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1.
Acta Chir Belg ; 120(1): 23-29, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30499377

RESUMO

Background: To present basic demographic and clinical characteristics of patients with adrenocortical carcinoma (ACC), to determine the overall survival rate and to analyze the results of immunohistochemical staining and its correlation with the length of survival.Material and methods: The study was conducted during the period between 1996 and 2010 and included 30 patients with ACC. Immunohistochemical staining (MMP9, melan A, inhibin, caltretinin, D2-40, synaptophysin and Ki-67) was performed.Results: ACC was diagnosed in 19 females and 11 men (1.7:1). The average age was 50.1 years. The median tumor size was 10 cm, the median weight 400 g. Majority of subjects had positive immunohistochemical staining for the markers of interest. Patients with any negative staining had shorter cancer-specific survival than ones with positive staining. According to the log-rank test results as well as according to the results of the univariate Cox analysis, negative staining for inhibin, D2-40 and synaptophysin and Ki-67 expression ≥7% were associated with poorer prognosis.Conclusions: The results of our study suggest that the absence of staining for some immunohistochemical markers and increased expression of Ki-67 are associated with a poorer prognosis and shorter survival of patients with ACC. Immunohistochemical markers may serve as a prognostic factor for ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/mortalidade , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Anticorpos Monoclonais Murinos/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Inibinas/metabolismo , Antígeno Ki-67/metabolismo , Antígeno MART-1/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Sinaptofisina/metabolismo , Adulto Jovem
2.
BMC Cancer ; 19(1): 1165, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783819

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumour. Due to a high tumour recurrence rate, the post-operative overall survival (OS) and disease-free survival (DFS) of ACCs is limited. Our research aims to identify the role of the epithelial-mesenchymal transition (EMT) related genes FSCN1 and FOXM1 in the tumour microenvironment and assess their prognostic value in ACCs. METHODS: Clinical and specimen data from 130 adrenocortical carcinoma (ACC) patients was acquired from the Cancer Genome Atlas (TCGA) database (n = 79) and a West China Hospital (WCH) cohort (n = 51). In the WCH cohort, archived formalin-fixed paraffin embedded (FFPE) samples were collected for immunohistochemical analysis. The correlation between the EMT genes and the tumour microenvironment status was estimated based on the Tumour Immune Estimation Resource (TIMER) algorithm. Kaplan-Meier analysis, followed by univariate and multivariate regression analyses, were performed to identify the prognostic association of FSCN1 and FOXM1. RESULTS: FSCN1 and FOXM1 were over-expressed in ACC tissue when compared with adrenocortical adenoma and normal adrenal tissue. Over-expression of FSCN1 or FOXM1 was associated with the tumour microenvironment and immune signatures in ACCs. Patients with higher expression of FSCN1 or FOXM1 were more likely to have worse prognoses. The prognostic effects were further verified in both early (stage I/II) and advanced (stage III/IV) ACCs. Furthermore, FSCN1 and FOXM1 appeared as independent prognostic factors in ACC. CONCLUSIONS: These results show that FSCN1 and FOXM1 are independent prognostic factors in ACCs and over-expression of FSCN1 or FOXM1 indicates a worse prognosis.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Proteínas de Transporte/metabolismo , Proteína Forkhead Box M1/metabolismo , Proteínas dos Microfilamentos/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/imunologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/imunologia , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Regulação para Cima , Adulto Jovem
3.
Eur J Endocrinol ; 181(6): 681-689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639772

RESUMO

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro. Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy. Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety. Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria. Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Temozolomida/efeitos adversos , Temozolomida/uso terapêutico , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteínas Supressoras de Tumor/metabolismo
4.
Proc Natl Acad Sci U S A ; 116(44): 22269-22274, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611400

RESUMO

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Ferroptose/efeitos dos fármacos , Células 3T3 , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Insulina/metabolismo , Ferro/metabolismo , Ácido Linoleico/metabolismo , Camundongos , Mitotano/toxicidade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/metabolismo , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Transferrina/metabolismo
5.
Drug Des Devel Ther ; 13: 2787-2798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496655

RESUMO

Objective: Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods: In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results: The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion: Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Tapsigargina/farmacologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Animais , Antineoplásicos Fitogênicos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Thapsia/química , Tapsigargina/química , Células Tumorais Cultivadas
6.
J Trace Elem Med Biol ; 56: 52-59, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442954

RESUMO

INTRODUCTION: Iron metabolism is tightly controlled in human cells. Dysregulation of iron metabolism-related genes has been characterized as a promising prognostic biomarker in cancers. However, the expression patterns and prognostic roles of iron metabolism-related genes remain unknown in adrenocortical carcinoma (ACC). OBJECTIVES: The primary objective of this study was to explore the expression patterns and prognostic roles of iron metabolism-related genes in ACC using publicly available datasets. METHODS: In the present study, we compared the expression patterns of 36 iron metabolism-related genes between ACC tumors (n = 77) and normal adrenal tissues (n = 128) based on The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) data. The associations between clinical variables (including survival rate and pathological stage) and expression levels of iron mentalism-related genes were further explored. All the bioinformatics analyses were performed using the GEPIA or the Metascape tool. RESULTS: Twelve iron metabolism-related genes were differentially expressed between ACC tumors and normal controls. Among them, reduced expression levels of ferroportin1 (FPN1) and ceruloplasmin (CP) were significantly correlated with poor survival of ACC patients. Specially, the expression levels of FPN1 were negatively correlated with the pathological stages of ACC. A pan-cancer analysis characterized the reduced expression of FPN1 and CP as an ACC-specific signature among 33 types of cancers. Functional enrichment analysis suggested that both FPN1 and CP might be implicated in several immune processes. CONCLUSION: Reduced expression of FPN1 and CP was identified as a potential signature for poor prognosis of ACC in this study. Mechanisms underlying the prognostic value of FPN1 or CP in ACC deserve further experimental investigation.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Ceruloplasmina/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Estudos de Casos e Controles , Proteínas de Transporte de Cátions/genética , Ceruloplasmina/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Ferro/metabolismo , Prognóstico , Transdução de Sinais/genética , Análise de Sobrevida , Microambiente Tumoral/genética
8.
J Steroid Biochem Mol Biol ; 192: 105413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202858

RESUMO

In steroid-producing cells, cholesterol transport from the outer to the inner mitochondrial membrane is the first and rate-limiting step for the synthesis of all steroid hormones. Cholesterol can be transported into mitochondria by specific mitochondrial protein carriers like the steroidogenic acute regulatory protein (StAR). StAR is phosphorylated by mitochondrial ERK in a cAMP-dependent transduction pathway to achieve maximal steroid production. Mitochondria are highly dynamic organelles that undergo replication, mitophagy and morphology changes, all processes allowed by mitochondrial fusion and fission, known as mitochondrial dynamics. Mitofusin (Mfn) 1 and 2 are GTPases involved in the regulation of fusion, while dynamin-related protein 1 (Drp1) is the major regulator of mitochondrial fission. Despite the role of mitochondrial dynamics in neurological and endocrine disorders, little is known about fusion/fission in steroidogenic tissues. In this context, the present work aimed to study the role of angiotensin II (Ang II) in protein subcellular compartmentalization, mitochondrial dynamics and the involvement of this process in the regulation of aldosterone synthesis. We demonstrate here that Ang II stimulation promoted the recruitment and activation of PKCε, ERK and its upstream kinase MEK to the mitochondria, all of them essential for steroid synthesis. Moreover, Ang II prompted a shift from punctate to tubular/elongated (fusion) mitochondrial shape, in line with the observation of hormone-dependent upregulation of Mfn2 levels. Concomitantly, mitochondrial Drp1 was diminished, driving mitochondria toward fusion. Moreover, Mfn2 expression is required for StAR, ERK and MEK mitochondrial localization and ultimately for aldosterone synthesis. Collectively, this study provides fresh insights into the importance of hormonal regulation in mitochondrial dynamics as a novel mechanism involved in aldosterone production.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Carcinoma Adrenocortical/metabolismo , Angiotensina II/farmacologia , Colesterol/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Quinases/metabolismo , Vasoconstritores/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Transporte Biológico , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação , Células Tumorais Cultivadas
9.
J Pak Med Assoc ; 69(5): 717-719, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31105294

RESUMO

Adrenocortical carcinoma is a rare and aggressive malignancy with an incidence of 0.5-2 per million per year and its overall prognosis is very poor. This study was aimed to point out the factors associated with tumour recurrence and patient's survival after complete surgical resection of this aggressive malignancy. Patients admitted from January 2011 till December 2015 were retrospectively reviewed using case notes. In these five years 29 patients were admitted with adrenal tumour out of which 13 had adrenocortical carcinoma. On five year follow up, six (46.2%) patients developed recurrence. MEAN disease free survival was 31.0 ± 23.92 (2-63) months 53.8% while MEAN overall survival was 46.69 ± 22.81 (14-80) months 92.3%. Results concluded that hormonally active tumour on clinical presentation, positive surgical resection margins, positive nodal status and poorly differentiated tumour on histopathology are the factors associated with tumour recurrence and patient's survival.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Adrenalectomia , Carcinoma Adrenocortical/terapia , Antineoplásicos Hormonais/uso terapêutico , Mitotano/uso terapêutico , Adolescente , Corticosteroides/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Quimioterapia Adjuvante , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Paquistão , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
10.
Mol Cell Biochem ; 458(1-2): 1-10, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30989475

RESUMO

As an uncommon malignancy in the adrenal gland, adrenocortical carcinoma (ACC) is characterized by thorny diagnosis and poor clinical outcome, necessitating innovative treatment strategies. Sirtuin 6 (SIRT6), a tumor suppressor, modulates aerobic glycolysis of malignant cells and has an impact on tumorigenesis. This study focused on investigating SIRT6 expression in ACC and how it generates cancer phenotypes. SIRT6 expression was inhibited in ACC tissues according to western blotting, real-time polymerase chain reaction, and immunohistochemistry. MTT assay, TUNEL assay, and flow cytometry were performed to evaluate the contribution of SIRT6 to cell invasion, proliferation, death, and migration. It was shown that SIRT6 knockdown promoted cell invasion, proliferation, and migration, and inhibited cell death. Moreover, it was found that SIRT6 knockdown upregulated TLR4 and reinforced phosphorylation of the nuclear transcription factor-kappa B (NF-κB) subunit p65 as well as inhibitor of nuclear factor kappa-B kinase. Additionally, SIRT6 knockdown significantly enhanced expression of calcitonin gene-related peptide as well as transient receptor potential vanilloid subtype 1. It also reinforced reactive oxygen species generation. Overall, our research findings demonstrate that SIRT6 serves as a tumor suppressor via regulation of the NF-κB pathway, which could offer an innovative strategy to treat ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Movimento Celular , Proliferação de Células , Sirtuínas/metabolismo , Fator de Transcrição RelA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Invasividade Neoplásica , Sirtuínas/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/genética , Proteínas Supressoras de Tumor/genética
11.
J Am Coll Surg ; 229(3): 305-315, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31034883

RESUMO

BACKGROUND: Insulin-like growth factor (IGF) dysregulation and gene copy number variations (CNV) are hallmarks of adrenocortical carcinoma (ACC). The contribution of IGF CNVs in adrenal carcinogenesis has not been studied previously. In addition, studies demonstrating an association between SLC12A7 gene amplifications and enhanced metastatic behavior in ACC, as well as reported IGF-SLC12A7 signaling interactions in other cancers, suggest a potential IGF-SLC12A7 signaling circuitry in ACC. Here we investigate the potential complicity of IGF-SLC12A7 signaling in ACC. STUDY DESIGN: Insulin-like growth factor CNVs were determined by whole-exome sequencing analysis in an exploratory cohort of ACC. Quantitative polymerase chain reaction methods determined IGF1 and IGF2 expression levels and were evaluated for correlation with SLC12A7 expression and tumor characteristics. Insulin-like growth factor CNVs and expression patterns were compared with The Cancer Genome Atlas. In vitro studies determined the relationship of IGF and SLC12A7 co-expression in 2 ACC cell lines, SW-13 and NCI-H295R. Immunohistochemistry assessed IGF1 receptor (IGF1R) activation. RESULTS: The IGF1 gene was amplified in 9 of 19 ACC samples, similar to findings in The Cancer Genome Atlas database. The IGF1 overexpression was observed in 5 samples and was associated with SLC12A7 overexpression and non-functional, early-stage tumors (p < 0.05). In contrast, IGF2 overexpression was associated with larger tumors (p < 0.05). In vitro IGF treatment of ACC cell lines did not stimulate SLC12A7 expression, and endogenous overexpression and silencing of SLC12A7 significantly altered IGF1 and IGF1R expression without impacting other IGFs. The IGF1R activation was associated with IGF1 overexpression in ACC tumor samples. CONCLUSIONS: These findings indicate that IGF1 overexpression, caused in part by gene amplifications, is correlated with SLC12A7 overexpression in non-functional, early-stage ACCs, suggesting a potentially targeted IGF1-SLC12A7 therapeutic opportunity for these tumors.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Fator de Crescimento Insulin-Like I/genética , Receptor IGF Tipo 1/genética , Simportadores/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Simportadores/metabolismo
12.
Endocrine ; 64(3): 673-684, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30838516

RESUMO

PURPOSE: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. METHODS: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. RESULTS: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. CONCLUSIONS: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Imidazóis/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Anticancer Res ; 39(3): 1151-1159, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842144

RESUMO

BACKGROUND/AIM: Morphological features, combined with Ki-67 proliferative index, remain the standard for discriminating benign and malignant adrenocortical tumors. The aim of this study was to evaluate the role of minichromosome maintenance proteins MCM-3, MCM-5, MCM-7, and Ki-67 as proliferative markers in adrenocortical tumors. MATERIALS AND METHODS: Specimens of 81 adrenocortical adenomas and 3 adrenocortical carcinomas were stained with antibodies against MCM-3, 5, 7 and Ki-67. RESULTS: Malignant tumors were characterized by a greater size (p=0.017), volume (p=0.017), and higher levels of Ki-67 (p=0.005), MCM-3 (p=0.005), MCM-7 (p=0.008), but not MCM-5 (p=0.069). The markers' levels were independent from the tumors' size and volume, the patient's age and hormonal status. ROC curves showed Ki-67 (AUC 0.984), MCM-3 (AUC 0.984), and MCM-7 (AUC 0.950), but not MCM-5 (AUC 0.820) to be reliable markers. CONCLUSION: Ki-67, MCM-3, and MCM-7, but not MCM-5 are reliable proliferative and diagnostic markers in discerning benign and malignant adrenocortical tumors.


Assuntos
Adenoma/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Biomarcadores Tumorais/metabolismo , Antígeno Ki-67/metabolismo , Componente 3 do Complexo de Manutenção de Minicromossomo/metabolismo , Componente 7 do Complexo de Manutenção de Minicromossomo/metabolismo , Adenoma/diagnóstico , Neoplasias do Córtex Suprarrenal/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
ANZ J Surg ; 89(1-2): 48-52, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30710432

RESUMO

BACKGROUND: Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21-year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt. METHODS: A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken. RESULTS: Thirty-five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki-67 index were strong prognostic indicators for survival. CONCLUSIONS: Early stage, complete resection and Ki-67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometastatic disease along with multimodal adjuvant treatment has led to long-term survivors of patients with Stage 4 disease in our aggregate cohort.


Assuntos
Neoplasias do Córtex Suprarrenal/cirurgia , Neoplasias das Glândulas Suprarrenais/cirurgia , Carcinoma Adrenocortical/cirurgia , Terapia Combinada/métodos , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Austrália/epidemiologia , Feminino , Humanos , Comunicação Interdisciplinar , Antígeno Ki-67/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
15.
J Cell Biochem ; 120(1): 894-906, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256438

RESUMO

Unraveling molecular mechanisms that regulate tumor development and proliferation is of the utmost importance in the quest to decrease the high mortality rate of adrenocortical carcinomas (ACC). Our aim was to evaluate the role of two of the mitogen-activated protein kinase (MAPK) signaling pathways (extracellular signal-regulated protein kinases [ERKs 1/2] and p38) in the adrenocortical tumorigenesis, as well as the therapeutic potential of MAPK/ERK inhibition. ERKs 1/2 and p38 activation were evaluated in incidentalomas (INC; n = 10), benign Cushing's syndrome (BCS; n = 12), malignant Cushing's syndrome (MCS; n = 6) and normal adrenal glands (NAG; 8). ACC cell line (H295R) was used to evaluate the ability of PD184352 (0.1, 1, and 10 µM), a specific MEK-MAPK-ERK pathway inhibitor, to modulate cell proliferation, viability, metabolism, and steroidogenesis. ERKs 1/2 activation was significantly higher in MCS (2.83 ± 0.17) compared with NAG (1.00 ± 0.19 "arbitrary units"), INC (1.20 ± 0.13) and BCS (2.09 ± 0.09). Phospho-p38 expression was absent in all the MCS analyzed. MAPK/ERK kinase (MEK) inhibition with PD184352 significantly decreased proliferation as well as steroidogenesis and also increased the redox state of the H295R cells. This data suggests that MEK-MAPK-ERK signaling has a role in adrenocortical tumorigenesis that could be potentially used as a diagnostic marker for malignancy and targeted treatment in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Benzamidas/farmacologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Proteína Quinase 3 Ativada por Mitógeno , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
J Steroid Biochem Mol Biol ; 185: 137-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30125658

RESUMO

Angiotensin 1-7 (Ang 1-7), which is a protein cleaved from angiotensin II (A-II), binds to the MAS receptor. Ang 1-7 has been demonstrated to exert protective effects against A-II-mediated cardiac, atherosclerotic, and renal damages. The aims of our study were to demonstrate the inhibitory role of Ang 1-7 in A-II-mediated aldosterone production by interacting with the MAS receptor in human adrenocortical carcinoma (HAC15) cells, and clarify the intracellular signaling mechanisms underlying the inhibition of aldosterone production by Ang 1-7. Ang 1-7 significantly suppressed A-II-stimulated aldosterone production, and partially abrogated A-II-induced upregulation of CYP11B2 expression. Treatment with a selective Ang 1-7 antagonist abrogated Ang 1-7-mediated inhibition of aldosterone production in HAC15 cells. Incubation of A-II-treated HAC15 cells with conditioned medium containing Ang 1-7 was demonstrated to suppress A-II-mediated aldosterone production and CYP11B2 expression. Proteomic analysis showed that Ang 1-7 predominantly inhibited the phosphorylation of JAK-STAT proteins in A-II stimulated HAC15 cells. Treatment of HAC15 cells with a STAT3 inhibitor partially but significantly repressed A-II-mediated aldosterone production by 63.2%. Similarly, treatment with a STAT5 inhibitor significantly abrogated A-II-stimulated aldosterone production in HAC15 cells by 60.7%. In conclusion, we demonstrated that Ang 1-7 negatively regulates A-II-mediated aldosterone production, and the observed inhibition of aldosterone production was associated with JAK/STAT signaling in human adrenal cells. Therefore, activation of Ang 1-7 or stimulation of the MAS receptor, which inhibits aldosterone production, is a promising therapeutic approach for the prevention of cardiovascular events that can directly affect the target organs.


Assuntos
Aldosterona/biossíntese , Angiotensina II/metabolismo , Angiotensina I/metabolismo , Janus Quinases/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Carcinoma Adrenocortical/metabolismo , Angiotensina I/antagonistas & inibidores , Doenças Cardiovasculares/tratamento farmacológico , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Citocromo P-450 CYP11B2/biossíntese , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
Endocrine ; 63(3): 592-601, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30367443

RESUMO

PURPOSE: The management of patients with adrenocortical carcinoma (ACC) is challenging. As mitotane and chemotherapy show limited efficacy, there is an urgent need to develop therapeutic approaches. The aim of this study was to investigate the antitumor activity of progesterone and explore the molecular mechanisms underlying its cytotoxic effects in the NCI-H295R cell line and primary cell cultures derived from ACC patients. METHODS: Cell viability, cell cycle, and apoptosis were analyzed in untreated and progesterone-treated ACC cells. The ability of progesterone to affect the Wnt/ß-catenin pathway in NCI-H295R cells was investigated by immunofluorescence. Progesterone and mitotane combination experiments were also performed to evaluate their interaction on NCI-H295R cell viability. RESULTS: We demonstrated that progesterone exerted a concentration-dependent inhibition of ACC cell viability. Apoptosis was the main mechanism, as demonstrated by a significant increase of apoptosis and cleaved-Caspase-3 levels. Reduction of ß-catenin nuclear translocation may contribute to the progesterone cytotoxic effect. The progesterone antineoplastic activity was synergically increased when mitotane was added to the cell culture medium. CONCLUSIONS: Our results show that progesterone has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of progesterone with mitotane provides the rationale for testing this combination in a clinical study.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Proteínas de Membrana/metabolismo , Mitotano/uso terapêutico , Cultura Primária de Células , Progesterona/farmacologia , Progestinas/farmacologia , Receptores de Progesterona/metabolismo , beta Catenina/metabolismo
19.
J Clin Endocrinol Metab ; 104(5): 1712-1724, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476173

RESUMO

CONTEXT: Novel tumor markers are urgently needed to better stratify adrenocortical cancer (ACC) patients and improve therapies for this aggressive neoplasm. OBJECTIVE: To assess the diagnostic and prognostic value of the actin-bundling protein fascin-1 (FSCN1) in adrenocortical tumors. DESIGN, SETTING AND PARTICIPANTS: A local series of 37 malignant/37 benign adrenocortical tumors at Careggi University Hospital and two independent validation ACC cohorts (Cochin, TCGA) from the European Network for the Study of Adrenal Tumors were studied. MAIN OUTCOME MEASURES: FSCN1 expression was quantified by immunohistochemistry, Western blot and quantitative RT-PCR in ACC specimens; overall and disease-free survival associated with FSCN1 expression were assessed by Kaplan-Meier analysis and compared with that of Ki67 labeling index and tumor stage. RESULTS: Despite the low diagnostic power, in the Florence ACC series, FSCN1 immunohistochemical detection appeared as an independent prognostic factor, also refining results obtained with staging and Ki67 labeling index. The robust prognostic power of FSCN1 levels was further confirmed in two independent ACC cohorts. A positive correlation was found between FSCN1 and steroidogenic factor-1 (SF-1), with a substantially higher expression of both factors in ACCs at advanced stages and with at least one of the three Weiss score parameters associated with invasiveness. Moreover, we demonstrated FSCN1 role in promoting cell invasion in a human ACC cell line only in the case of increased SF-1 dosage. CONCLUSIONS: These findings show that FSCN1 is a novel independent prognostic marker in ACC and may serve as a potential therapeutic target to block tumor spread.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Proteínas dos Microfilamentos/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Adulto Jovem
20.
Surgery ; 165(1): 202-210, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413320

RESUMO

BACKGROUND: Adrenocortical carcinoma is a rare and aggressive malignancy with poor survival. With limited treatment options and high risk of relapse, identifying improved targets and therapies for adrenocortical carcinoma is important. We hypothesized that analysis of the database of The Cancer Genome Atlas could identify important novel biomarkers for improved therapeutic targeting of adrenocortical carcinoma. METHODS: We utilized the University of Alabama interactive web resource to identify novel biomarkers observed in 79 adrenocortical carcinoma patients. Identified biomarkers were then examined for prognostic correlations using the cBioPortal and analyzed for statistical significance using STATA 13.0. RESULTS: The Cancer Genome Atlas data mining in the University of Alabama interactive web resource for pathways associated with poor survival of patients with adrenocortical carcinoma revealed significant upregulation of genes involved in DNA damage and regulation of cell-cycle pathways, such as AURKA, AURKB, CDK1, CDK4, CDK6, PLK1, CHEK1, CHEK2, CDC7, BUB3, and MCM3 (P < .001-.05). On outcome correlation, greater expression levels of all the genes except CDK4 were associated with worse survival compared with medium or low levels of gene expression (P < .001 all) irrespective of age orsex. Consistent with our University of Alabama interactive web resource findings, data mining in the cBioPortal also revealed upregulation of genes regulating DNA-damage and cell cycle-related genes in 82% of patients (z score = 1.5). CONCLUSION: Large data mining from the The Cancer Genome Atlas and cBioPortal databases identified overexpression of genes involved in DNA damage and those regulating pathways of the cell cycle, which correlated with poorer overall survival in adrenocortical carcinoma patients.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/mortalidade , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteínas de Ciclo Celular/genética , Conjuntos de Dados como Assunto , Regulação para Baixo , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Feminino , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Prognóstico , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Quinase Piruvato Desidrogenase (Transferência de Acetil) , RNA Mensageiro/metabolismo , Regulação para Cima
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