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1.
Curr Oncol ; 28(6): 5346-5355, 2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-34940085

RESUMO

Epithelioid trophoblastic tumours are rare neoplasms showing differentiation towards the chorion leave-type intermediate cytotrophoblast, with only a handful of cases being reported in the literature. These tumours are slow-growing and are typically confined to the uterus for extended periods of time. While the pathogenesis is unclear, they are thought to arise from a remnant intermediate trophoblast originating from prior normal pregnancies or, less frequently, gestational trophoblastic tumours. A protracted time period between the gestational event and tumour development is typical. This case describes a 49-year-old previously healthy female who presented with a completely asymptomatic uterine mass, discovered incidentally during a routine gynaecological assessment. The pathological analysis of the hysterectomy specimen confirmed an epithelioid trophoblastic tumour, involving the uterus and cervix. This is a rare gynaecological tumour. A comparative short tandem repeat analysis revealed genetic similarities to a previous healthy gestation seventeen years prior. She was successful treated with adjuvant pembrolizumab, with no evidence of disease recurrence to date.


Assuntos
Doença Trofoblástica Gestacional , Neoplasias Uterinas , Anticorpos Monoclonais Humanizados , Feminino , Ligação Genética , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/genética , Doença Trofoblástica Gestacional/cirurgia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Gravidez , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/cirurgia
2.
Transl Oncol ; 14(12): 101229, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34592589

RESUMO

Tumour metastasis accounts for over 90% of cancer related deaths. The platelet is a key blood component, which facilitates efficient metastasis. This study aimed to understand the molecular mechanisms involved in tumour-platelet cell interactions. The interaction between cancer cells and platelets was examined in 15 epithelial cell lines, representing 7 cancer types. Gene expression analysis of EMT-associated and cancer stemness genes was performed by RT-PCR. Whole transcriptome analysis (WTA) was performed using Affymetrix 2.0ST arrays on a platelet co-cultured ovarian model. Platelet adhesion and activation occurred across all tumour types. WTA identified increases in cellular movement, migration, invasion, adhesion, development, differentiation and inflammation genes and decreases in processes associated with cell death and survival following platelet interaction. Increased invasive capacity was also observed in a subset of cell lines. A cross-comparison with a platelet co-cultured mouse model identified 5 common altered genes; PAI-1, PLEK2, CD73, TNC, and SDPR. Platelet cancer cell interactions are a key factor in driving the pro-metastatic phenotype and appear to be mediated by 5 key genes which have established roles in metastasis. Targeting these metastasis mediators could improve cancer patient outcomes.

3.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360598

RESUMO

Gynecological cancers (GCs) are currently among the major threats to female health. Moreover, there are different histologic subtypes of these cancers, which are defined as 'rare' due to an annual incidence of <6 per 100,000 women. The majority of these tend to be associated with a poor prognosis. Long non-coding RNAs (lncRNAs) play a critical role in the normal development of organisms as well as in tumorigenesis. LncRNAs can be classified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signaling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity. However, there still needs to be a deeper understanding of the mechanisms by which lncRNAs are involved in the regulation of numerous biological functions in humans, both in normal health and disease. The lncRNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) has been identified as a tumor-related lncRNA. ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers).


Assuntos
Neoplasias dos Genitais Femininos/patologia , RNA Longo não Codificante/genética , Animais , Feminino , Neoplasias dos Genitais Femininos/genética , Humanos
4.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204445

RESUMO

Choriocarcinoma (CC), a subtype of trophoblastic disease, is a rare and highly aggressive neoplasm. There are two main CC subtypes: gestational and non-gestational, (so called when it develops as a component of a germ cell tumor or is related to a somatic mutation of a poorly differentiated carcinoma), each with very diverse biological activity. A therapeutic approach is highly effective in patients with early-stage CC. The advanced stage of the disease also has a good prognosis with around 95% of patients cured following chemotherapy. However, advancements in diagnosis and treatment are always needed to improve outcomes for patients with CC. Long non-coding (lnc) RNAs are non-coding transcripts that are longer than 200 nucleotides. LncRNAs can act as oncogenes or tumor suppressor genes. Deregulation of their expression has a key role in tumor development, angiogenesis, differentiation, migration, apoptosis, and proliferation. Furthermore, detection of cancer-associated lncRNAs in body fluids, such as blood, saliva, and urine of cancer patients, is emerging as a novel method for cancer diagnosis. Although there is evidence for the potential role of lncRNAs in a number of cancers of the female genital tract, their role in CC is poorly understood. This review summarizes the current knowledge of lncRNAs in gestational CC and how this may be applied to future therapeutic strategies in the treatment of this rare cancer.


Assuntos
Coriocarcinoma/genética , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias Uterinas/genética , Biomarcadores Tumorais , Coriocarcinoma/diagnóstico , Coriocarcinoma/metabolismo , Feminino , Humanos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Gravidez , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo
5.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917022

RESUMO

Gynecological cancers pose an important public health issue, with a high incidence among women of all ages. Gynecological cancers such as malignant germ-cell tumors, sex-cord-stromal tumors, uterine sarcomas and carcinosarcomas, gestational trophoblastic neoplasia, vulvar carcinoma and melanoma of the female genital tract, are defined as rare with an annual incidence of <6 per 100,000 women. Rare gynecological cancers (RGCs) are associated with poor prognosis, and given the low incidence of each entity, there is the risk of delayed diagnosis due to clinical inexperience and limited therapeutic options. There has been a growing interest in the field of microRNAs (miRNAs), a class of small non-coding RNAs of ∼22 nucleotides in length, because of their potential to regulate diverse biological processes. miRNAs usually induce mRNA degradation and translational repression by interacting with the 3' untranslated region (3'-UTR) of target mRNAs, as well as other regions and gene promoters, as well as activating translation or regulating transcription under certain conditions. Recent research has revealed the enormous promise of miRNAs for improving the diagnosis, therapy and prognosis of all major gynecological cancers. However, to date, only a few studies have been performed on RGCs. In this review, we summarize the data currently available regarding RGCs.


Assuntos
Biomarcadores Tumorais , Neoplasias dos Genitais Femininos/diagnóstico , Neoplasias dos Genitais Femininos/genética , MicroRNAs/genética , MicroRNA Circulante , Tomada de Decisão Clínica , Gerenciamento Clínico , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias dos Genitais Femininos/terapia , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Gravidez , Prognóstico , Interferência de RNA , RNA Mensageiro , Resultado do Tratamento
6.
Thromb Res ; 200: 91-98, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571724

RESUMO

INTRODUCTION: Ovarian cancer patients are at high risk of thrombosis particularly during chemotherapy treatment however the mechanism is not understood. The aim of this study is to investigate the role of the activated protein C (aPC) pathway in the procoagulant activity observed in ovarian cancer patients undergoing neoadjuvant chemotherapy. PATIENTS AND METHODS: Thrombin generation was determined before and after addition of thrombomodulin (TM) in high grade serous ovarian cancer (HGSOC) patients treated with neoadjuvant chemotherapy (n = 29) compared with HGSOC patients who were chemo naïve (n = 23) and patients with benign tumours (n = 29). Plasma expression of proteins from the aPC pathway was analysed. mRNA expression was determined in endothelial (EA.hy926) and ovarian (OAW42) cell lines following addition of carboplatin and paclitaxel. RESULTS: Lower levels of ETP (p < 0.007; p < 0.003) and peak thrombin (p < 0.0008; p < 0.0018) were found in the neoadjuvant group compared with both chemo naïve and benign groups. Following addition of TM, ETP (p < 0.0005) and peak thrombin (p < 0.0049) were higher in the neoadjuvant group compared with the benign controls indicating an increase in aPC resistance. Increased TM and lower levels of protein S were found in the neoadjuvant group compared with benign controls (p < 0.05; p < 0.003). Factor V levels were increased in the neoadjuvant group compared with the chemo naïve group (p < 0.05). Carboplatin and paclitaxel altered the expression of EPCR and thrombomodulin in OAW42 cells with a modest effect on EA.hy926 cells. CONCLUSION: Chemotherapy induced procoagulant activity in HGSOC is associated with an alteration in expression of key members of the aPC pathway. This acquired aPC resistance may explain the procoagulant phenotype associated with ovarian cancer patients undergoing chemotherapy.


Assuntos
Neoplasias Ovarianas , Proteína C , Carboplatina/uso terapêutico , Feminino , Humanos , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico
7.
Cancers (Basel) ; 13(3)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33514073

RESUMO

More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100,000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on expert opinion, retrospective studies, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges through the creation of a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, "Basic and Translational Research on Rare Gynecological Cancer") have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state-of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide.

8.
Gynecol Oncol ; 160(2): 514-519, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33213897

RESUMO

OBJECTIVES: To investigate whether HE4 and CA125 could identify endometrioid adenocarcinoma patients who might most benefit from full staging surgery with lymphadenectomy. METHODS: Sequential patients with a preoperative banked serum and histology of endometrioid adenocarcinoma of endometrium who had undergone surgical staging with lymph node dissection over a 5-year period between 2011 and 2016 were included from a tertiary Gynaecological Cancer Centre, Dublin, Ireland. Preoperative serum HE4 and CA125 were measured using ELISA, with the cut-offs HE4 81 pmol/L and CA125 35 U/ml. Predictive values were estimated using AUC, sensitivity, specificity and odds ratios. RESULTS: 9.5% of the cohort had lymph node metastases. A HE4 cut-off of 81 pmol/L yielded a sensitivity of 78.6% and specificity of 53.4% for predicting lymph node metastases. Sensitivity of CA125 at 35 U/ml was 57% and specificity 91.4%. The AUC was 0.66 (0.52-0.80) for HE4 and 0.74 (0.58-0.91) for CA125. Sensitivity was 92.8% and specificity 51.1% when an elevation of either HE4 or CA125 was included, AUC was 0.72 (0.61-0.83), this combination yielded the highest NPV of 98.6%. Sensitivity was 42.9% and specificity 93.8% if both markers were elevated simultaneously, AUC was 0.68 (0.51-0.86). Preoperative clinical predictors of high-grade preoperative histology and radiology had sensitivities of 21.4% and 41.7%, respectively. Patients with a HE4 above 81 pmol/L had an odds ratio of 4.2 (1.12-15.74), p < 0.05, of lymph node metastases and CA125 had an odds ratio of 14.2 (4.16-48.31), p < 0.001. CONCLUSIONS: Serum HE4 and CA125 improved on existing methods for risk stratification of endometrioid carcinomas and warrant further investigation.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Carcinoma Endometrioide/diagnóstico , Neoplasias do Endométrio/diagnóstico , Metástase Linfática/diagnóstico , Proteínas de Membrana/sangue , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Endométrio/patologia , Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/patologia , Pessoa de Meia-Idade , Gradação de Tumores/estatística & dados numéricos , Estadiamento de Neoplasias/estatística & dados numéricos , Valor Preditivo dos Testes , Período Pré-Operatório , Curva ROC , Valores de Referência , Estudos Retrospectivos , Medição de Risco/métodos , Salpingo-Ooforectomia
9.
Cancer Epidemiol ; 68: 101793, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32841926

RESUMO

BACKGROUND: Human papillomavirus (HPV) is considered the strongest epidemiologic risk factor for cervical cancer. However, it is not a sufficient cause given the high prevalence of transient infections. We examined the relationship between exposure to tobacco smoke, measured using urinary nicotine metabolite concentrations, and p16/Ki-67 co-expression in cervical smears and subsequent risk of developing CIN2+/CIN3+ lesions in HPV positive women. METHODS: This prospective longitudinal study enrolled women presenting to colposcopy with cytological abnormalities LSIL/ASCUS at the National Maternity Hospital, Dublin. Women gave a urine sample which was used to perform the Nicotine Metabolite Assay (Siemens). HPV positive (HC2) cervical smears were stained by immunocytochemistry for p16/Ki-67 (CINtec PLUS, Roche). Two year follow-up data, including histological diagnosis, was collected for each woman. Crude and adjusted odds ratios were calculated using logistic regression to investigate associations between tobacco smoke, p16/Ki-67 positivity and CIN2+/CIN3 + . RESULTS: In total, 275 HPV positive women were included. Women with nicotine metabolite concentrations above 500 ng/mL, indicative of smoking, were classified as smokers. Smokers were at an increased risk of testing positive for p16/Ki-67 (OR 1.678; 1.027-2.740) and CIN2+ and CIN3+ (OR 1.816; 1.107-2.977 and OR 2.453; 1.200-5.013) in compared to non-smokers. In p16/Ki-67 positive women, smoking further increased their risk of CIN2+/CIN3+ (OR 2.290; 1.017-5.159 and OR 3.506 (1.534-8.017). CONCLUSION: HPV positive women exposed to tobacco smoke are at a higher risk of testing positive for p16/Ki-67 co-expression. Risk of high-grade disease is almost doubled in women who are exposed to tobacco smoke.


Assuntos
Neoplasia Intraepitelial Cervical/epidemiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Antígeno Ki-67/metabolismo , Nicotina/urina , Infecções por Papillomavirus/complicações , Poluição por Fumaça de Tabaco/análise , Neoplasias do Colo do Útero/epidemiologia , Adolescente , Adulto , Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/virologia , Colposcopia , Feminino , Humanos , Estudos Longitudinais , Gradação de Tumores , Teste de Papanicolaou , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Gravidez , Estudos Prospectivos , Poluição por Fumaça de Tabaco/efeitos adversos , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem
10.
Res Pract Thromb Haemost ; 4(5): 848-859, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32685894

RESUMO

BACKGROUND: Gynecologic cancers are associated with high rates of venous thromboembolism (VTE), which is exacerbated by pelvic surgery and chemotherapy. OBJECTIVES: The aim of this study was to develop and validate a risk score for VTE in patients with gynecologic cancer and to test the predictive ability of the score following addition of procoagulant biomarker data. PATIENTS AND METHODS: Clinical and laboratory variables were used to develop a risk score for the prediction of VTE in patients with gynecological cancer (n = 616), which was validated in a separate cohort of patients (n = 406). Endogenous thrombin potential and D-dimer levels were determined in a subset (n = 290) of patients and used to produce an extended score in the validation cohort. RESULTS: Multivariable regression analysis identified BMI >30, hemoglobin <11.5 g/dL and chemotherapy as independent predictors of VTE, which formed the Thrombogyn score. Following competing risk regression analysis, subdistribution hazard ratios (SHRs), adjusted for cancer stage, were 8.16 (95% confidence interval [CI], 1.69-43.77) in the high-risk group (score = 2-3) and 4.12 (95% CI, 0.85-20.15) in the intermediate-risk group (score = 1) compared with the low-risk group (score = 0). SHRs for the validation cohort were 6.26 (95% CI, 1.24-31.39) and 3.00 (95% CI, 0.67-13.32), respectively. Cumulative incidence of VTE in the validation cohort high-risk group was 10.34% (95% CI, 6.51-16.41) per women-years compared with 1.06% (95% CI, 0.26-4.26) in the low-risk group. Using the extended Thrombogyn score, adjusted SHRs were 16.83 (95% CI, 4.20-67.37) in the high-risk group with a cumulative incidence of 21.15% (95% CI, 10.32-45.24). External validation of the score is required. CONCLUSIONS: The Thrombogyn score identifies patients with gynecologic cancer at high and low risk of VTE. Addition of biomarker data improves the predictive power of the score.

11.
Breast Cancer Res Treat ; 181(3): 571-580, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378053

RESUMO

PURPOSE: The association between pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC) for breast cancer and Circulating Tumour Cells (CTCs) is not clear. The aim of this study was to assess whether CTC enumeration could be used to predict pathological response to NAC in breast cancer as measured by the Miller-Payne grading system. METHODS: Twenty-six patients were recruited, and blood samples were taken pre- and post-NAC. CTCs were isolated using the ScreenCell device and stained using a modified Giemsa stain. CTCs were enumerated by 2 pathologists and classified as single CTCs, doublets, clusters/microemboli and correlated with the pathological response as measured by the Miller-Payne grading system. χ2 or ANOVA was performed in SPSS 24.0 statistics software for associations. RESULTS: 89% of patients had invasive ductal carcinoma (IDC) and 11% invasive lobular carcinoma (ILC). At baseline 85% of patients had CTCs present, median 7 (0-161) CTCs per 3 ml of whole blood. Post-chemotherapy, 58% had an increase in CTCs. This did not correlate with the Miller-Payne grade of response. No significant association was identified between the number of CTCs and clinical characteristics; however, we did observe a correlation between pre-treatment CTC counts and body mass index, p < 0.05. CONCLUSIONS: Patients with a complete response to NAC still had CTCs present, suggesting enumeration is not sufficient to aid surgery stratification. Additional characterisation and larger studies are needed to further characterise CTCs isolated pre- and post-chemotherapy. Long-term follow-up of these patients will determine the significance of CTCs in NAC breast cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Terapia Neoadjuvante/mortalidade , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Células Neoplásicas Circulantes/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida
12.
PLoS One ; 14(3): e0211538, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30908480

RESUMO

Tumour cell immune evasion is a principal hallmark of successful metastasis. Tumour cells in the vasculature adopt a platelet cloak that efficiently suppresses the innate immune system by directly inhibiting Natural Killer (NK) cells, which normally function to neutralise spreading cancers. Here we describe two novel mechanisms of tumour cell evasion of NK cell anti-tumour functions. The first, an 'immune decoy' mechanism in which platelets induce the release of soluble NKG2D ligands from the tumour cell to mask detection and actively suppress NK cell degranulation and inflammatory cytokine (IFNγ) production, concomitantly. This represents a double-hit to immune clearance of malignant cells during metastasis. The second mechanism, a platelet-derived TGFß-mediated suppression of the CD226/CD96-CD112/CD155 axis, is a novel pathway with poorly understood anti-cancer functions. We have demonstrated that platelets robustly suppress surface expression of CD226 and CD96 on the NK cell surface and their associated ligands on the tumour cell to further enhance NK cell suppression. These highly evolved mechanisms promote successful tumour immune evasion during metastasis and provide a unique opportunity for studying the complexity of cellular interactions in the metastatic cascade and thus novel targets for cancer immunotherapy.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Plaquetas/imunologia , Células Matadoras Naturais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Metástase Neoplásica/imunologia , Evasão Tumoral , Antígenos CD/metabolismo , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade Inata , Interferon gama/metabolismo , Nectinas/metabolismo , Receptores Virais/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
13.
BMC Cancer ; 15: 547, 2015 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-26205780

RESUMO

BACKGROUND: Ovarian cancer is associated with poor long-term survival due to late diagnosis and development of chemoresistance. Tumour hypoxia is associated with many features of tumour aggressiveness including increased cellular proliferation, inhibition of apoptosis, increased invasion and metastasis, and chemoresistance, mostly mediated through hypoxia-inducible factor (HIF)-1α. While HIF-1α has been associated with platinum resistance in a variety of cancers, including ovarian, relatively little is known about the importance of the duration of hypoxia. Similarly, the gene pathways activated in ovarian cancer which cause chemoresistance as a result of hypoxia are poorly understood. This study aimed to firstly investigate the effect of hypoxia duration on resistance to cisplatin in an ovarian cancer chemoresistance cell line model and to identify genes whose expression was associated with hypoxia-induced chemoresistance. METHODS: Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines were exposed to various combinations of hypoxia and/or chemotherapeutic drugs as part of a 'hypoxia matrix' designed to cover clinically relevant scenarios in terms of tumour hypoxia. Response to cisplatin was measured by the MTT assay. RNA was extracted from cells treated as part of the hypoxia matrix and interrogated on Affymetrix Human Gene ST 1.0 arrays. Differential gene expression analysis was performed for cells exposed to hypoxia and/or cisplatin. From this, four potential markers of chemoresistance were selected for evaluation in a cohort of ovarian tumour samples by RT-PCR. RESULTS: Hypoxia increased resistance to cisplatin in A2780 and A2780cis cells. A plethora of genes were differentially expressed in cells exposed to hypoxia and cisplatin which could be associated with chemoresistance. In ovarian tumour samples, we found trends for upregulation of ANGPTL4 in partial responders and down-regulation in non-responders compared with responders to chemotherapy; down-regulation of HER3 in partial and non-responders compared to responders; and down-regulation of HIF-1α in non-responders compared with responders. CONCLUSION: This study has further characterized the relationship between hypoxia and chemoresistance in an ovarian cancer model. We have also identified many potential biomarkers of hypoxia and platinum resistance and provided an initial validation of a subset of these markers in ovarian cancer tissues.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Angiopoietinas/genética , Biomarcadores Tumorais/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Ovarianas/patologia , Receptor ErbB-3/genética
14.
Int J Mol Sci ; 14(1): 2085-103, 2013 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-23340649

RESUMO

Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Neoplasias , Inibidores de Proteases/farmacologia , Linhagem Celular Tumoral , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo
15.
J Ovarian Res ; 5(1): 2, 2012 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-22260314

RESUMO

BACKGROUND: Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease. METHODS: Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples. RESULTS: Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component. CONCLUSION: We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in ovarian disease. Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.

16.
J Ovarian Res ; 2: 19, 2009 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-20015364

RESUMO

BACKGROUND: Tumours with high proportions of differentiated cells are considered to be of a lower grade to those containing high proportions of undifferentiated cells. This property may be linked to the differentiation properties of stem cell-like populations within malignancies. We aim to identify molecular mechanism associated with the generation of tumours with differing grades from malignant stem cell populations with different differentiation potentials. In this study we assessed microRNA (miRNA) regulation in two populations of malignant Embryonal Carcinoma (EC) stem cell, which differentiate (NTera2) or remain undifferentiated (2102Ep) during tumourigenesis, and compared this to miRNA regulation in ovarian serous carcinoma (OSC) patient samples. METHODS: miRNA expression was assessed in NTera2 and 2102Ep cells in the undifferentiated and differentiated states and compared to that of OSC samples using miRNA qPCR. RESULTS: Our analysis reveals a substantial overlap between miRNA regulation in 2102Ep cells and OSC samples in terms of miRNA biosynthesis and expression of mature miRNAs, particularly those of the miR-17/92 family and clustering to chromosomes 14 and 19. In the undifferentiated state 2102Ep cells expressed mature miRNAs at up to 15,000 fold increased levels despite decreased expression of miRNA biosynthesis genes Drosha and Dicer. 2102Ep cells avoid differentiation, which we show is associated with consistent levels of expression of miRNA biosynthesis genes and mature miRNAs while expression of miRNAs clustering to chromosomes 14 and 19 is deemphasised. OSC patient samples displayed decreased expression of miRNA biosynthesis genes, decreased expression of mature miRNAs and prominent clustering to chromosome 14 but not 19. This indicates that miRNA biosynthesis and levels of miRNA expression, particularly from chromosome 14, are tightly regulated both in progenitor cells and in tumour samples. CONCLUSION: miRNA biosynthesis and expression of mature miRNAs, particularly the miR-17/92 family and those clustering to chromosomes 14 and 19, are highly regulated in both progenitor cells and tumour samples. Strikingly, 2102Ep cells are not simply malfunctioning but respond to differentiation specifically, a mechanism that is highly relevant to OSC samples. Our identification and future manipulation of these miRNAs may facilitate generation of lower grade malignancies from these high-grade cells.

17.
Mod Pathol ; 22(2): 197-205, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18677302

RESUMO

MicroRNAs are a group of small non-coding RNAs approximately 22 nucleotides in length. Recent work has shown differential expression of mature microRNAs in human cancers. We characterized the alteration in expression of a select group of microRNAs in primary peritoneal carcinoma relative to matched cases of ovarian serous carcinoma. MicroRNA expression was analysed using semi-quantitative stem-loop RT-PCR on a set of 34 formalin-fixed paraffin-embedded samples. Protein expression of p53 and bcl-2 was quantified in the corresponding tissue microarray. We provide definitive evidence that there is downregulation of a select group of microRNAs in tumours meeting Gynaecological Oncology Group criteria for primary peritoneal carcinoma relative to ovarian serous carcinoma. Specifically, we show decreased p53 expression and downregulation of miR-195 and miR-497 from the microRNA cluster site at chromosome 17p13.1 in primary peritoneal carcinoma relative to ovarian serous carcinoma. miR-195 and miR-497 may have potential roles as tumour-suppressor genes in primary peritoneal tumourigenesis.


Assuntos
Carcinoma/genética , Cromossomos Humanos Par 17 , Regulação Neoplásica da Expressão Gênica , MicroRNAs/análise , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/química , Carcinoma/patologia , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/química , Neoplasias Peritoneais/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/análise
18.
Mod Pathol ; 21(6): 676-84, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18327211

RESUMO

MicroRNAs are a group of small non-coding RNAs approximately 22 nucleotides in length. Recent work has shown differential expression of mature microRNAs in human cancers. Production and function of microRNAs require coordinated processing by proteins of the microRNA machinery. Dicer and Drosha (RNase III endonucleases) are essential components of the microRNA machinery. Recently, the ribosome anti-association factor eIF6 has also been found to have a role in microRNA-mediated post-transcriptional silencing. We characterized the alterations in the expression of genes encoding proteins of microRNA machinery in ovarian serous carcinoma. Protein expression of eIF6 and Dicer was quantified in a tissue microarray of 66 ovarian serous carcinomas. Dicer, Drosha and eIF6 mRNA expression was analysed using quantitative reverse transcription-PCR on an independent set of 50 formalin-fixed, paraffin-embedded ovarian serous carcinoma samples. Expression profiles of eIF6 and Dicer were correlated with clinicopathological and patient survival data. We provide definitive evidence that eIF6 and Dicer are both upregulated in a significant proportion of ovarian serous carcinomas and are associated with specific clinicopathological features, most notably low eIF6 expression being associated with reduced disease-free survival. The status of eIF6 and proteins of the microRNA machinery may help predict toxicity and susceptibility to future interfering RNA-based therapy.


Assuntos
Cistadenocarcinoma Seroso/patologia , Fatores de Iniciação em Eucariotos/biossíntese , Neoplasias Ovarianas/patologia , Ribonuclease III/biossíntese , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/mortalidade , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos
20.
Planta Med ; 71(5): 435-9, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15931582

RESUMO

The aim of this study was to identify genomic aberrations in endometrial cancer cells treated with the phyto-estrogenic compounds tectorigenin, irigenin and apigenin and to compare with those treated with beta-estradiol using array-based comparative genomic hybridisation (array CGH). The microarray contains 287 targets and includes telomeres, microdeletions, oncogenes and tumour suppressor genes and has increased mapping resolution compared to conventional CGH. An endometrial cancer cell line (Ishikawa) was cultured and treated with the phyto-estrogens. Treated cells were examined using the CGH microarray. Over 20 % of the array genes were aberrated in the cells treated with beta-estradiol, tectorigenin and irigenin compared to 3 % in those treated with the same concentration of apigenin. Protein kinase c zeta form, insulin, insulin receptor and protein-tyrosine phosphatase non-receptor-type 1 which are involved in insulin metabolism were aberrated by tectorigenin and irigenin. Apigenin may play a role in the treatment of endometrial cancer and in the treatment of postmenopausal women. Further studies in normal endometrium and primary endometrial cancer cells are needed to elucidate the role of the phyto-estrogens.


Assuntos
Aberrações Cromossômicas , Neoplasias do Endométrio/genética , Iridaceae , Fitoestrógenos/farmacologia , Fitoterapia , Apigenina/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , DNA de Neoplasias/análise , Estradiol/farmacologia , Feminino , Perfilação da Expressão Gênica , Humanos , Isoflavonas/farmacologia , Extratos Vegetais/farmacologia , RNA Mensageiro/análise
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