers account for a disproportionate amount of the cancer morbidity and mortality in children, and have seen few advances in survival in the past decade, despite many large, complicated, and expensive trials of various chemotherapy combinations. To improve the outcomes of children with bone sarcomas, a better understanding of the biology of these cancers is needed, together with informed use of targeted therapies that exploit the unique biology of each disease. Here we summarize the current state of knowledge regarding the contribution of receptor tyrosine kinases, intracellular signaling pathways, bone biology and physiology, the immune system, and the tumor microenvironment in promoting and maintaining the malignant phenotype. These observations are coupled with a review of the therapies that target each of these mechanisms, focusing on recent or ongoing clinical trials if such information is available. It is our hope that, by better understanding the biology of osteosarcoma and Ewing sarcoma, rational combination therapies can be designed and systematically tested, leading to improved outcomes for a group of children who desperately need them.
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Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Humanos , Pediatría , Transducción de SeñalRESUMEN
PURPOSE: To evaluate the impact of treated extra-pulmonary metastatic disease on overall (OS) and event-free survival (EFS) for pediatric osteosarcoma patients undergoing pulmonary metastatectomy. METHODS: We retrospectively reviewed pediatric patients who were treated for osteosarcoma at our institution from 2001 to 2011 and received pulmonary metastatectomy (n=76). We compared OS and EFS between patients with metastases limited to the lungs (Group A, n=58) to those with treated extra-pulmonary metastases (Group B, n=18) at the time of first pulmonary metastatectomy. RESULTS: The estimated median OS and EFS from first pulmonary metastatectomy were 2.0years (95% CI 1.5-2.8years) and 5.5months (95% CI 3.0-8.1months), respectively. Median OS was significantly greater for Group A (2.6years, 95% CI 1.9-3.8) compared to Group B (0.9years, 95% CI 0.6-1.5) (log rank p=0.0001). Median EFS was significantly greater for Group A (7.9months, 95% CI 5.0-10.7) compared to Group B (1.6months, 95% CI 0.8-2.7) (log rank p<0.0001). Independent predictors of OS included extra-pulmonary metastatic disease at the time of first thoracotomy, bilateral pulmonary metastases, and >4 nodules resected at first thoracotomy (all p<0.001). CONCLUSIONS: Osteosarcoma patients with treated extra-pulmonary metastatic disease at the time of pulmonary metastatectomy have significantly worse survival compared to those with disease limited to the lungs.
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Neoplasias Óseas/patología , Neoplasias Pulmonares/cirugía , Osteosarcoma/secundario , Neumonectomía , Adolescente , Neoplasias Óseas/mortalidad , Neoplasias Óseas/cirugía , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Masculino , Neoplasias Primarias Secundarias/cirugía , Osteosarcoma/mortalidad , Osteosarcoma/cirugía , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Texas/epidemiología , Adulto JovenRESUMEN
PURPOSE: The purpose of this study was to identify health disparities in children with non-CNS solid tumor malignancies and examine their impact on disease presentation and outcome. METHODS: We examined the records of all children (age≤18years) diagnosed with a non-CNS solid tumor malignancy and enrolled in the Texas Cancer Registry between 1995 and 2009 (n=4603). The primary outcome measures were disease stage and overall survival (OS). Covariates included gender, age, race/ethnicity, year of diagnosis, socioeconomic status (SES), and driving distance to the nearest pediatric cancer treatment facility. Statistical analyses included life table methods, logistic, and Cox regression. Statistical significance was defined as p<0.05. RESULTS: Children with advanced-stage disease were more likely to be male, <10years old, and Hispanic or non-Hispanic Blacks (all p<0.05). Distance to treatment and SES did not impact stage of disease at presentation. However, Hispanic and non-Hispanic Blacks and patients in the lowest SES quartile had the worst 1- and 5-year survival (all p<0.05). The adjusted OS differed by age, race, and stage, but not SES or distance to the nearest treatment facility. CONCLUSIONS: Race/ethnicity plays an important role in survival for children with non-CNS solid tumor malignancies. Future work should better define these differences to establish mechanisms to decrease their impact.
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Etnicidad , Estado de Salud , Estadificación de Neoplasias , Neoplasias/etnología , Grupos Raciales , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Neoplasias/diagnóstico , Estudios Retrospectivos , Factores Socioeconómicos , Texas/epidemiologíaRESUMEN
Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 µg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.
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Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/química , Polietilenglicoles/química , Polímeros/química , Alquinos/química , Animales , Azidas/química , Neoplasias Óseas/patología , Catálisis , Línea Celular Tumoral , Cobre/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Ésteres , Semivida , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Micelas , Modelos Moleculares , Conformación Molecular , Osteosarcoma/patología , Polímeros/metabolismo , Polímeros/farmacocinética , Distribución TisularRESUMEN
PURPOSE: Natural killer (NK) cell cytotoxicity correlates with the ligation of activating receptors (e.g., NKG2D) by their ligands (e.g., MHC class I-related chains [MIC] A and B) on target cells. Histone deacetylase inhibitors (HDACi) at high concentrations inhibit tumor growth and can increase NKG2D ligand expression on tumor targets, but are widely regarded as toxic to NK cells. METHODS: We investigated the mechanism of entinostat, a benzamide-derivative narrow-spectrum HDACi, in augmenting the cytotoxicity of NK cells against human colon carcinoma and sarcoma by assessing gene and protein expression, histone acetylation, and cytotoxicity in in vitro and murine models. RESULTS: We observed that entinostat dose- and time-dependent increase in MIC expression in tumor targets and NKG2D in primary human NK cells, both correlating with increased acetylated histone 3 (AcH3) binding to associated promoters. Entinostat pretreatment of colon carcinoma and sarcoma cells, NK cells, or both led to enhanced overall cytotoxicity in vitro, which was reversed by NKG2D blockade, and inhibited growth of tumor xenografts. Lastly, we showed decreased expression of MICA and ULBP2 transcription in primary human osteosarcoma. CONCLUSIONS: Entinostat enhances NK cell killing of cancer cells through upregulation of both NKG2D and its ligands, suggesting an attractive approach for augmenting NK cell immunotherapy of solid tumors such as colon carcinoma and sarcomas.
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Antineoplásicos/farmacología , Benzamidas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Células Asesinas Naturales/efectos de los fármacos , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Piridinas/farmacología , Sarcoma/tratamiento farmacológico , Acetilación , Animales , Antineoplásicos/toxicidad , Benzamidas/toxicidad , Sitios de Unión , Línea Celular Tumoral , Técnicas de Cocultivo , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Inhibidores de Histona Desacetilasas/toxicidad , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ligandos , Ratones Endogámicos NOD , Ratones Transgénicos , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Regiones Promotoras Genéticas , Piridinas/toxicidad , Sarcoma/genética , Sarcoma/inmunología , Sarcoma/metabolismo , Sarcoma/patología , Factores de Tiempo , Transcripción Genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A phase I trial of PF-03084014, an oral reversible γ-secretase inhibitor, in solid tumor malignancies shows drug tolerability in patients. Evidence of Notch pathway inhibition was demonstrated in peripheral blood. A surprisingly high rate of response was seen in desmoid tumors, a rare but sometimes locally aggressive sarcoma.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/administración & dosificación , Neoplasias/tratamiento farmacológico , Tetrahidronaftalenos/administración & dosificación , Valina/análogos & derivados , Femenino , Humanos , MasculinoRESUMEN
The Notch pathway has been described as an oncogene in osteosarcoma, but the myriad functions of all the members of this complex signaling pathway, both in malignant cells and nonmalignant components of tumors, make it more difficult to define Notch as simply an oncogene or a tumor suppressor. The cell-autonomous behaviors caused by Notch pathway manipulation may vary between cell lines but can include changes in proliferation, migration, invasiveness, oxidative stress resistance, and expression of markers associated with stemness or tumor-initiating cells. Beyond these roles, Notch signaling also plays a vital role in regulating tumor angiogenesis and vasculogenesis, which are vital aspects of osteosarcoma growth and behavior in vivo. Further, osteosarcoma cells themselves express relatively low levels of Notch ligand, making it likely that nonmalignant cells, especially endothelial cells and pericytes, are the major source of Notch activation in osteosarcoma tumors in vivo and in patients. As a result, Notch pathway expression is not expected to be uniform across a tumor but likely to be highest in those areas immediately adjacent to blood vessels. Therapeutic targeting of the Notch pathway is likewise expected to be complicated. Most pharmacologic approaches thus far have focused on inhibition of gamma secretase, a protease of the presenilin complex. This enzyme, however, has numerous other target proteins that would be expected to affect osteosarcoma behavior, including CD44, the WNT/ß-catenin pathway, and Her-4. In addition, Notch plays a vital role in tissue and organ homeostasis in numerous systems, and toxicities, especially GI intolerance, have limited the effectiveness of gamma secretase inhibitors. New approaches are in development, and the downstream targets of Notch pathway signaling also may turn out to be good targets for therapy. In summary, a full understanding of the complex functions of Notch in osteosarcoma is only now unfolding, and this deeper knowledge will help position the field to better utilize novel therapies as they are developed.
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Neoplasias Óseas/irrigación sanguínea , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/irrigación sanguínea , Osteosarcoma/irrigación sanguínea , Receptores Notch/genética , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Neovascularización Patológica , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/secundario , Receptores Notch/agonistas , Receptores Notch/antagonistas & inhibidores , Transducción de SeñalRESUMEN
Cancer of any type often can be described by an arrest, alteration or disruption in the normal development of a tissue or organ, and understanding of the normal counterpart's development can aid in understanding the malignant state. This is certainly true for osteosarcoma and the normal developmental pathways that guide osteoblast development that are changed in the genesis of osteogenic sarcoma. A carefully regulated crescendo-decrescendo expression of RUNX2 accompanies the transition from mesenchymal stem cell to immature osteoblast to mature osteoblast. This pivotal role is controlled by several pathways, including bone morphogenic protein (BMP), Wnt/ß-catenin, fibroblast growth factor (FGF), and protein kinase C (PKC). The HIPPO pathway and its downstream target YAP help to regulate proliferation of immature osteoblasts and their maturation into non-proliferating mature osteoblasts. This pathway also helps regulate expression of the mature osteoblast protein osteocalcin. YAP also regulates expression of MT1-MMP, a membrane-bound matrix metalloprotease responsible for remodeling the extracellular matrix surrounding the osteoblasts. YAP, in turn, can be regulated by the ERBB family protein Her-4. Osteosarcoma may be thought of as a cell held at the immature osteoblast stage, retaining some of the characteristics of that developmental stage. Disruptions of several of these pathways have been described in osteosarcoma, including BMP, Wnt/b-catenin, RUNX2, HIPPO/YAP, and Her-4. Further, PKC can be activated by several receptor tyrosine kinases implicated in osteosarcoma, including the ERBB family (EGFR, Her-2 and Her-4 in osteosarcoma), IGF1R, FGF, and others. Understanding these functions may aid in the understanding the mechanisms underpinning clinical observations in osteosarcoma, including both the lytic and blastic phenotypes of tumors, the invasiveness of the disease, and the tendency for treated tumors to ossify rather than shrink. Through a better understanding of the relationship between normal osteoblast development and osteosarcoma, we may gain insights into novel therapeutic avenues and improved outcomes.
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Neoplasias Óseas/metabolismo , Regulación Neoplásica de la Expresión Génica , Osteoblastos/metabolismo , Osteosarcoma/metabolismo , Transducción de Señal/genética , Antineoplásicos/uso terapéutico , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Diferenciación Celular , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Vía de Señalización Hippo , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/patología , Osteocalcina/genética , Osteocalcina/metabolismo , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: Survival of patients with osteosarcoma lung metastases has not improved in 20 years. We evaluated the efficacy of combining natural killer (NK) cells with aerosol interleukin-2 (IL-2) to achieve organ-specific NK cell migration and expansion in the metastatic organ, and to decrease toxicity associated with systemic IL-2. PROCEDURE: Five human osteosarcoma cell lines and 103 patient samples (47 primary and 56 metastatic) were analyzed for NKG2D ligand (NKG2DL) expression. Therapeutic efficacy of aerosol IL-2 + NK cells was evaluated in vivo compared with aerosol IL-2 alone and NK cells without aerosol IL-2. RESULTS: Osteosarcoma cell lines and patient samples expressed various levels of NKG2DL. NK-mediated killing was NKG2DL-dependent and correlated with expression levels. Aerosol IL-2 increased NK cell numbers in the lung and within metastatic nodules but not in other organs. Therapeutic efficacy, as judged by tumor number, size, and quantification of apoptosis, was also increased compared with NK cells or aerosol IL-2 alone. There were no IL-2-associated systemic toxicities. CONCLUSION: Aerosol IL-2 augmented the efficacy of NK cell therapy against osteosarcoma lung metastasis, without inducing systemic toxicity. Our data suggest that lung-targeted IL-2 delivery circumvents toxicities induced by systemic administration. Combining aerosol IL-2 with NK cell infusions, may be a potential new therapeutic approach for patients with osteosarcoma lung metastasis.
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Administración por Inhalación , Neoplasias Óseas/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Interleucina-2/administración & dosificación , Células Asesinas Naturales/trasplante , Neoplasias Pulmonares/terapia , Osteosarcoma/terapia , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Terapia Combinada , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Proteínas Ligadas a GPI/metabolismo , Humanos , Técnicas para Inmunoenzimas , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología , Células Tumorales CultivadasRESUMEN
The two most common primary bone malignancies, osteosarcoma (OS), and Ewing sarcoma (ES), are both aggressive, highly metastatic cancers that most often strike teens, though both can be found in younger children and adults. Despite distinct origins and pathogenesis, both diseases share several mechanisms of progression and metastasis, including neovascularization, invasion, anoikis resistance, chemoresistance, and evasion of the immune response. Some of these processes are well-studies in more common carcinoma models, and the observation from adult diseases may be readily applied to pediatric bone sarcomas. Neovascularization, which includes angiogenesis and vasculogenesis, is a clear example of a process that is likely to be similar between carcinomas and sarcomas, since the responding cells are the same in each case. Chemoresistance mechanisms also may be similar between other cancers and the bone sarcomas. Since OS and ES are mesenchymal in origin, the process of epithelial-to-mesenchymal transition is largely absent in bone sarcomas, necessitating different approaches to study progression and metastasis in these diseases. One process that is less well-studied in bone sarcomas is dormancy, which allows micrometastatic disease to remain viable but not growing in distant sites - typically the lungs - for months or years before renewing growth to become overt metastatic disease. By understanding the basic biology of these processes, novel therapeutic strategies may be developed that could improve survival in children with OS or ES.
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The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+)ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph(+)ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ~30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+)ALL as compared to just 4.8% of Ph(-)ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+)ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.
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Apoptosis/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Cromosoma Filadelfia/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto JovenRESUMEN
PURPOSE: The purpose of this study was to characterize the complications associated with surgical treatment of pediatric melanoma. METHODS: We retrospectively reviewed all pediatric patients who received surgical treatment for melanoma at our institution between 1992 and 2010. We compared complications between three groups: wide local excision only (WLE), WLE and sentinel lymph node biopsy (SLNB), and WLE and completion lymph node dissection (CLND). RESULTS: One hundred twenty-five patients were identified: 37 patients received WLE only, 47 received WLE and SLNB, and 41 patients had WLE and CLND. Complication rates differed between the three groups: 19% in WLE, 11% in WLE+SLNB, and 39% in WLE+CLND (P=.006). The risk of complications was significantly lower among patients having WLE+SLNB versus WLE+CLND (OR 0.19, 95% CI 0.06-0.57, P=.0032). Lymphedema was a common complication with a higher incidence in the CLND group compared to the SLNB group (19.5% vs. 2.1%, P=.01). Complications were more frequent in inguinal compared to axillary dissections (52.0% vs. 17.1%, P=.006). CONCLUSIONS: In the surgical treatment of pediatric melanoma, the addition of a completion lymph node dissection significantly increases complication risk. Thus, it is critical to determine which patients truly benefit from this procedure.
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Procedimientos Quirúrgicos Dermatologicos/métodos , Escisión del Ganglio Linfático , Melanoma/cirugía , Complicaciones Posoperatorias/etiología , Neoplasias Cutáneas/cirugía , Adolescente , Axila , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Conducto Inguinal , Modelos Logísticos , Masculino , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Riesgo , Biopsia del Ganglio Linfático Centinela , Resultado del TratamientoRESUMEN
BACKGROUND: The UBE4B gene, which is located on chromosome 1p36, encodes a ubiquitin ligase that interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a protein involved in epidermal growth factor receptor (EGFR) trafficking, suggesting a link between EGFR trafficking and neuroblastoma pathogenesis. The authors analyzed the roles of UBE4B in the outcomes of patients with neuroblastoma and in neuroblastoma tumor cell proliferation, EGFR trafficking, and response to EGFR inhibition. METHODS: The association between UBE4B expression and the survival of patients with neuroblastoma was examined using available microarray data sets. UBE4B and EGFR protein levels were measured in patient tumor samples, EGFR degradation rates were measured in neuroblastoma cell lines, and the effects of UBE4B on neuroblastoma tumor cell growth were analyzed. The effects of the EGFR inhibitor cetuximab were examined in neuroblastoma cells that expressed wild-type and mutant UBE4B. RESULTS: Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma. UBE4B overexpression reduced neuroblastoma tumor cell proliferation, and UBE4B expression was inversely related to EGFR expression in tumor samples. EGFR degradation rates correlated with cellular UBE4B levels. Enhanced expression of catalytically active UBE4B resulted in reduced sensitivity to EGFR inhibition. CONCLUSIONS: The current study demonstrates associations between UBE4B expression and the outcomes of patients with neuroblastoma and between UBE4B and EGFR expression in neuroblastoma tumor samples. Moreover, levels of UBE4B influence neuroblastoma tumor cell proliferation, EGFR degradation, and response to EGFR inhibition. These results suggest UBE4B-mediated growth factor receptor trafficking may contribute to the poor prognosis of patients who have neuroblastoma tumors with 1p36 deletions and that UBE4B expression may be a marker that can predict responses of neuroblastoma tumors to treatment.
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Receptores ErbB/antagonistas & inhibidores , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/genética , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab , Deleción Cromosómica , Cromosomas Humanos Par 1 , Receptores ErbB/metabolismo , Humanos , Neuroblastoma/genética , Neuroblastoma/mortalidad , Neuroblastoma/patología , Resultado del Tratamiento , Ubiquitina-Proteína LigasasRESUMEN
Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs. Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may lead the development of new therapeutic strategies for GISTs patients.
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Neoplasias Gastrointestinales/prevención & control , Tumores del Estroma Gastrointestinal/prevención & control , Receptores Notch/fisiología , Transducción de Señal/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Proteínas de Homeodominio/fisiología , Humanos , Ácidos Hidroxámicos/farmacología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/análisis , Proteínas Proto-Oncogénicas c-kit/genética , ARN Mensajero/análisis , Proteínas Represoras/fisiología , Factor de Transcripción HES-1RESUMEN
BACKGROUND: Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics. METHODS: Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman's rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts. RESULTS: Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p=0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts. CONCLUSIONS: Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.
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Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Proteínas de Unión al ADN/metabolismo , Proteómica , Neoplasias Colorrectales/patología , ADN/metabolismo , Proteínas de Unión al ADN/genética , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ganglios Linfáticos/patología , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas Asociadas a Matriz Nuclear/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción de Octámeros/genética , Factores de Transcripción de Octámeros/metabolismo , Factor de Empalme Asociado a PTB , Unión Proteica , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , RecQ Helicasas/genética , RecQ Helicasas/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Factor de Empalme U2AF , Helicasa del Síndrome de Werner , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: Neuroblastoma (NBL) is a common pediatric solid tumor, and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment. Chemotherapy resistance at relapse contributes heavily to treatment failure. The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms. On the basis of previous work and on data from publicly available studies, the authors hypothesized that human epidermal growth factor receptor 4 (Her4) contributes to resistance. METHODS: Her4 expression was reduced with small-hairpin RNA (shRNA) to over express intracellular HER4, and the authors tested its impact on tumor cell survival under various culture conditions. The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA (mRNA) array. RESULTS: HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture. With HER4 knockdown, NBL cells became less resistant to anoikis and serum starvation. Moreover, HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin, doxorubicin, etoposide, and activated ifosfamide. In mRNA array analysis, HER4 knockdown predominately altered genes related to cell cycle regulation. In NBL spheres compared with monolayers, cell proliferation was decreased, and cyclin D expression was reduced. HER4 knockdown reversed cyclin D suppression. Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance. CONCLUSIONS: The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli, including anoikis, nutrient deficiency, and cytotoxic chemotherapy. The intracellular fragment of HER4 was sufficient to confer this phenotype. HER4 functions as a cell cycle suppressor, maintaining resistance to cellular stress. The current findings indicate that HER4 overexpression may be associated with refractory disease, and HER4 may be an important therapeutic target.
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Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Receptores ErbB/fisiología , Neuroblastoma/genética , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Supervivencia Celular , Receptores ErbB/genética , Expresión Génica , Humanos , Neuroblastoma/tratamiento farmacológico , ARN Mensajero/biosíntesis , ARN Interferente Pequeño/farmacología , Receptor ErbB-4RESUMEN
The ability of osteosarcoma cells to form lung metastases has been inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to circumvent FasL-mediated apoptosis upon entrance into the FasL(+) lung microenvironment. However, the mechanism of Fas regulation remains unclear. Here, we show that miRNA plays a role in the downregulation of Fas expression in osteosarcoma. Expression levels of several members of the miR-17-92 cluster including miR-20a and miR-19a were found to be higher in metastatic low-Fas-expressing LM7 cells than in the parental nonmetastatic high-Fas-expressing SAOS-2 cells. We also found an inverse correlation between Fas and miR-20a expression in all 8 cell lines derived from patient samples. Overexpression of miR-20a consistently resulted in the downregulation of Fas expression in SAOS-2 cells and thus in decreased sensitivity to FasL. Conversely, inhibiting miR-20a in LM7 cells increased Fas expression and their sensitivity to FasL. Mice injected with LM7 stably transfected with anti-miR-20a had fewer metastases than those with control plasmids. Taken together, our findings suggest that miR-20a, encoded by miR-17-92, downregulates Fas expression in osteosarcoma, thus contributing to the metastatic potential of osteosarcoma cells by altering the phenotype and allowing survival in the FasL(+) lung microenvironment.