RESUMO
BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disease that affects multiple organs and affects the quality of life. Mutations in TSC1 and TSC2 genes are causing dysregulations in the mammalian target of the rapamycin (mTOR) pathway, inducing mostly benign but also malignant tumors, including renal cell carcinoma (RCC). The diagnosis of TSC, based on established clinical and genetic criteria, is essential for the optimal surveillance and management of patients. CASE PRESENTATION: With the current report, we present the case of two sisters who were consequently diagnosed with early-stage chromophobe-like RCC, possibly familial given their young age. The younger sister also had a previous diagnosis of differentiated thyroid carcinoma, for which she had been treated properly. Genetic testing of both revealed the same heterozygous TSC2 variant that is currently regarded as a variant of unknown significance, while both patients did not fulfill the clinical criteria for the diagnosis of TSC. Owing to these data, we opted to manage and surveil both sisters as TSC patients, while we also considered the specific TSC2 variant to be pathogenic - but of low penetrance - based on clinical judgment and functional analyses. Furthermore, we discussed the implementation of mTOR inhibitors for the treatment of TSC complications. CONCLUSION: As novel pathogenic variants of TSC genes are constantly being explored, the identification of TSC variants of unknown significance in combination with absent clinical diagnostic criteria cannot exclude a TSC diagnosis. We support the implementation of clinical judgment in assisting the diagnosis of TSC, as well as the enrollment of patients in clinical trials due to the rarity of the disease.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Esclerose Tuberosa , Feminino , Humanos , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Qualidade de Vida , MutaçãoRESUMO
Uterine angiolipoleiomyomas are rare, benign mixed mesenchymal lesions. A manifestation in the gynecological region is quite uncommon, with few cases described in the literature so far. We present an interesting case of a 59-year-old woman diagnosed with uterine angiolipoleiomyoma, and the results of the conducted systematic review of the literature. The patient presented with a pelvic mass masquerading as a leiomyoma on the ultrasound and postmenopausal vaginal bleeding. At laparotomy, a large uterus was noticed and the histopathology set the diagnosis of angiolipoleiomyoma. Immunohistochemistry revealed negativity for Melan-A and HMB-45 melanoma-specific antibodies and positivity for Van Gieson and orcein histochemical stains.
Assuntos
Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Imuno-Histoquímica , Leiomioma/diagnóstico por imagem , Leiomioma/cirurgia , Pessoa de Meia-Idade , Ultrassonografia , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/cirurgia , Útero/patologiaRESUMO
Monoclonal antibodies against programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1) are the main representatives in the field of immunotherapy and their indications are constantly increasing in medical oncology and hematology during the last decade. They are associated with long-lasting responses and an acceptable toxicity profile, although they may infrequently cause life-threatening complications requiring prolonged hospitalization or urgent interventions. With the current report, we present the case of a 75-year-old woman diagnosed with stage IV lung adenocarcinoma, who developed acute abdominal pain without preceding symptomatology while on pembrolizumab-pemetrexed maintenance treatment. A contained rupture of the appendix was found, for which she was managed conservatively. Subsequent endoscopic as well as histopathological findings from biopsies obtained via colonoscopy associated the clinical and imaging findings with grade 4 immune-mediated colitis. Interestingly, high-grade colitis is more frequent with anti-CTLA-4 agents in comparison to anti-PD-1 agents; moreover, most cases of anti-PD-1-mediated colitis present with preceding symptomatology (like diarrhea or vomiting), while cases or colonic perforation are extremely rare if ever described.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Apendicite/induzido quimicamente , Pemetrexede/uso terapêutico , Ruptura Espontânea/induzido quimicamente , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Thymic epithelial tumors represent 0.2-1.5% among all malignant neoplasms. They are slow-growing tumors with an overall recurrence rate around 10% and 90% of them are located in the anterior mediastinum. In this review we focused on the classification, histopathology, molecular pathology and prognosis of thymic epithelial tumors, mainly thymoma and thymic carcinoma.
Assuntos
Neoplasias Epiteliais e Glandulares/classificação , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias do Timo/classificação , Neoplasias do Timo/patologia , Carcinoma/classificação , Carcinoma/patologia , Humanos , Prognóstico , Timoma/classificação , Timoma/patologiaAssuntos
Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , MutaçãoRESUMO
Histone H2AX undergoes phosphorylation as an answer to DNA double-strand breaks, which in turn are part of the oncogenic procedure. The detection of gamma-H2AX can potentially serve as a biomarker for transformation of normal tissue to premalignant and consequently to malignant tissues. The aim of this study was to evaluate the clinical significance of gamma-H2AX expression in breast cancer. Gamma-H2AX expression in tissues from 110 breast cancer patients was analyzed by immunohistochemistry and correlated with clinicopathological variables. Greater tumor size, higher grade, and the number of affected lymph nodes are significantly associated with greater values of gamma-H2AX. In addition, gamma-H2AX differs significantly among patients' International Federation of Gynecology and Obstetrics stage. Higher values of estrogen receptor and progesterone receptor are significantly associated with lower gamma-H2AX values. In conclusion, a positive association between gamma-H2AX expression and infaust histopathological parameters was observed.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama/metabolismo , Histonas/biossíntese , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fosforilação , Receptores de Estrogênio , Receptores de ProgesteronaRESUMO
Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane-induced and the genetically engineered K-rasG12D -driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras- G12D -driven lung cancer pathogenesis.Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634-44. ©2018 AACR.
Assuntos
Carcinogênese/patologia , Neoplasias Pulmonares/patologia , Lisofosfolipídeos/metabolismo , Fosfatidato Fosfatase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Idoso , Animais , Conjuntos de Dados como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Diester Fosfórico Hidrolases/genética , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais , Uretana/toxicidadeRESUMO
BACKGROUND-AIM: To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes. METHODS: Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis. RESULTS: Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively. CONCLUSIONS: It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Ciclina D1/análise , Ciclina E/análise , Inibidor de Quinase Dependente de Ciclina p21/análise , Inibidor de Quinase Dependente de Ciclina p27/análise , Proteínas Oncogênicas/análise , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Antineoplásicos/uso terapêutico , Mama/efeitos dos fármacos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Adulto JovemRESUMO
PURPOSE: To identify the role of systemic chemotherapy in the management of appendiceal malignancies. METHODS: Over a 10-year period (2005 -2014), 52 patients with appendiceal neoplasms were treated at our Peritoneal Surface Malignancy Unit [14 (26.9%) disseminated peritoneal adenomucinosis (DPAM), 30 (57.7%) peritoneal mucinous carcinomatosis of appendiceal origin (PMCA) and 8 (15.4%) PMCA-I]. All patients (100%) underwent cytoreductive surgery (CRS) & hyperthermic intraperitoneal chemotherapy (HIPEC), while 20 (38.5%) of them also received perioperative systemic chemotherapy. RESULTS: Mean peritoneal cancer index (PCI) was 23.6. Completeness of cytoreduction score (CC-S) was: CC-0 in 26 patients (50%), CC-1 in 20 patients (38.5%) and CC-2 in 6 patients (11.5%). High grade malignancy was reported in 27 patients (51.9%) and low grade malignancy in 25 patients (48.1%). More than half of the patients developed recurrence (n=36, 69.2%), while death was reported in 40.4% (n=21). Median overall survival (OS) in all histologic groups was 24 months for patients who received perioperative systemic chemotherapy and 14 months for patients who did not (p=0.048). Median disease free survival (DFS) in all histologic groups was 19 months for patients who received perioperative systemic chemotherapy and 10 months for patients who did not (p=0.034). CONCLUSION: We suggest that perioperative systemic chemotherapy serves as a helpful therapeutic tool in the management of peritoneal mucinous appendiceal carcinomas treated with cytoreductive surgery & HIPEC.
Assuntos
Adenocarcinoma Mucinoso/terapia , Neoplasias do Apêndice/terapia , Procedimentos Cirúrgicos de Citorredução/métodos , Hipertermia Induzida/métodos , Neoplasias Peritoneais/terapia , Adenocarcinoma Mucinoso/mortalidade , Adulto , Idoso , Neoplasias do Apêndice/mortalidade , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/mortalidadeRESUMO
AIM: To determine if cholecystectomy and liver's round ligament removal is a necessary step during cytoreductive surgery (CRS) and HIPEC METHODS: This was a retrospective observational study based on records from 180 patients treated in our center from 2005 to 2014. All patients have been offered CRS and HIPEC for peritoneal pseudomixoma (20 patients), peritoneal mesothelioma (7 patients), peritoneal carcinomatosis from ovarian cancer (66 patients), colorectal cancer (42 patients), gastric cancer (10 patients), mucinous adenocarcinoma of the appendix (28), and other abdominal malignancies (7 patients). We performed a cholecystectomy and we removed the round ligament of the liver in all patients, even if there wasn't a macroscopic tumor infiltration of the above anatomical structures. We reviewed the histological reports of all 180 patients. RESULTS: Patients with peritoneal carcinomatosis from mucinous adenocarcinoma of the appendix were treated more aggressively, due to the macroscopic appearance of the disease. Histologic report show no evidence of metastases at the round ligament of the liver in 21, 4% of the patients that were treated with CRS although it was estimated to be involved based on the macroscopic examination at the time of surgery. Tumor involvement of the gallbladder was overestimated, macroscopically, at the same patients in 25% of the cases. In patients with peritoneal carcinomatosis from ovarian cancer, macroscopic appearance of the gallbladder may be delusive. In 25% of the above patients there was a microscopic tumor involvement of the gallbladder, although there was not macroscopic evidence of the disease. CONCLUSION: More extended cytoreductive surgery is needed in case of peritoneal carcinimatosis from ovarian cancer. In case of PC from mucinous adenocarcinoma of the appendix, it's difficult to calculate the extent of the disease and avoid unnecessary surgical excisions. More data is needed to confirm the above. KEY WORDS: Cytoreductive surgery, Gallbladder, HIPEC, Peritoneal carcinomatosis, Round ligament of the liver.
Assuntos
Colecistectomia , Procedimentos Cirúrgicos de Citorredução , Fígado/cirurgia , Neoplasias Peritoneais/cirurgia , Ligamentos Redondos/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Hipertermia Induzida , Estudos RetrospectivosRESUMO
The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.
Assuntos
Receptores Notch/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/metabolismo , Feminino , Dosagem de Genes , Genes Supressores de Tumor , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Mutação , Receptor Notch1/deficiência , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptores Notch/deficiência , Receptores Notch/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Several studies have recently indicated the prognostic or predictive role of several biomarkers in colorectal cancer. We sought to investigate the prognostic value of prostaglandin synthase 2 (PTGS2), cyclooxygenase 2 (COX2), thymidylate synthetase (TYMS), thymidine phosphorylase (TYMP), dihydropyrimidine dehydrogenase (DPYD) and topoisomerase I (TOPO1) in colorectal cancer patients treated with 5-FU-based regimens, such as De Gramont and FOLFOX in the adjuvant setting. MATERIALS AND METHODS: In total, 96 formalin-fixed paraffin-embedded and 30 fresh-frozen tumor tissue samples were evaluated using immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and microarray gene expression profiling, respectively. RESULTS: The majority of tumors exhibited protein overexpression of COX2 (69%), TYMS (75%) and TOPO1 (75%). There was a significant association of TYMP protein expression with T classification, gender and stage (p=0.040, p=0.041 and p=0.011, respectively). TOPO1 protein expression was correlated with TOPO1 mRNA expression and was positively associated with stage (p=0.002) and lymph node infiltration (p=0.004). In univariate analysis, patients with high TYMS mRNA expression were shown to have a significantly lower risk for progression and death (Wald's p=0.030 and p=0.015, respectively). However, in multivariate analysis, only a trend for decreased risk for death was shown in patients with high TYMS mRNA expression (Wald's p=0.083), while patients with high PTGS2 mRNA expression had a trend for lower risk for progression (p=0.064). Using supervised hierarchical clustering, based on the expression in fresh-frozen tumor tissue of PTGS2, TYMS, TYMP and DPYD, our 30 patients were separated into two clusters. One of the clusters was enriched with patients with infiltrated lymph nodes (p<0.05), suggesting that these genes might have an impact on the tumor's ability to metastasize. CONCLUSION: These findings indicate a possible prognostic role of TYMS mRNA expression and highlight a cluster of genes associated with nodal metastases that warrant further investigation in a larger cohort of patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Análise por Conglomerados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Timidilato Sintase/genética , Resultado do TratamentoRESUMO
AIM: The aim of this study was to investigate the expression of CXC chemokine ligand-12 (CXCL12), CXC chemokine receptor 4 CXCR4 and of vascular endothelial growth factor receptor 3 (VEGFR3) in primary urothelial bladder carcinoma and their recurrence in relation to grade and pT status. MATERIALS AND METHODS: Immunohistochemistry was applied to 67 primary tumor (PC) sections and their recurrenct tumors (RC). RESULTS: The expression of CXCL12 both in PC and in RC was positively associated with tumor grade (p<0.0001 and p<0.0001, respectively) and pT stage (p=0.001 and p=0.007, respectively). The expression of CXCR4 in both PC and RC was also positively related to grade (p=0.001 and p<0.0001, respectively) and pT stage (p=0.008 and p=0.005, respectively). We compared the expression of CXCL12 and CXCR4 in PC related to RC and found that both were more intense in RC than in PC (p<0.0001 and p<0.0001, respectively). In PC and in RC there was no association between the expression of VEGFR3 with tumor grade and pT stage. CONCLUSION: CXCL12 and CXCR4 expression was related to adverse prognostic markers in urothelial bladder carcinoma through their association with grade and pT stage both in PC and RC. The CXCL12-CXCR4 axis may influence the expression of VEGFR3 in urothelial bladder carcinoma and promote tumor recurrence.
Assuntos
Quimiocina CXCL12/biossíntese , Receptores CXCR4/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Humanos , Imuno-Histoquímica , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Estadiamento de NeoplasiasRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults. Increased lysophosphatidic acid (LPA) concentrations have been reported in the alveolar space of both idiopathic pulmonary fibrosis patients and a corresponding animal model, whereas the genetic deletion or pharmacological inhibition of LPA receptor 1 attenuated the development of the modeled disease, suggesting a direct involvement of LPA in disease pathogenesis. In this report, increased concentrations of autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular LPA production, were detected in both murine and human fibrotic lungs. The genetic deletion of ATX from bronchial epithelial cells or macrophages attenuated disease severity, establishing ATX as a novel player in IPF pathogenesis. Furthermore, the pharmacological inhibition of ATX attenuated the development of the modeled disease, suggesting that ATX is a possible therapeutic target in IPF.
Assuntos
Fibrose Pulmonar Idiopática/enzimologia , Pulmão/enzimologia , Diester Fosfórico Hidrolases/metabolismo , Adulto , Idoso , Anilidas/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/química , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Fibrose Pulmonar Idiopática/patologia , Lisofosfolipídeos/metabolismo , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Organofosfonatos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/genética , Mucosa Respiratória/enzimologia , Mucosa Respiratória/patologiaRESUMO
BACKGROUND: HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy. METHODS: In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry). RESULTS: HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel. CONCLUSIONS: This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000506998.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Antígenos de Neoplasias/metabolismo , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epirubicina/uso terapêutico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Antibióticos Antineoplásicos/farmacologia , Antígenos de Neoplasias/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Epirubicina/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Neoplásicos/genética , Humanos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Inclusão em Parafina , Proteínas de Ligação a Poli-ADP-Ribose , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor ErbB-2/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Risco , Fixação de Tecidos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A/B type (hnRNP A1, A2/B1, A3) are highly related multifunctional proteins participating in alternative splicing by antagonising other splicing factors, notably ASF/SF2. The altered expression pattern of hnRNP A2/B1 and/or splicing variant B1 alone in human lung cancer and their potential to serve as molecular markers for early diagnosis remain issues of intense investigation. The main objective of the present study was to use paired tumour/non-tumour biopsies from patients with non-small cell lung cancer (NSCLC) to investigate the expression profiles of hnRNP A1, A2/B1 and A3 in conjunction with ASF/SF2. METHODS: We combined western blotting of tissue homogenates with immunohistochemical examination of fixed tissue sections and quantification of mRNA expression levels in tumour versus adjacent normal-looking areas of the lung in the same patient. RESULTS: Our study, in addition to clear evidence of mostly uncoupled deregulation of hnRNPs A/B, has revealed hnRNP A1 to be the most deregulated protein with a high frequency of over-expression (76%), followed by A3 (52%) and A2/B1 (43%). Moreover, direct comparison of protein/mRNA levels showed a lack of correlation in the case of hnRNP A1 (as well as of ASF/SF2), but not of A2/B1, suggesting that different mechanisms underlie their deregulation. CONCLUSION: Our results provide strong evidence for the up-regulation of hnRNP A/B in NSCLC, and they support the existence of distinct mechanisms responsible for their deregulated expression.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Pulmão/metabolismo , RNA Mensageiro/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/secundário , Idoso , Western Blotting , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Feminino , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Humanos , Técnicas Imunoenzimáticas , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Processamento de Serina-Arginina , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans, the major proteoglycans in the extracellular matrix and cell surfaces. Traditionally, heparanase activity was implicated in cellular invasion associated with angiogenesis, inflammation, and cancer metastasis. More recently, heparanase up-regulation was documented in an increasing number of primary human tumors. Iotan this study, we sought to investigate the expression of heparanase messenger RNA (mRNA) in normal cervical tissue and intraepithelial cervical lesion and its clinicopathologic importance in invasive cervical cancer. Gene expression of heparanase was assessed by quantitative real-time reverse transcriptase polymerase chain reaction in 28 normal cervical, 26 intraepithelial neoplastic, and 48 cervical cancer tissue samples. Heparanase mRNA expression was different between the 3 groups and lower in normal cervical specimens in relationship with intraepithelial cervical lesions and invasive cervical cancer tissue samples (P = 0.048). Gradually increasing expression of heparanase was evident as the cells progressed from low-grade to high-grade squamous intraepithelial lesions (P = 0.002). In invasive cervical cancer cases, there was a direct correlation between heparanase expression and tumor size (P = 0.002). In cases treated with radical hysterectomy and pelvic lymphadenectomy, the heparanase mRNA expression was significantly higher in tumors exhibiting lymph vascular space invasion (P = 0.044) and in cases with big tumor size (P = 0.005). In our study, we did not find any significant correlation between disease-free and overall survival rates and expression of heparanase (P = 0.396 and P = 0.712, respectively). The results of this study suggest that the gene expression of heparanase in cervical cancer enhances growth, invasion, and angiogenesis of the tumor and may have therapeutic applications.
Assuntos
Carcinoma de Células Escamosas/genética , Colo do Útero/metabolismo , Glucuronidase/genética , Displasia do Colo do Útero/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Feminino , Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glucuronidase/análise , Glucuronidase/metabolismo , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Neovascularização Patológica/enzimologia , Neovascularização Patológica/genética , Análise de Sobrevida , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/metabolismo , Displasia do Colo do Útero/mortalidade , Displasia do Colo do Útero/patologiaRESUMO
Acheron (Achn), a phylogenetically-conserved member of the Lupus antigen family of RNA binding proteins, was initially identified as a novel cell death-associated gene from the intersegmental muscles of the tobacco hawkmoth Manduca sexta. C(2)C(12) cells are a standard model for the study of myogenesis. When deprived of growth factors, these cells can be induced to: form multinucleated myotubes, arrest as quiescent satellite-like reserve cells, or undergo apoptosis. Achn expression is induced in myoblasts that form myotubes and acts upstream of the muscle specific transcription factor MyoD. Forced expression of ectopic Achn resulted in the formation of larger myotubes and massive reserve cell death relative to controls. Conversely, dominant-negative or antisense Achn blocked myotube formation following loss of growth factors, suggesting that Achn plays an essential, permissive role in myogenesis. Studies in zebrafish embryos support this hypothesis. Reduction of Achn with antisense morpholinos led to muscle fiber loss and an increase in the number of surviving cells in the somites, while ectopic Achn enhanced muscle fiber formation and reduced cell numbers. These results display a crucial evolutionarily conserved role for Achn in myogenesis and suggest that it plays key roles in the processes of differentiation and self-renewal.
Assuntos
Autoantígenos/fisiologia , Regulação da Expressão Gênica , Músculos/citologia , Ribonucleoproteínas/fisiologia , Animais , Apoptose , Autoantígenos/metabolismo , Diferenciação Celular , Linhagem Celular , Sobrevivência Celular , Manduca/metabolismo , Camundongos , Modelos Biológicos , Músculos/embriologia , Músculos/metabolismo , Proteína MyoD/metabolismo , Filogenia , Ribonucleoproteínas/metabolismo , Células-Tronco/citologia , Peixe-Zebra , Antígeno SS-BRESUMO
[This corrects the article DOI: 10.2478/s11658-008-0046-1.].
RESUMO
Acheron, a Lupus antigen ortholog, was identified as a novel death-associated transcript from the intersegmental muscles of the moth Manduca sexta. Acheron is phylogenetically-conserved and represents a new sub-family of Lupus antigen proteins. Acheron is expressed predominantly in neurons and muscle in vertebrates, and regulates several developmental events including myogenesis, neurogenesis and possibly metastasis. Using Acheron as bait, we performed a yeast two-hybrid screen with a mouse embryo cDNA library and identified CASK-C, a novel CASK/Lin-2 isoform, as an Acheron binding partner. Acheron and CASK-C bind via the C-terminus of Acheron and the CaMKII-like domain of CASK-C. Co-immunoprecipitation assays verify this interaction and demonstrate that Acheron also forms a complex with all members of the Id (inhibitor of differentiation) proteins. Taken together, these data suggest a mechanism by which Acheron may regulate development and pathology.