RESUMO
Bone Morphogenetic Protein 7 (BMP7) is an extracellular signalling protein that belongs to the transforming growth factor-ß (TGF- ß) superfamily. Previous transcriptomic data suggested that BMP7 expression may be disrupted in ovarian carcinoma and may play an important role in the aggressiveness of the disease. However, the protein expression in patient tumours has not been well studied. The current study aimed to assess BMP7 protein expression in a large cohort of ovarian carcinoma patient tumour samples to establish its associations with different clinical endpoints. Ovarian carcinoma tissue samples from 575 patients who underwent surgery for different subtypes of ovarian cancer were used. BMP7 protein expression was analysed by immunohistochemistry using tissue microarray and full face tumour sections. High BMP7 expression is associated with aggressive ovarian cancer clinicopathological variables including advanced FIGO stage, high grade, residual disease and poor overall survival. Elevated cytoplasmic and nuclear BMP7 expression was significantly associated with advanced FIGO stage, high tumour grade, presence of residual tumours and high-grade serous carcinomas (p = 0.001, 0.005, 0.004, <0.001 and p < 0.001, <0.001, 0.002, 0.001 respectively). Increased cytoplasmic and nuclear BMP7 expression was also significantly associated with an adverse overall survival (p = 0.001 and 0.046 respectively). The study highlights the potential of BMP7 as a prognostic tool and as a potential novel target for ovarian cancer therapies to limit disease progression.
Assuntos
Carcinoma , Neoplasias Ovarianas , Humanos , Feminino , Proteína Morfogenética Óssea 7/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Imuno-Histoquímica , Carcinoma/patologia , Fator de Crescimento Transformador beta/metabolismo , Estadiamento de NeoplasiasRESUMO
TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Austrália , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , América do Norte , Variações Dependentes do Observador , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Análise Serial de Tecidos , Reino UnidoRESUMO
Dopamine and cyclic-AMP activated phosphoprotein Mr32kDa (DARPP-32) is a central signalling protein in neurotransmission. Following DARPP-32 phosphorylation by protein kinase A (PKA), DARPP-32 becomes a potent protein phosphatase 1 (PP1) inhibitor. DARPP-32 can itself inhibit PKA following DARPP-32 phosphorylation by cyclin-dependent kinase 5 (Cdk5). Increasing evidence indicates a role for DARPP-32 and its associated signalling pathways in cancer; however, its role in ovarian cancer remains unclear. Using immunohistochemistry, expression of DARPP-32, PP1 and Cdk5 was determined in a large cohort of primary tumours from ovarian cancer patients (n = 428, 445 and 434 respectively) to evaluate associations between clinical outcome and clinicopathological criteria. Low cytoplasmic and nuclear DARPP-32 expression was associated with shorter patient overall survival and progression-free survival (P = .001, .001, .004 and .037 respectively). Low nuclear and cytoplasmic DARPP-32 expression remained significantly associated with overall survival in multivariate Cox regression (P = .045, hazard ratio (HR) = 0.734, 95% confidence interval (CI) = 0.542-0.993 and P = .001, HR = 0.494, 95% CI = 0.325-0.749, respectively). High cytoplasmic and nuclear PP1 expression was associated with shorter patient overall survival and high cytoplasmic PP1 expression with shorter progression-free survival (P = .005, .033, and .037, respectively). High Cdk5 expression was associated with shorter progression-free survival (P = .006). These data suggest a role for DARPP-32 and associated signalling kinases as prognostic markers with clinical utility in ovarian cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Proteína Fosfatase 1/metabolismo , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Taxa de SobrevidaRESUMO
INTRODUCTION: Women with polycystic ovary syndrome have a three-fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein-1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein-1 gene expression with serum lipid profiles. MATERIAL AND METHODS: A cross-sectional study was performed at Nottingham University Hospital, UK. A total of 102 women (polycystic ovary syndrome, endometrial cancer and controls; 34 participants in each group) were recruited. Clinical and biochemical assessments were performed before endometrial biopsies were obtained from all participants. Taqman real-time polymerase chain reaction for endometrial sterol regulatory element binding protein-1 gene and its systemic protein expression were analyzed. RESULTS: The body mass indices of women with polycystic ovary syndrome (29.28 ± 2.91 kg/m2 ) and controls (28.58 ± 2.62 kg/m2 ) were not significantly different. Women with endometrial cancer had a higher mean body mass index (32.22 ± 5.70 kg/m2 ). Sterol regulatory element binding protein-1 gene expression was significantly increased in polycystic ovary syndrome and endometrial cancer endometrium compared with controls (p < 0.0001). Sterol regulatory element binding protein-1 gene expression was positively correlated with body mass index (r = 0.017, p = 0.921) and waist-hip ratio (r = 0.023, p = 0.544) in polycystic ovary syndrome, but this was not statistically significant. Similarly, statistically insignificant positive correlations were found between endometrial sterol regulatory element binding protein-1 gene expression and body mass index in endometrial cancer (r = 0.643, p = 0.06) and waist-hip ratio (r = 0.096, p = 0.073). Sterol regulatory element binding protein-1 gene expression was significantly positively correlated with triglyceride in both polycystic ovary syndrome and endometrial cancer (p = 0.028 and p = 0.027, respectively). Quantitative serum sterol regulatory element binding protein-1 gene correlated with endometrial gene expression (p < 0.05). CONCLUSIONS: Sterol regulatory element binding protein-1 gene expression is significantly increased in the endometrium of women with polycystic ovary syndrome and women with endometrial cancer compared with controls and positively correlates with serum triglyceride in both polycystic ovary syndrome and endometrial cancer.
Assuntos
Neoplasias do Endométrio/genética , Síndrome do Ovário Policístico/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto , Estudos de Casos e Controles , Estudos Transversais , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/metabolismo , Endométrio/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoAssuntos
Dor Abdominal/etiologia , Tubas Uterinas/patologia , Arterite de Células Gigantes/complicações , Redução de Peso , Dor Abdominal/diagnóstico por imagem , Dor Abdominal/patologia , Idoso , Feminino , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Células Gigantes/patologia , Humanos , Tomografia por Emissão de PósitronsRESUMO
Current data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis. Measures to improve insulin resistance could therefore play a role in reducing the risk of EC in women with PCOS. Metformin is an insulin sensitising agent which is safe, widely available and currently licensed for type-2 diabetes. It has been clearly shown in both animal and human studies that metformin is of value in reversing endometrial hyperplasia. Metformin may therefore prevent EC in PCOS. This article reviews the use of metformin in reducing EC risk in PCOS and makes a case for future research on this topic.
Assuntos
Neoplasias do Endométrio/prevenção & controle , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Hiperplasia Endometrial/complicações , Feminino , Humanos , Síndrome do Ovário Policístico/complicações , Progesterona/uso terapêutico , RiscoRESUMO
BACKGROUND: Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS: 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS: 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION: PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING: Carraresi Foundation and others.
Assuntos
Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma Mucinoso/mortalidade , Carcinoma Endometrioide/mortalidade , Cistadenocarcinoma Seroso/mortalidade , Neoplasias Ovarianas/mortalidade , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Estudos de Casos e Controles , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Prognóstico , Taxa de Sobrevida , Análise Serial de TecidosRESUMO
AIMS: The aim of this study was to assess the expression of angiogenic chemokines (CXCR4/CXCL12) and the vascular endothelial growth factor in ovarian clear cell carcinoma, comparing levels against those in ovarian high-grade serous carcinoma. MATERIAL AND METHODS: Tissue microarray samples from 136 cases of epithelial ovarian carcinoma (108 high-grade serous carcinoma and 28 clear cell carcinoma) were reviewed with World Health Organization histological criteria strictly applied to categorize cases according to histological subtype. Only cases without prior exposure to chemotherapy were included. Sections were stained with vascular endothelial growth factor, CXCR4, CXCL12 and assessed using conventional histological scoring (H-scoring). RESULTS: Patients with clear cell carcinoma presented at an early stage of the disease (74% stage 1 and 2) and had a significantly better progression-free (P=0.042) survival than those with high-grade serous carcinoma. Low expression profile of the tested markers was seen in cases of clear cell carcinoma contrary to that seen in high-grade serous carcinoma. CONCLUSION: The current study reports, for the first time, the difference in expression of a set of angiogeneic prognostic markers between clear cell carcinoma and high-grade serous carcinoma, offering a possible explanation for the apparent chemotherapy resistance. These results are relevant for the design of future clinical studies of first-line treatment for patients with ovarian clear cell carcinoma.
Assuntos
Adenocarcinoma de Células Claras/metabolismo , Quimiocina CXCL12/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Estudos RetrospectivosRESUMO
Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Assuntos
Carcinoma Endometrioide , Neoplasias Ovarianas , Humanos , Feminino , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário , Carcinoma Endometrioide/metabolismoRESUMO
Ovarian cancer is routinely treated with surgery and platinum-based chemotherapy. Resistance is a major obstacle in the efficacy of this chemotherapy regimen and the ability to identify those patients at risk of developing resistance is of considerable clinical importance. The expression of calpain-1, calpain-2 and calpastatin were determined using standard immunohistochemistry on a tissue microarray of 154 primary ovarian carcinomas from patients subsequently treated with platinum-based adjuvant chemotherapy. High levels of calpain-2 expression was significantly associated with platinum resistant tumours (P = 0.031). Furthermore, high expression of calpain-2 was significantly associated with progression-free (P = 0.049) and overall survival (P = 0.006) in this cohort. The association between calpain-2 expression and overall survival remained significant in multivariate analysis accounting for tumour grade, stage, optimal debulking and platinum sensitivity (hazard ratio = 2.174; 95% confidence interval = 1.144-4.130; P = 0.018). The results suggest that determining calpain-2 expression in ovarian carcinomas may allow prognostic stratification of patients treated with surgery and platinum-based chemotherapy. The findings of this study warrant validation in a larger clinical cohort.
Assuntos
Calpaína/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Compostos de Platina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Calpaína/genética , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Seguimentos , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
INTRODUCTION: The PlasmaJet (PJ) coagulator uses neutral pure argon plasma to achieve coagulation. Helica thermal coagulator (HTC) achieves coagulation with helium gas. HTC is currently used in the treatment of mild to moderate endometriosis. OBJECTIVE: The objective of this study was to compare the tissue damage caused by PJ to the HTC in the uterus, ovary and fallopian tube. Our hypothesis was that PJ is a safe technology to use and the tissue damage caused is comparable to HTC. METHODS: Fifteen subjects undergoing hysterectomy with or without salpingo-oophorectomy were prospectively recruited for in vivo assessment of the two instruments. Both instruments were used on a small area of uterus, ovary and fallopian tube following the ligation of uterine artery pedicle. PJ was used at a power setting of 20 % for duration of 5 s at a clinically acceptable distance of 0.5 to 1 cm from the tissue surface. HTC was used at a widely accepted low power setting in the treatment of endometriosis for a similar duration and distance. Tissue damage was evaluated histologically. ANOVA was used to compare the mean differences. RESULTS: Data were normally distributed. Five subjects had a subtotal hysterectomy and 10 had hysterectomy with salpingo-oophorectomy. A total of 15 uteri, 10 ovaries and 10 fallopian tubes were histologically analysed for the tissue effect of PJ and HTC. There was no significant difference in the mean ± SD depth of tissue damage seen between PJ and HTC in the uterus (0.63 ± 0.19 vs. 0.68 ± 0.18; P = 0.481), ovary (0.61 ± 0.14 vs. 0.67 ± 0.15; P = 0.420) and fallopian tube (0.63 ± 0.18 vs. 0.60 ± 0.13; P = 0.688). A significantly lesser lateral spread of tissue damage (width) was seen with PJ than HTC in all three tissue types (uterus: 4.66 ± 0.91 vs. 7.67 ± 1.21, P < 0.001; ovary: 4.05 ± 0.61 vs. 5.90 ± 0.95, P < 0.001; fallopian tube: 4.50 ± 0.77 vs. 6.00 ± 1.28, P = 0.034). CONCLUSION: The depth of tissue damage caused by PJ at 20 % power is comparable to that with HTC on gynaecological tissues. The lateral spread (width of tissue damage) is however lesser with PJ than with HTC.
Assuntos
Eletrocoagulação/instrumentação , Histerectomia/instrumentação , Adulto , Eletrocoagulação/efeitos adversos , Endometriose/cirurgia , Tubas Uterinas/lesões , Tubas Uterinas/cirurgia , Feminino , Humanos , Histerectomia/efeitos adversos , Histerectomia/métodos , Pessoa de Meia-Idade , Ovariectomia/instrumentação , Ovariectomia/métodos , Ovário/lesões , Ovário/cirurgia , Útero/lesões , Útero/cirurgiaRESUMO
Actinomyces israelii are gram-positive filamentous bacteria forming yellow sulfur granules. They are the most well known complication of intrauterine contraceptive devices (IUCD). Healthcare staff dealing with reporting cervical smears should be aware of pseudoactinomyces entity in a cervical smears and biopsies as it may raise a false alarm to the clinician and may lead to unnecessary removal of IUCD and/or medical treatment.
Assuntos
Actinomyces/isolamento & purificação , Actinomicose/microbiologia , Muco do Colo Uterino/microbiologia , Colo do Útero/microbiologia , Actinomicose/diagnóstico , Adulto , Biópsia , Colo do Útero/ultraestrutura , Feminino , Humanos , Dispositivos Intrauterinos/microbiologia , Esfregaço Vaginal , Displasia do Colo do Útero/patologiaRESUMO
PURPOSE: Angiogenesis has a vital role in tumor growth and metastasis, and vascular endothelial growth factor (VEGF) represents a potent cytokine in this process. However, the influence of VEGF in ovarian cancer remains controversial. Interest has focused on the use of antiangiogenic drugs in ovarian cancer. This study aims to establish the pattern of expression and effect on prognosis of VEGF in a large population of ovarian cancer patients and to potentially identify a cohort in whom antiangiogenic therapy is appropriate. EXPERIMENTAL DESIGN: Using a tissue microarray of 339 primary ovarian cancers, the expression of VEGF was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors and survival was studied. RESULTS: Tumors expressing high levels of VEGF had significantly poorer survival (P = 0.04). Factors shown to predict prognosis independently of each other were age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. VEGF was independently predictive of prognosis on multivariate analysis (P = 0.02). There was no correlation between VEGF and any clinicopathologic variable. High expression of VEGF was seen in only 7% of the tumors, suggesting that the role of antiangiogenic drugs may be limited to a small subset of patients. CONCLUSION: High VEGF expression occurs in a small proportion of ovarian cancers, and this independently predicts poor prognosis. The small percentage of tumors with high levels of VEGF activity suggests that the role of bevacizumab may potentially be limited to a few patients; these patients could be targeted by molecular profiling.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Ovarianas/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Prognóstico , Análise Serial de TecidosRESUMO
PURPOSE: We have previously reported on the prognostic importance of the calpain family of proteins in ovarian cancer, especially calpain-2. Spleen tyrosine kinase (Syk) phosphorylates a variety of cytoskeletal proteins with studies suggesting potential interactions between Syk and conventional calpains. Microtubule-associated protein 4 (MAP4) has been reported to be regulated by Syk. METHODS: The current study assessed Syk and MAP4 protein expression, by immunohistochemistry on a tissue microarray comprised of cores from primary ovarian carcinomas (n = 575), to evaluate associations with patient clinical outcomes and other clinicopathological factors and sought to determine whether there were any correlations between the expression of Syk, MAP4 and the calpain system. RESULTS: MAP4 expression was significantly associated with ovarian cancer histological subtype (P < 0.001), stage (P = 0.001), grade (P < 0.001) and residual tumour (P = 0.005). Despite this finding, we found no significant association existing between MAP4 expression and overall survival. Syk expression was also found significantly associated with histological subtype (P < 0.001). Syk seems to play a contradictory role with respect to tumour progression: low cytoplasmic Syk expression was significantly associated with low stage (P = 0.013), and low nuclear Syk expression with chemo-resistance in patients treated with taxane-containing therapy (P = 0.006). Interestingly, despite the lack of association in the whole cohort, high nuclear Syk expression was significantly associated with better overall survival in certain subgroups (P = 0.001). CONCLUSIONS: The current study indicates a lack of correlation between calpain-2 expression and Syk and MAP4. Syk, MAP4 and calpain-1 appeared to significantly correlate with each other in the whole cohort, with calpain-1 being more highly associated with MAP4 and Syk in mucinous carcinomas. Overall, the current results suggest that Syk, MAP4, and calpain-1 expression are correlated with each other and these proteins may be involved in early stages of tumour spread.
Assuntos
Proteínas Associadas aos Microtúbulos/biossíntese , Neoplasias Ovarianas/metabolismo , Quinase Syk/biossíntese , Calpaína/biossíntese , Citoplasma/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/patologia , Análise Serial de TecidosRESUMO
PURPOSE: Expression of members of the calpain system are associated with clinical outcome of patients with, amongst others, breast and ovarian cancers, with calpain-2 expression in ovarian cancer being implicated in chemo-resistance and survival. This study aimed, using a large patient cohort and in vitro models, to verify its importance and further investigate the role in ovarian cancer chemoresponse. METHODS: Calpain-1, calpain-2, calpain-4 and calpastatin expression were evaluated in primary ovarian carcinomas (n = 575) by immunohistochemistry. Protein expression was assessed, via western blotting, in five ovarian cancer cell lines with various sensitivities towards cisplatin/carboplatin. In vitro calpain activity was inhibited by calpeptin treatment to assess changes in platinum sensitivity by proliferation assay, with expression of genes associated with epithelial-mesenchymal transition being examined by RT2 Profiler™ PCR Array. RESULTS: The current study confirmed previous data that high calpain-2 expression is associated with poor overall survival (P = 0.026) and that calpain-1 was not associated with overall survival or progression-free survival. Low expression of calpastatin (P = 0.010) and calpain-4 (P = 0.003) were also associated with adverse survival. Such prognostic associations do not seem to be linked with altered tumour sensitivity towards platinum-based chemotherapy. Interestingly, low calpain-1 expression was more frequent in patients with confined tumours (stage 1) (χ2 = 11.310, df = 1, P = 0.001). Calpain and calpastatin expression varied among ovarian cancer cell lines yet their expression levels were similar between chemo-sensitive cells and resistant counterparts. Moreover, calpeptin treatment did not alter cellular response to platinum-based chemotherapy or epithelial-mesenchymal transition-related gene expression. CONCLUSIONS: The conventional calpains and calpastatin have been confirmed to play an important role in ovarian cancer; however, the precise mechanisms whereby they exert effects remain to be elucidated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Calpaína/metabolismo , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Proliferação de Células , Estudos de Coortes , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Transição Epitelial-Mesenquimal , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
PURPOSE: Despite improvements in cancer treatment, the prognosis of ovarian cancer remains low and imperfectly predicted by traditional pathologic criteria. Biomarkers that predict prognosis independently of such criteria shed light on important molecular variations, aiding in the development and targeting of novel therapies. Previous work has shown human leukocyte antigen (HLA) class I antigen expression to be independently predictive of prognosis in colorectal and breast cancer. We investigated the prognostic potential of HLA class I antigen expression by studying a large series of ovarian cancers. EXPERIMENTAL DESIGN: A tissue microarray of 339 ovarian cancer cases linked to prospectively recorded clinicopathologic and follow-up data was constructed. This was stained following a standard immunohistochemical protocol for HLA class I heavy chain (HC-10) and beta(2)-microglobulin (beta(2)-m). HLA class I antigen expression was compared with clinicopathologic factors and overall disease-specific survival using the Pearson chi(2) test, Kaplan-Meier curves, and the log-rank test. Cox regression was used to test for the independence and magnitude of effects. RESULTS: There were no univariate correlations between HLA class I antigen expression and clinicopathologic factors. Deviation from an HC-10(+)/beta(2)-m(+) phenotype correlated with reduced survival in univariate analysis (log-rank, 5.69; P = 0.017); a retained HC-10(+)/beta(2)-m(+) phenotype predicted improved prognosis independently of age, stage, level of cytoreduction, and chemotherapy usage on multivariate analysis (hazard ratio, 0.587; 95% confidence interval, 0.442-0.781; P < 0.001). CONCLUSIONS: HLA class I antigen expression is an independent prognostic marker in ovarian cancer, its loss correlating with a poor prognostic outcome.
Assuntos
Biomarcadores Tumorais/análise , Expressão Gênica , Antígenos de Histocompatibilidade Classe I/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adulto , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Análise Serial de TecidosRESUMO
PURPOSE: There is evidence that IFN gamma plays an important role in ovarian cancer development. IFN gamma produces numerous antitumor effects and it may be evasion of these effects which allows tumor progression. We postulate that genetic instability in tumor cells may lead to modulation of expression of the IFN gamma receptor, thus leading to altered tumor biology and patient prognosis. This hypothesis would support the theory of immunoediting in ovarian cancer. EXPERIMENTAL DESIGN: Using tissue microarray technology of 339 primary ovarian cancers, the expression of IFN gamma receptor was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors was studied. RESULTS: Tumors expressing high levels of IFN gamma receptor had significantly improved survival (P=0.017) compared with tumors expressing low levels of the receptor; this was also seen with complete receptor loss (P=0.014). Factors shown to predict prognosis independently of each other were the following: age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. The level of IFN gamma receptor expression and complete receptor loss were independently predictive of prognosis on multivariate analysis. There was no correlation between receptor status and any of the standard clinicopathologic variables. CONCLUSIONS: Loss of IFN gamma receptor independently predicts poor prognosis in ovarian cancer. Loss of receptor expression may be responsible for the limited success in the therapeutic use of IFN gamma in ovarian cancer trials and highlights a subgroup of high expressing IFN gamma receptor tumors which are more likely to be susceptible to such treatments.
Assuntos
Neoplasias Ovarianas/genética , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Análise de Sobrevida , Receptor de Interferon gamaRESUMO
High-mobility group protein B1 (HMGB1) has been implicated in numerous tumour types where expression regulates tumour cell growth and survival. We hypothesised that high HMGB1 expression in ovarian tumours would predict poor patient survival. Using tissue microarrays of primary ovarian cancers combined with a comprehensive database of clinicopathological variables, the expression of HMGB1 was assessed by immunohistochemistry in two independent cohorts (n=194 and n=360) using a monoclonal antibody specific for HMGB1. Kaplan-Meier analysis showed an association of HMGB1 expression with progression free survival in the primary cohort (p=0.023). In the validation cohort, expression was associated with overall survival (p=0.002). Low expression of HMGB1 was protective and in a multivariate model HMGB1 expression was shown to be an independent predictor of poor survival in ovarian cancer (p=0.006). The role of HMGB1 in cancer is complex. As high levels of HMGB1 expression are likely to render ovarian cancer cells resistant to chemotherapy, therapies targeting the HMGB1 axis may be appropriate in the treatment of ovarian cancer patients.
RESUMO
BACKGROUND: Endometrial cancer (EC) is the most common gynaecological cancer amongst women in the UK. Although previous studies have found that women with polycystic ovary syndrome (PCOS) have at least a three-fold increase in endometrial cancer (EC) risk compared to women without PCOS, the precise molecular mechanisms which link between PCOS and EC remain unclear. It has been suggested that insulin resistance may contribute to the increased risk of EC in PCOS. The specific expression of genes related to the insulin-signalling pathway including the IGF system in the endometrium of women with PCOS has however never been measured and compared to that in women with EC without PCOS and control women without EC or PCOS. . OBJECTIVES: To test the hypothesis that insulin signalling plays a key role in the development of EC in women with PCOS by measuring and comparing the expression of three key genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in endometrial tissue obtained from three groups of women; PCOS without EC, women with EC without PCOS and non-PCOS women without EC (controls). We also aimed to determine the correlation between the gene expressions to various clinical variables among participants. METHODS: This was a cross-sectional study of 102 women in 3 groups (PCOS, EC and controls) at a University teaching hospital in the United Kingdom. Clinical assessment (blood pressure, body mass index (BMI) and waist-hip-circumference ratio), venepuntures (fasting blood sugar, insulin, lipid profile, hormones) and endometrial tissue biopsies were taken in all participants. Endometrial tissue RNA extraction was performed before real time polymerase-chain-reaction for the genes of interest (IGF1, IGFBP1 and PTEN) was carried out. To compare the baseline characteristics of the study population, One-Way-ANOVA test or the Independent t-test was used. For variables that were not normally distributed, the Spearman correlation test was used to calculate the r value. A "p" value of <0.05 was considered statistically significant. RESULTS: IGF1, IGFBP1 and PTEN gene expression were significantly up-regulated in the endometrium of PCOS and EC women compared to controls. However there was no significant difference in the expression of these genes in PCOS compared to EC endometrium. The BMI of women with PCOS and controls, were not significantly different (29.28 (± 2.91) vs 28.58 (± 2.62) kg/m(2)) respectively, women with EC however had a higher mean BMI (32.22 (± 5.70) kg/m(2)). PCOS women were younger (31.8 (± 5.97) years) than women with EC (63.44 (± 10.07) years) and controls (43.68 (± 13.12) years). The changes in gene expression were independent of BMI, waist hip ratio, estradiol and androgen levels. Protein validation test in the serum samples in the three groups were consistent with the gene findings. CONCLUSION: Women with PCOS and EC have an increased endometrial expression of genes (IGF1, IGFBP1 and PTEN) involved in the insulin signalling pathway compared with control women. This may explain the increased risk of EC in PCOS women. This study provides a strong basis for clinical trials aiming to prevent EC in women with PCOS by investigating drugs targeting the insulin signalling pathway. This panel of genes may also serve as clinically useful early biomarkers which predict which women with PCOS will go on to develop EC.