RESUMEN
Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks.
Asunto(s)
Secuencias Repetidas en Tándem/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Adulto , Animales , Secuencia de Bases , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Femenino , Expresión Génica , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Mucosa Bucal/metabolismo , Polimorfismo de Nucleótido Simple , Unión Proteica , Factores de Transcripción/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/deficiencia , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)-/- mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3' transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.
Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Elementos de Nucleótido Esparcido Largo/genética , Retroelementos/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Transformación Celular Neoplásica/genética , Femenino , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Mamíferos/genética , Ratones Noqueados , Persona de Mediana Edad , Mutagénesis Insercional , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Transformación Celular Neoplásica/genética , Inactivación Metabólica/genética , Hígado/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Androstanoles/farmacología , Animales , Transformación Celular Neoplásica/metabolismo , Receptor de Androstano Constitutivo , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Hepatitis/genética , Hepatitis/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Transducción de Señal/genética , Activación Transcripcional/efectos de los fármacos , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high- and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low-grade primary PDACs and cell lines, where it maintained the acetylation of grade-specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression.
Asunto(s)
Adenocarcinoma/patología , Carcinoma Ductal Pancreático/patología , Regulación de la Expresión Génica , Línea Celular Tumoral , Epigénesis Genética , Perfilación de la Expresión Génica , Marcadores Genéticos , Humanos , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo, as well as coculture with macrophages in vitro. Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in pre-established tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumor-associated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-dependent transcription. CONCLUSION: ST18 expression in epithelial cells is induced by tumor-associated macrophages, contributing to the reciprocal feed-forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18-dependent epithelium-macrophage interactions in a therapeutic setting. (Hepatology 2017;65:1708-1719).
Asunto(s)
Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas Experimentales/etiología , Factores de Transcripción/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Ratones Endogámicos C57BLRESUMEN
We have previously shown in triple-negative breast cancer (TNBC) models that a triple therapy (TT) including intermittent cyclophosphamide (C), vinorelbine (V), and anti-PD-1 activates antigen-presenting cells (APC) and generates stem like-T cells able to control local and metastatic tumor progression. In the present manuscript, we report the generation of a highly aggressive, anti-PD-1 resistant model of a high-grade, Myc-driven B-cell non-Hodgkin's lymphoma (NHL) that can be controlled in vivo by TT but not by other chemotherapeutic agents, including cytarabine (AraC), platinum (P), and doxorubicin (D). The immunological memory elicited in tumor-bearing mice by TT (but not by other treatments) can effectively control NHL re-challenge even at very high inoculum doses. TT re-shaped the landscape of circulating innate NK cells and adaptive immune cells, including B and T cells, and significantly reduced exhausted CD4+ and CD8+ TIM3+PD-1+ T cells in the spleens of treated mice.
RESUMEN
Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients does not respond to immune and/or targeted therapies owing to primary and acquired resistance, high-grade immune-related adverse events, and a lack of alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay on the basis of a drop-out genetic screen in metastatic melanoma patient-derived xenografts. We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of AURKA and MAPK/extracellular signal-regulated kinase kinase employing the combination of alisertib and trametinib is highly effective in a cohort of metastatic melanoma patient-derived xenografts, both ex vivo and in vivo. Alisertib and trametinib combination therapy outperforms standard-of-care therapy in both BRAF-mutant patient-derived xenografts and targeted therapy-resistant models. Furthermore, alisertib and trametinib treatment modulates several critical cancer pathways, including an early metabolic reprogramming that leads to the transcriptional upregulation of the fatty acid oxidation pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed, the triple combination of alisertib and trametinib with the fatty acid oxidation inhibitor etomoxir proved to be further beneficial, inducing tumor regression and remarkably prolonging the overall survival of the mice.
Asunto(s)
Aurora Quinasa A , Melanoma , Humanos , Ratones , Animales , Aurora Quinasa A/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Pirimidinonas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Ácidos Grasos , Proteínas Proto-Oncogénicas B-raf/genética , MutaciónRESUMEN
MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS-010759. In a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro-oxidant at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.
Asunto(s)
Linfoma de Células B , Linfoma , Humanos , Línea Celular Tumoral , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Linfoma de Células B/tratamiento farmacológico , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory compound venetoclax synergized with IACS-010759 against double-hit lymphoma (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.
Asunto(s)
Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Oncogenes , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , RespiraciónRESUMEN
Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4, and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6-but not Mga-accelerates Myc-induced lymphomagenesis in Eµ-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.
Asunto(s)
Carcinogénesis , Complejo Represivo Polycomb 1 , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Carcinogénesis/genética , Ratones , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismoRESUMEN
Deubiquitinating enzymes are key regulators of the ubiquitin-proteasome system and cell cycle, and their dysfunction leads to tumorigenesis. Our in vivo drop-out screens in patient-derived xenograft models identify USP7 as a regulator of melanoma. We show that USP7 downregulation induces cellular senescence, arresting melanoma growth in vivo and proliferation in vitro in BRAF- and NRAS-mutant melanoma. We provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a global transcriptomic and proteomics analysis. We show that RRM2 is a USP7 target and is regulated by USP7 during S phase of the cell cycle. Ectopic expression of RRM2 in USP7-depleted cells rescues the senescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.
Asunto(s)
Inhibidores de Histona Desacetilasas , Melanoma , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas , Histona Demetilasas/genética , Humanos , Melanoma/patología , Complejo de la Endopetidasa Proteasomal , Proteínas Proto-Oncogénicas B-raf/genética , Tiofenos , Peptidasa Específica de Ubiquitina 7/metabolismo , UbiquitinasRESUMEN
Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (bis-capronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Organoplatinos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Aductos de ADN/metabolismo , Reparación de la Incompatibilidad de ADN , Diseño de Fármacos , Resistencia a Antineoplásicos , Estabilidad de Medicamentos , Femenino , Humanos , Ratones , Ratones Desnudos , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacocinética , Oxaliplatino , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND OBJECTIVES: Cholangiocarcinoma can be classified as intrahepatic (ICC) or perihilar (PCC). The objectives of this study is to evaluate the surgical outcomes of patients with PCC and ICC, identify the main prognostic factors related to survival and compare the outcome and the prognostic factors of PCC and ICC. METHODS: Ninety-five out of 152 patients observed between January 1990 and December 2007 at Surgical Division of University of Verona Medical School underwent the resection of ICC (33 patients) or PCC (62 patients). RESULTS: Overall median survival was 24 months with a 3- and 5-year survival rate of 45% and 23%, respectively. Prognostic factors for survival were macroscopic types of the tumor, the resection of extrahepatic bile duct, radical resection, lymph node metastases, and macro-vascular invasion. Survival was related with the macroscopic type of the tumors with a 5-year survival rate of 26% and 13% for ICC and PCC, respectively. Univariate analysis identified that negative clinico-pathological factors where significant more frequently found in PCC compared to ICC. CONCLUSION: We identified that ICC have longer survival rate compared to PCC. PCC showed a higher frequency of negative clinico-pathological factors such as non-radical (R+) resection, perineural infiltration and macro-vascular invasion.
Asunto(s)
Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos/cirugía , Colangiocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/diagnóstico , Colangiocarcinoma/diagnóstico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de RiesgoRESUMEN
Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secreted proteins and prevent ER stress. We found that pancreatic ductal adenocarcinomas (PDACs) overexpress the myelin regulatory factor (MYRF), an ER membrane-associated transcription factor (TF) released by self-cleavage. MYRF was expressed in the well-differentiated secretory cancer cells, but not in the poorly differentiated quasi-mesenchymal cells that coexist in the same tumor. MYRF expression was controlled by the epithelial identity TF HNF1B, and it acted to fine-tune the expression of genes encoding highly glycosylated, cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed signs of ER stress, impaired proliferation, and an inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypocellular tumors. These data indicate a role of MYRF in the control of ER homeostasis in highly secretory PDAC cells.
Asunto(s)
Retículo Endoplásmico/metabolismo , Homeostasis , Proteínas de la Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Factores de Transcripción/metabolismo , Diferenciación Celular/genética , Línea Celular Tumoral , Proliferación Celular , Cromatina/metabolismo , ADN de Neoplasias/metabolismo , Retículo Endoplásmico/ultraestructura , Estrés del Retículo Endoplásmico/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/genética , Clasificación del Tumor , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/ultraestructura , Unión Proteica , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor. The resectability rate is low because at the time of diagnosis this disease is frequently beyond the limits of surgical therapy. Curative resection (R0) is the most effective treatment and the only therapy associated with prolonged disease-free survival. Based on the gross appearance of the tumor the Liver Cancer Study Group of Japan (LCSGJ) defined three types: mass-forming type (MF), periductal infiltrating type (PI), intraductal growth (IG) type. The prognostic significance of gross type has been demonstrated in Eastern countries, but this issue has not been clarified in Western countries. The aim of this study was to identify the prognostic factors for survival in a group of patients submitted to surgical resection for ICC. METHODS: Between 1990 and 2007 a total of 81 consecutive patients with ICC were submitted to surgery. Patients with peritoneal carcinomatosis, extensive vascular involvement, or multiple intrahepatic metastases were excluded from surgical resection. Tumors were classified according to TMN stage (6th edition, 2002) and LCSGJ gross type classification. Tumor gross appearance on the cut surface was categorized into the following types according to the classification proposed by the Liver Cancer Study Group of Japan: MF, PI, or IG type. RESULTS: During the study period 52 patients were submitted to surgical resection with curative intent, whereas in 29 patients surgery was limited to explorative laparotomy. Curative resection (R0) was achieved in 43 patients (83%); and a major hepatic resection was performed in 63% (33/52) of the patients. Extrahepatic bile duct resection was carried out in 36% (19/52) of cases. According to the LCSGJ classification, the MF type was present in 34 patients (65%), the MF + PI type in 13 (25%), the PI type in 3 (6%), and the IG type in 2 (4%). Overall median survival time was 40 months, with a 1-, 3-, and 5-year actuarial survival rates of 83%, 50%, 20%, respectively. Survival was significantly related to the macroscopic gross type, with a median survival of 50 months for patients with the MF type, 19 months for the MF + PI type, 15 months for the PI type, and 17 months for the IG type. At univariate analysis, the macroscopic gross appearance of the tumor, the presence of lymph node metastasis, involvement of extrahepatic bile ducts, the presence of macroscopic vascular invasion, and positive resection margins were significant related to survival. At multivariate analysis, macroscopic vascular invasion and lymph nodes metastases were significant related to survival with hazard ratios of 4.11 and 2.79, respectively. Further statistical analyses were carried out to identify the relation between macroscopic gross type and prognosis. We identified that the MF + PI type tumors were significantly associated with negative prognostic factors, such as the involvement of extrahepatic bile ducts, the presence of lymph nodes metastases, the presence of macroscopic vascular invasion, the presence of perineural invasion, and higher T stage. CONCLUSIONS: Curative resection of ICC is the only therapy that can achieve long-term survival. The best results were observed in patients who underwent R0 resection for MF tumors without lymph node metastases or vascular invasion. Important predictive factors related to poor survival are MF + PI macroscopic tumor type, lymph node metastases, and vascular invasion. In these patients, other therapeutic approaches (i.e., adjuvant or neoadjuvant therapy) should be evaluated to improve results.
Asunto(s)
Neoplasias de los Conductos Biliares/mortalidad , Conductos Biliares Intrahepáticos , Colangiocarcinoma/mortalidad , Hepatectomía/métodos , Neoplasias Hepáticas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Colangiocarcinoma/patología , Colangiocarcinoma/cirugía , Femenino , Hepatectomía/mortalidad , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Percutaneous radiofrequency ablation (RFA) demonstrated good results for the treatment of hepatocellular carcinoma (HCC) in cirrhotic patients; it is still not clear whether the overall survival and disease-free survival after RFA are comparable with surgical resection. The aims of this study are to compare the overall survival and disease-free survival in two groups of cirrhotic patients with HCC submitted to surgery or RFA. METHODS: Two hundred cirrhotic patients with HCCs smaller than 6 cm were included in this retrospective study: 109 underwent RFA and 91 underwent surgical resection at a single Division of Surgery of University of Verona. RESULTS: Median follow-up time was 27 months. Overall survival was significantly longer in the resection group in comparison with the RFA group with a median survival of 57 and 28 months, respectively (P=0.01). In Child-Pugh class B patients and in patients with multiple HCC, survival was not significantly different between the two groups. In patients with HCC smaller than 3 cm, the overall survival and disease-free survival for RFA and resection were not significantly different in univariate and multivariate analysis. Whereas in patients with HCC greater than 3 cm, surgery showed improvement in outcome in both univariate and multivariate analysis. CONCLUSIONS: Surgical resection significantly improves the overall survival and disease-free survival in comparison with RFA. In a selected group of patients (Child-Pugh class B, multiple HCC, or in HCCAsunto(s)
Carcinoma Hepatocelular/cirugía
, Ablación por Catéter/métodos
, Hepatectomía/métodos
, Cirrosis Hepática/complicaciones
, Neoplasias Hepáticas/cirugía
, Anciano
, Carcinoma Hepatocelular/complicaciones
, Carcinoma Hepatocelular/mortalidad
, Femenino
, Estudios de Seguimiento
, Humanos
, Italia/epidemiología
, Cirrosis Hepática/diagnóstico
, Neoplasias Hepáticas/complicaciones
, Neoplasias Hepáticas/mortalidad
, Imagen por Resonancia Magnética
, Masculino
, Estudios Retrospectivos
, Tasa de Supervivencia/tendencias
, Factores de Tiempo
, Tomografía Computarizada por Rayos X
, Resultado del Tratamiento
RESUMEN
High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. BCL2 activation in mouse Eµ-myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Sulfonamidas/uso terapéutico , Tigeciclina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Femenino , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidoresRESUMEN
BACKGROUND: Surgical simulation based on augmented reality (AR), mixing the benefits of physical and virtual simulation, represents a step forward in surgical training. However, available systems are unable to update the virtual anatomy following deformations impressed on actual anatomy. METHODS: A proof-of-concept solution is described providing AR visualization of hidden deformable tubular structures using nitinol tubes sensorized with electromagnetic sensors. This system was tested in vitro on a setup comprised of sensorized cystic, left and right hepatic, and proper hepatic arteries. In the trial session, the surgeon deformed the tubular structures with surgical forceps in 10 positions. RESULTS: The mean, standard deviation, and maximum misalignment between virtual and real arteries were 0.35, 0.22, and 0.99 mm, respectively. CONCLUSION: The alignment accuracy obtained demonstrates the feasibility of the approach, which can be adopted in advanced AR simulations, in particular as an aid to the identification and isolation of tubular structures. Copyright © 2015 John Wiley & Sons, Ltd.
Asunto(s)
Laparoscopía/métodos , Entrenamiento Simulado , Cirugía Asistida por Computador/métodos , Calibración , Colecistectomía/métodos , Radiación Electromagnética , Cirugía General/educación , Cirugía General/métodos , Humanos , Laparoscopía/instrumentación , Reproducibilidad de los Resultados , Programas Informáticos , Interfaz Usuario-ComputadorRESUMEN
The Smyd2 protein (Set- and Mynd domain containing protein 2) is a methyl-transferase that can modify both histones and cytoplasmic proteins. Smyd2 is over-expressed in several cancer types and was shown to be limiting for tumor development in the pancreas. However, genetic evidence for a role of Smyd2 in other cancers or in mouse development was missing to date. Using germ line-deleted mouse strains, we now show that Smyd2 and the related protein Smyd3 are dispensable for normal development. Ablation of Smyd2 did not affect hematopoiesis, but retarded the development of leukemia promoted by MLL-AF9, a fusion oncogene associated with acute myeloid leukemia (AML) in humans. Smyd2-deleted leukemic cells showed a competitive disadvantage relative to wild-type cells, either in vitro or in vivo. The Smyd2 gene was directly activated by the oncogenic transcription factor Myc in either MLL9-AF9-induced leukemias, Myc-induced lymphomas, or fibroblasts. However, unlike leukemias, the development of lymphomas was not dependent upon Smyd2. Our data indicate that Smyd2 has a critical role downstream of Myc in AML.
Asunto(s)
Transformación Celular Neoplásica/genética , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Regulación Leucémica de la Expresión Génica , Hematopoyesis/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activated mRNAs in mouse B-cell lymphomas, unraveling a critical role for the mitochondrial ribosomal protein (MRP) Ptcd3 in tumor maintenance. Other MRP-coding genes were also up regulated in Myc-induced lymphoma, pointing to a coordinate activation of the mitochondrial translation machinery. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro, and significantly extended lifespan in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.