RESUMO
Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.
Assuntos
Dissulfiram , Neoplasias , Animais , Humanos , Linhagem Celular Tumoral , Dissulfiram/metabolismo , Neoplasias/metabolismo , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/metabolismoRESUMO
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.
Assuntos
Proteína BRCA1/genética , DNA Ligase Dependente de ATP/genética , DNA de Cadeia Simples , Proteína Homóloga a MRE11/genética , Neoplasias Ovarianas/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Animais , Biópsia , Sistemas CRISPR-Cas , Linhagem Celular , Núcleo Celular/metabolismo , Proliferação de Células , Aberrações Cromossômicas , Dano ao DNA , DNA Ligase Dependente de ATP/metabolismo , Feminino , Humanos , Lentivirus/genética , Neoplasias Mamárias Animais , Camundongos , Mutação , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Interferente Pequeno/metabolismo , TransgenesRESUMO
Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. DNA fiber assays and electron microscopy visualization of replication intermediates show that Tpr deficient cells exhibit slow and asymmetric replication forks under replication stress. Tpr deficiency evokes enhanced levels of DNA-RNA hybrids. Additionally, complementary proteomic strategies identify a network of Tpr-interacting proteins mediating RNA processing, such as MATR3 and SUGP2, and functional experiments confirm that their depletion trigger cellular phenotypes shared with Tpr deficiency. Mechanistic studies reveal the interplay of Tpr with GANP, a component of the TREX-2 complex. The Tpr-GANP interaction is supported by their shared protein level alterations in a cohort of ovarian carcinomas. Our results reveal links between nucleoporins, DNA transcription and replication, and the existence of a network physically connecting replication forks with transcription, splicing, and mRNA export machinery.
Assuntos
Replicação do DNA , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Acetiltransferases/genética , Acetiltransferases/metabolismo , Sobrevivência Celular , Dano ao DNA , Instabilidade Genômica , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética , Transporte de RNARESUMO
Germ cell tumors represent 20-25% of ovarian tumors, and 95% of them are benign. The most frequent type is the mature benign teratoma (dermoid cysts). The proportion of cases in which malignancy occurs is 0.17-2%. Seventy-five percent to 90% of malignancies are squamous cell carcinomas (SCC). We present a case of squamous cell carcinoma originating from a mature cystic teratoma that was diagnosed after intraoperative pathology study in a 64-year-old woman who consulted for an adnexal tumor causing abdominal pain. Laparoscopic surgery was scheduled, describing an enlarged right ovary (13 cm) which was included in the ipsilateral broad ligament and adhered to the posterior aspect of the uterus in its distal third as well as the rectum. It was converted to laparotomy and we performed a hysterectomy + double anexectomy + omentectomy + resection of sigma with end-to-end anastomosis after intraoperative pathological study reported for malignancy compatible with squamous cell carcinoma. It was labeled as FIGO III stage. Chemotherapy was decided as adjuvant therapy with carboplatin + paclitaxel (Carbo-Taxol) scheme. We review the existing literature to provide evidence on a rare pathology with important repercussions for our patients.
RESUMO
Los tumores uterinos que recuerdan a las células de los cordones sexuales son una entidad clínica rara, clasifica-dos en tipo I (tumores del estroma endometrial con elementos de las células que recuerdan a las células de los cordones sexuales del ovario) y tipo II (tumores uterinos que recuerdan a las células de los cordones sexuales del ovario). Lo más frecuente es el hallazgo casual en una pieza quirúrgica y en el contexto de una metrorragia perimenopáusica. Aunque los tumores uterinos que recuerdan a las células de los cordones sexuales son tumores de baja malignidad y de escasa recurrencia, no hay consenso sobre la radicalidad del tratamiento. Se presenta un caso clínico de un hallazgo anatomopatológico tras una histerectomía compatible con tumores uterinos que recuerdan a las células de los cordones sexuales en el contexto de un útero miomatoso en una paciente de 46 años con historia de hipermenorreas y dolor pélvico
Uterine tumors resembling the sex cord cells are a rare clinical entity, classified as type I (Endometrial stromal tumor with sex-cord-like elements [ESTSCLE]) and type II (Uterine tumors resembling ovarian sex cord tumors [UTROSCT]). Most often it found incidentally in a surgical specimen and in the context of a perimenopausal ute-rine bleeding. Although uterine tumors resembling the sex cord cells are generally low-grade tumors and low recurrence, there is no clinical consensus on how much should be radical treatment. A case of a pathological finding occurs after abdominal hysterectomy compatible with uterine tumors resembling the sex cord cells in the context of a fibroid uterus in a 46-year woman with a history of hipermenorreas and pelvic pain
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Ovarianas/patologia , Leiomioma/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , Neoplasias Ovarianas/cirurgia , Metrorragia/etiologia , Redução de Peso , Dor Abdominal/etiologia , Leiomioma/cirurgiaRESUMO
Objective: The objective of our study was to identify prognostic factors, management strategies, and outcomes for locally advanced cervical cancer in our hospital. Material and methods: We performed a retrospective study of 156 patients with locally advanced cervical cancer (FIGO IB2-IVA). All patients underwent staging of the para-aortic lymph nodes by computed tomography. A total of 93 patients with para-aortic lymph nodes with no signs of malignancy in the imaging tests underwent pretherapy surgical staging up to the level of the left renal vein. All patients were treated with chemoradiation. Results: The study included a total of 156 patients. The average age was 54.04 years (range 28-97 years). Squamous cell carcinoma was the most frequent histological type (82.1%). Most patients had FIGO stage IIB disease (43.6%). Histopathology revealed metastatic disease in the para-aortic lymph nodes in 19.3% of patients. The status of the para-aortic lymph nodes was the only factor that was independently associated with an increased risk of mortality (OR 33 [95% CI, 8-135.89], p<0.0001). Conclusions: Patients with an advanced tumor stage at the time of diagnosis and those with pathological para-aortic lymph nodes are at greater risk of developing distant metastases and of more frequent disease-related mortality. In this group of high-risk patients, a more marked therapeutic effort must be made in order to improve survival
Objetivo: El objetivo del estudio fue identificar los factores pronósticos, las estrategias de manejo y los resultados de los cánceres cervicales localmente avanzados tratados en nuestro hospital. Material y métodos: Estudio retrospectivo de 156 pacientes con cánceres cervicales localmente avanzados (FIGO IB2-IVA). A todas las pacientes se les realizó estadiaje de los ganglios linfáticos paraaórticos mediante Tomografía Axial Computarizada. 93 pacientes con ganglios linfáticos paraaórticos sin signos de malignidad en las pruebas de imagen fueron sometidas a estadiaje quirúrgico preterapéutico hasta el nivel de la vena renal izquierda. Todas las pacientes fueron tratadas con quimio-radioterapia. Resultados: El estudio incluyo un total de 156 pacientes. La edad media fue de 54,04 años (rango 28-97 años). El carcinoma de células escamosas fue el tipo histológico más frecuente (82,1%). La mayoría de las paciente tenían un estadio FIGO IIB (43,6%). El estudio anatomopatológico reveló enfermedad metastásica en ganglios paraórticos en un 19,3% de la pacientes. El estado de los ganglios para-aórticos fue el único factor que se asoció de manera independiente con el incremento del riesgo de mortalidad [OR 33 (IC 95% 8-135,89; p<0,0001]. Conclusiones: Las pacientes con un estadio tumoral avanzado en el momento del diagnóstico y aquellas con ganglios paraórticos patológicos tienen mayor riesgo de desarrollar metástasis a distancia y mayores tasas de mortalidad causadas por la enfermedad. En este grupo de pacientes de alto riesgo se debe realizar un esfuerzo terapéutico superior con el fin de mejorar la supervivencia de esta enfermedad
Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo do Útero/terapia , Quimiorradioterapia/métodos , Metástase Linfática/patologia , Neoplasias do Colo do Útero/epidemiologia , Excisão de Linfonodo/estatística & dados numéricos , Sobreviventes de Câncer/estatística & dados numéricosRESUMO
La enfermedad de Paget pigmentada de la mama es una variante clinicopatológica infrecuente de la enfermedad de Paget, la cual debe incluirse en el diagnóstico diferencial de las lesiones pigmentadas del pezón. Se presenta el caso de una mujer de 49 años que consulta al presentar una mácula pigmentada en el pezón derecho de 9 meses de evolución; y cuyo estudio histológico e inmunohistoquímico permitió diagnosticar una Enfermedad de Paget que se acompaña de una hiperplasia melanocitaria atípica, diferenciándola de un melanoma maligno
Pigmented mammary Paget disease is an uncommon clinicopathological variant of Paget's disease, which should be included in the differential diagnosis of pigmented lesions on the nipple. We present the case of a 49-year-old woman with a 9-month-old pigmented lesión on her right nipple. The histological and immunohistochemical study allowed the diagnosis of a Paget's disease with intense atypical melanocytic hyperplasia, differentiating it from a malignant melanoma
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Doença de Paget Mamária/patologia , Neoplasias da Mama/patologia , Mamilos/patologia , Melanoma/patologia , Mastectomia Segmentar/métodos , Diagnóstico Diferencial , Mamilos/cirurgiaRESUMO
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.
Assuntos
Glicosídeo Hidrolases/genética , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mutações Sintéticas Letais , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Recombinação Homóloga/efeitos dos fármacos , Recombinação Homóloga/genética , Humanos , Camundongos da Linhagem 129 , Camundongos Knockout , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli ADP Ribosilação/efeitos dos fármacosRESUMO
The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.
Assuntos
Deficiência de GATA2/complicações , Influenza Humana/diagnóstico , Influenza Humana/etiologia , Biomarcadores , Citocinas/sangue , Análise Mutacional de DNA , Evolução Fatal , Feminino , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Fator de Transcrição GATA2/genética , Humanos , Imunofenotipagem , Vírus da Influenza A , Influenza Humana/virologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , LinhagemRESUMO
Topoisomerase IIß-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOPBP1's role in HR, with potential clinical implications for cancer treatment.
Assuntos
Proteínas de Transporte/metabolismo , Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Recombinação Homóloga , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Rad51 Recombinase/metabolismo , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Células HeLa , Humanos , Proteínas Nucleares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Rad51 Recombinase/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , TransfecçãoRESUMO
Genetic defects in the IL-12-IL-23/IFN-gamma circuit confer Mendelian susceptibility to mycobacteria and salmonella. The IL-12/IFN-gamma axis is essential for anti-tumoral immunity in mice. Cancer susceptibility has not been recognised in these patients so far. We report three relatives with IL-12R beta 1 deficiency. At the age of 25 years old, one patient presented with oesophageal squamous cell carcinoma (OSCC). The patient had no previous risk factors for OSCC. He died at the age of 29 years. OSCC is exceedingly rare in individuals under 30 years and frequently relates to alcohol intake and smoking. Disorders of the IL-12-IL-23/IFN-gamma axis may predispose to cancer.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Receptores de Interleucina-12/deficiência , Adolescente , Adulto , Carcinoma de Células Escamosas/patologia , Criança , Neoplasias Esofágicas/patologia , Evolução Fatal , Feminino , Humanos , Masculino , Receptores de Interleucina-12/metabolismo , Adulto JovemRESUMO
Introducción: El nefroma mesoblástico congénito (NMC) (hamartoma leiomiomatoso o mesenquimal) es una neoplasia renal congénita. Se diagnostica en los seis primeros meses de vida. Su comportamiento clínico es benigno y el tratamiento es quirúrgico. Paciente y métodos: Describimos el caso de un paciente de una semana de edad que presenta una masa renal. En la ecografía es sólida y sustituye al riñón. El TAC muestra una lesión con márgenes mal delimitados y la estructura heterogénea. Macroscópicamente en la pieza quirúrgica se identificaba una masa intrarrenal bien delimitada, sólida, homogénea, blanquecina y con aspecto fasciculado. Microscópicamente se observa una neoformación compuesta por una población monótona de células fusiformes dispuestas en haces entrelazados. La lesión carece de cápsula y en la interfase con el parénquima renal normal hay células tumorales que rodean a los túbulos y a los glomérulos. Conclusiones: La edad en el momento del diagnóstico y la correcta extirpación del riñón son los dos factores pronósticos más relevantes
Introduction: Congenital mesoblastic nephroma (CMN) (leiomomatous or mesenchymal hamartoma) is a benign congenital renal neoplasm. This tumor is usually diagnosed along the first six months of life and surgery is current treatment. Patient and methods: A one week of life patient with a renal mass is reported. Ultrasonographically, the mass appearance was solid and replaces the kidney. Computerized tomography (CT) showed a lesion with irregular margins and heterogeneous structure. Grossly, a well delimited intrarenal mass, white, solid, homogeneus and fasciculated was identified. Microscopically, the tumor was composed by a monotonous population of fusiform cells showing an interlacing fasciculated pattern. The mass lacks capsule and the interphase with normal renal parenchyma showed spindle cells surrounding renal tubuli and glomerula. Conclusions: Best prognostic factors are the adequate extirpation and age at the diagnosis
