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BACKGROUND: Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. METHODS: A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome. RESULTS: At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age <61 years, tumor size <10 cm, margin-negative resection, and sporadic-tumor status. At the protein level, loss of cyclin D1 (p = 0.06), pEGFR (p = 0.023), pIGF-1R (p = 0.022), and PTEN (p < 0.001) and overexpression of AXL (p = 0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA, and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS), whereas RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R. DISCUSSION: Loss of cyclin D1, overexpression of AXL, and loss of PTEN are associated with poor cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and also could explain the aggressive phenotype seen in RA-UPS compared with the sporadic lesions.
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Biomarcadores de Tumor/metabolismo , Histiocitoma Fibroso Maligno/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Sarcoma/mortalidad , Neoplasias de los Tejidos Blandos/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Terapia Combinada , Femenino , Estudios de Seguimiento , Histiocitoma Fibroso Maligno/metabolismo , Histiocitoma Fibroso Maligno/patología , Histiocitoma Fibroso Maligno/terapia , Humanos , Técnicas para Inmunoenzimas , Masculino , MicroARNs/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Sarcoma/metabolismo , Sarcoma/patología , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/terapia , Tasa de Supervivencia , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
BACKGROUND: Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/ß-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment. METHODS: The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis. RESULTS: The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin. CONCLUSION: Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.
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Fibromatosis Agresiva/tratamiento farmacológico , Receptores Notch/antagonistas & inhibidores , Transducción de Señal/fisiología , Proteínas CCN de Señalización Intercelular/fisiología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fibromatosis Agresiva/etiología , Fibromatosis Agresiva/patología , Humanos , Invasividad Neoplásica , Receptores Notch/fisiología , Proteínas Represoras/fisiología , Tetrahidronaftalenos/farmacología , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
BACKGROUND: AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined. METHODS: Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo. RESULTS: In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo. CONCLUSIONS: Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.
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Liposarcoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Diferenciación Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Liposarcoma/patología , Invasividad Neoplásica/fisiopatología , Tirosina Quinasa del Receptor AxlRESUMEN
OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive group of soft tissue sarcomas that can arise sporadically, in the context of neurofibromatosis Type 1 (NF1) or at a site of prior irradiation. Large series profiling the features and outcomes of sporadic, NF1-associated, and radiation-associated MPNSTs are limited. The goal of this study was to elucidate differences between MPNST etiologies in a large single-institution retrospective study. METHODS Patients (n = 317) were identified through the tumor registry of The University of Texas MD Anderson Cancer Center. Clinicopathological features were retrospectively collected. Features were compared among MPNST subtypes for patients who had sufficient clinical history (n = 289), and clinicopathological features were used to identify adverse predictors of recurrence and survival outcomes. RESULTS Five-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and disease-specific survival (DSS) estimates were 56.6%, 49.6%, and 53.6%, respectively, for the high-grade MPNST cohort. Five-year DSS was lower in NF1-associated and radiation-associated MPNST than in sporadic MPNST (52%, 47%, and 67%, respectively, p = 0.140). Patients with radiation-associated MPNST had worse 5-year LRFS than those with the sporadic and NF1-associated subtypes (RT-associated vs sporadic, p = 0.010; RT-associated vs NF1-associated, p = 0.232). Truncally located tumors, positive surgical margins, local recurrence, and metastasis were predictors of adverse DSS in multivariate analysis. CONCLUSIONS Radiation-associated MPNSTs are associated with poorer local recurrence-free and disease-specific survival than sporadic and NF1-associated tumors. NF1-associated MPNSTs may have worse survival outcomes owing to large tumor size, compromising truncal location, and lower rate of negative resection margins compared with sporadic tumors.
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Recurrencia Local de Neoplasia/epidemiología , Neoplasias Inducidas por Radiación/epidemiología , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/epidemiología , Neurofibrosarcoma/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Inducidas por Radiación/patología , Neurofibromatosis 1/patología , Neurofibromatosis 1/terapia , Neurofibrosarcoma/etiología , Neurofibrosarcoma/patología , Neurofibrosarcoma/terapia , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy.
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Proliferación Celular/efectos de los fármacos , Neurilemoma/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Neurilemoma/genética , Neurilemoma/patología , Poli(ADP-Ribosa) Polimerasa-1/biosíntesis , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasas/biosíntesis , Poli(ADP-Ribosa) Polimerasas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
IMPORTANCE: Vascular leiomyosarcomas are a rare subtype of leiomyosarcomas that most commonly affect the inferior vena cava and account for 5% of all leiomyosarcomas. These tumors are aggressive malignant tumors for which adjuvant modalities have not shown increased efficacy compared with surgery. OBJECTIVES: To evaluate the outcomes of patients with vascular leiomyosarcoma and the association between vascular leiomyosarcomas and immunohistochemical molecular markers, to determine their potential prognostic and therapeutic utility. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of a cohort of 77 patients who presented to the University of Texas MD Anderson Cancer Center in Houston during the period from January 1993 to April 2012. Data were analyzed during the period from November 2012 to May 2015. All of the patients received a confirmed diagnosis of vascular leiomyosarcoma. Immunohistochemical studies for biomarkers were performed on a tissue microarray that included 26 primary specimens of vascular leiomyosarcoma. MAIN OUTCOMES AND MEASURES: Demographic and clinical factors were evaluated to assess clinical course, patterns of recurrence, and survival outcomes for patients with primary vascular leiomyosarcoma. A univariate Cox proportional hazards model was used to correlate disease-specific survival and time to recurrence with potential prognostic indicators. RESULTS: Sixty-three patients with localized disease who underwent surgical resection formed the study population, and their data were used for subsequent outcomes analysis. The median age at diagnosis was 58 years (range, 22-78 years). The majority of patients were female (41 patients [65%]) and white (51 patients [81%]). The 5-year disease-specific survival rate after tumor resection was 65%. The median time to local recurrence was 43 months, the median time to distant recurrence was 25 months, and the median time to concurrent local and distant recurrences was 15 months (P = .04). Strong expressions of cytoplasmic ß-catenin (hazard ratio, 5.33 [95% CI, 0.97-29.30]; P = .06) and insulinlike growth factor 1 receptor (hazard ratio, 2.74 [95% CI, 1.14-6.56]; P = .02) were associated with inferior disease-specific survival. CONCLUSIONS AND RELEVANCE: Vascular leiomyosarcomas are aggressive malignant tumors, with high recurrence rates. Expressions of ß-catenin and insulinlike growth factor 1 receptor were associated with poor disease-specific survival. Prospective studies should evaluate the clinical and therapeutic utility of these molecular markers.
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Biomarcadores de Tumor/análisis , Leiomiosarcoma/metabolismo , Neoplasias Vasculares/metabolismo , Adulto , Anciano , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Incidencia , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/terapia , Adulto JovenRESUMEN
Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPß, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.
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Biomarcadores de Tumor/metabolismo , Desdiferenciación Celular , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Factores de Transcripción de Tipo Kruppel/biosíntesis , Liposarcoma/metabolismo , Proteínas Proto-Oncogénicas/biosíntesis , Adipocitos/metabolismo , Adipocitos/patología , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Femenino , Histonas/genética , Humanos , Factor 6 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Liposarcoma/genética , Liposarcoma/patología , Masculino , Piperazinas/farmacología , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.