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1.
Anticancer Res ; 39(10): 5505-5513, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570444

RESUMO

BACKGROUND/AIM: The potential of the DNA mismatch repair (MMR) system as a prognostic predictor has been evaluated in several cancer types. However, associations between MMR and the prognostic factors of ovarian cancer are poorly understood. PATIENTS AND METHODS: MLH1 expression was evaluated by immunohistochemistry in patients with advanced serous ovarian cancer treated with platinum- and taxane-based chemotherapy. Associations between MLH1 expression and clinicopathological factors as well as claudin-4 expression were examined. RESULTS: Low MLH1 expression was significantly associated with increased progression-free and overall survival, and a normalisation of CA125 levels after chemotherapy. Additionally, low claudin-4 expression was more frequently found among the group with low MLH1 expression. CONCLUSION: Low MLH1 expression was associated with improved prognosis and is a possible predictor of the chemosensitivity of ovarian cancer. Claudin-4 might be involved in the molecular mechanisms underlying how MLH1 influences survival and chemosensitivity in patients with ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteína 1 Homóloga a MutL/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Taxoides/farmacologia , Idoso , Antígeno Ca-125/metabolismo , Claudina-4/metabolismo , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão
2.
Ann Agric Environ Med ; 26(3): 415-419, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31559796

RESUMO

INTRODUCTION AND OBJECTIVE: Peroxiredoxin-1 (PRDX-1) belongs to a family of antioxidant enzymes and has proved to be a versatile molecule regulating cell growth, differentiation and apoptosis. PRDX1-regulated signaling pathways play an important role in the progression and metastasis of human tumours, especially in breast, esophageal and lung cancers. The aim of the study was to evaluate the expression of PRDX-1 in ovarian cancer tissues, and to test the clinical value of PRDX-1 as a prognostic factor in this malignancy. MATERIAL AND METHODS: PRDX-1 expression was assessed by automated immunohistochemistry in tumours taken from 55 patients with ovarian cancer during primary surgery. Specimen were formalin-fixed and preserved in paraffin-embedded blocks. The results were correlated with clinicopathological data. RESULTS: A high expression of PRDX-1 was observed in 20% of cases, and was associated with worse compliance to chemotherapy protocol (P<0.002), worse response to chemotherapy (P<0.04), and higher levels of CA 125 after the 1st line treatment (P<0.004). PRDX-1 positive subjects had a significantly lower 5-year disease-free survival (9.1% vs. 42.6%, P<0.01) and a lower 5-year overall survival (9.1% vs. 56.7%; P<0.002). Multivariate analysis showed that a high expression of PRDX-1 is an independent prognostic factor of poor, overall survival (P<0.002) and a disease-free survival (P<0.01). CONCLUSIONS: Results of the study show that PRDX-1 expression in tumour tissues can be another biomarker of prognosis in patients with ovarian cancer.


Assuntos
Neoplasias Ovarianas/diagnóstico , Peroxirredoxinas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Peroxirredoxinas/genética , Prognóstico
3.
J Cancer Res Clin Oncol ; 145(10): 2519-2527, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485769

RESUMO

PURPOSE: Prostaglandin-mediated inflammatory reactions play a major role in different cancers. Recently, it has been observed that prostaglandin E2-receptor 3 (EP3) might be an independent prognostic factor for overall survival in cervical and endometrial cancer. The role of EP3 expression in ovarian cancer is currently unknown. METHODS: EP3 expression was analyzed by immunohistochemistry in 156 patient samples using the IR-scoring system. Expression levels were correlated with clinical and pathological parameters and with overall survival (OS) to assess for prognostic relevance. Data analysis was performed using Spearman's correlations, Kruskal-Wallis test and Kaplan-Meier estimates. RESULTS: EP3 expression was significantly higher in clear-cell carcinoma (p < 0.001) compared to the other histological subtypes. No further correlations with clinical parameters could be found. EP3 expression correlated significantly with FSH-receptor expression (p < 0.001), galectin-1 expression in the tumor (p = 0.012) and with cytoplasmatic TA-MUC1 expression (p = 0.001). None of these parameters showed significant correlation with OS. In the TA-MUC1 negative subgroup, EP3 negative patients showed significantly longer OS (median OS: 102 months vs. 34 months in EP3 positive patients, p = 0.035), while EP3 did not appear to have prognostic relevance in the TA-MUC1-positive subgroup. CONCLUSION: The potential prognostic relevance of EP3 expression for OS in TA-MUC1 negative patients might reflect an interplay between the COX and the MUC1 pathway, as it has been shown that MUC1 could induce COX2 expression. Our findings support the importance of the prostanoid signaling in TA-MUC1 negative ovarian cancer; however, future studies are necessary to characterize specific pathways and possible interactions.


Assuntos
Mucina-1/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Biomarcadores Tumorais , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Análise de Sobrevida
5.
Cancer Sci ; 110(10): 3204-3214, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385416

RESUMO

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV-3. Microarray and gene profiling analyses indicated that autophagy-related genes were enriched in selected malignant sublines. Detection of LC3-II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high-density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy-related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti-autophagy cancer drugs.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Perfilação da Expressão Gênica/métodos , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Proteínas de Ligação a RNA/genética , Animais , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Camundongos , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Medicina de Precisão , Prognóstico , Microambiente Tumoral
6.
J Cancer Res Clin Oncol ; 145(9): 2251-2259, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385026

RESUMO

PURPOSE: Fibroblast Growth Factor Receptor 4 (FGFR4) was proposed to hold prognostic significance in high-grade serous ovarian carcinoma (HGSOC). However, information on this deriving from large, representative patient panels is still missing, though such data would be indispensable to validate suitability of FGFR4 as prognostic marker or even pharmacological target. METHODS: 1063 ovarian cancer cases were included in this study. Immunohistochemistry (IHC) was performed using two different anti-FGFR4 specific antibodies (HPA027273, sc-124) on an automated staining system. IHC data of both FGFR4 antibodies were available from 995 cases. FGFR4 immunostaining was correlated to prognostic factors including survival using uni- and multivariate proportional hazard models. RESULTS: FGFR4 was positively associated with advanced FIGO stage, high grade and presence of residual disease. When progression free (PFS) of FGFR4 negative vs. positive patients was compared, patients scored as FGFR4 positive had significantly shortened PFS as compared to those that stained negative. All associations of FGFR4 and shortened PFS were lost during multivariate testing. No significant associations were found in terms of OS. CONCLUSIONS: We were not able to confirm FGFR4 as an independent negative prognosticator as described before. However, FGFR4 was highly prevalent in those cases harboring residual disease after debulking surgery. Since especially patients that could only be debulked sub-optimally may benefit from targeted adjuvant treatment, tyrosine kinase inhibitors targeting FGFRs might turn out to be an interesting future treatment option.


Assuntos
Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/cirurgia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/cirurgia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasia Residual , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Análise Serial de Tecidos , Resultado do Tratamento
7.
Life Sci ; 233: 116709, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369760

RESUMO

BACKGROUND: Cisplatin resistance has been found to contribute to the failure of ovarian carcinoma treatment. Oridonin is a natural en-kaurane tetracyclic diterpenoid compound discovered in Rabdosia rubescene (Henmsl.) Hara. Herein, we tested whether oridonin could exert chemo-sensitization activity on cisplatin-resistant ovarian carcinoma cells. METHODS: Firstly, A2780CP cells and SKOV3/DDP cells were exposed to cisplatin and/or oridonin treatment. Cell counting kit-8 (CCK-8) kit and Dead Cell Apoptosis Kit with Annexin V-FITC and PI were carried out to test cell viability and apoptosis, respectively. Then, pBeclin-1 was transfected to overexpress Beclin-1. 3-Methyladenine (3-MA) acted as autophagy inhibitor, while rapamycin acted as autophagy activator. Finally, the influence of cisplatin and/or oridonin treatment on human normal ovarian epithelial IOSE 364 cell viability and apoptosis were also detected. RESULTS: Oridonin incubation notably elevated the cisplatin-caused reduction of A2780CP and SKOV3/DDP cell viabilities and enhancement of cell apoptosis. Cisplatin-caused A2780CP and SKOV3/DDP cell autophagy was dramatically inhibited by oridonin. Overexpression of Beclin-1 mitigated the influence of oridonin on cisplatin-caused A2780CP and SKOV3/DDP cell autophagy. Inhibition of cell autophagy by 3-MA promoted the oridonin + cisplatin-caused A2780CP and SKOV3/DDP cell apoptosis, while activation of cell autophagy by rapamycin had opposite effects. Oridonin and cisplatin co-treatment had no significant effects on IOSE 364 cell viability and apoptosis. CONCLUSION: The chemo-sensitization activity of oridonin on cisplatin-resistant ovarian carcinoma cells was verified in this study. Oridonin elevated sensitivity of ovarian carcinoma cells to cisplatin via suppressing cisplatin-mediated autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cisplatino/farmacologia , Diterpenos de Caurano/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Neoplasias Ovarianas/patologia , Antineoplásicos/farmacologia , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
8.
Life Sci ; 233: 116715, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376371

RESUMO

AIMS: PDZ and LIM domain protein 4 (PDLIM4) is frequently repressed in cancer tissues. However, the expression and role of PDLIM4 in ovarian cancer has not been addressed. MAIN METHODS: In this study, we examined the expression and prognostic significance of PDLIM4 in ovarian cancer. The function of PDLIM4 in ovarian cancer cell growth, invasion, and tumorigenesis was further explored. KEY FINDINGS: PDLIM4 is downregulated in ovarian cancer compared to adjacent normal ovarian tissues. Downregulation of PDLIM4 is correlated with advanced tumor stage and lymph node metastasis. Low PDLIM4 expression is significantly associated with shorter overall survival in patients with ovarian cancer (P = 0.0136). Biologically, PDLIM4 overexpression suppresses the proliferation, colony formation, migration, and invasion of both CAOV3 and SKOV3 ovarian cancer cells, compared to empty vector-transfected cells. Consistently, in vivo data show that PDLIM4 overexpression inhibits the growth of SKOV3 xenograft tumors. Mechanistic investigation reveals that overexpression of PDLIM4 blocks the phosphorylation of STAT3 and represses STAT3-dependent transcriptional activation. Moreover, ectopic expression of PDLIM4 downregulates the expression of CCND1 and MMP9 in ovarian cancer cells. Rescue experiments demonstrate that overexpression of constitutively active STAT3 reverses PDLIM4-induced anticancer effects on ovarian cancer cells. SIGNIFICANCE: Overall, PDLIM4 downregulation is associated with aggressive tumor features and poor prognosis in ovarian cancer patients. PDLIM4 suppresses ovarian cancer cell growth and invasion by inhibiting STAT3 signaling. This study provides a potential therapeutic target for ovarian cancer.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM/metabolismo , Neoplasias Ovarianas/patologia , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Proteínas com Domínio LIM/genética , Metástase Linfática , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fosforilação , Prognóstico , Fator de Transcrição STAT3/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 39(7): 3803-3808, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262907

RESUMO

BACKGROUND: Platinum-based therapy represents the main pharmacological treatment for ovarian carcinoma. Since molecular targeting of receptor tyrosine kinases (RTK) affects factors that may modulate drug response, the aim of this study was to examine whether downstream targets of AXL RTK could be exploited to improve cell response to cisplatin. MATERIALS AND METHODS: Inhibitors of p38 (SB203580) and of signal transducer and activator of transcription 3 (stattic) were employed in combination with cisplatin in ovarian carcinoma cell lines. Apoptosis assay and western blot analysis were performed to evaluate cell response after treatment. RESULTS: SB203580 produced a synergistic effect in combination with cisplatin in cisplatin-resistant IGROV-1/Pt1 cells. In addition, a favorable drug interaction was observed in A2780 cells when pre-incubated with cisplatin prior to stattic. The analysis of cell response after combined treatment showed down-regulation of the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). CONCLUSION: Our results support the notion that downstream targets of AXL in ovarian carcinoma cells can be exploited to increase cisplatin activity in ovarian carcinoma models.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Imidazóis/farmacologia , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3
11.
DNA Cell Biol ; 38(7): 718-724, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188023

RESUMO

Human lung cancer cell lines A549 and A549/DDP, and ovarian cancer cell lines SKOV3 and SKOV3/DDP were subjected to thioridazine (Thio), cisplatin, or the combination; A549/DDP and SKOV3/DDP were the cisplatin-resistant sublines. Cell viability, apoptosis, and cell cycle were detected; the mitochondrial membrane potential and proteins related to mitochondrial apoptosis were determined. Thio induced cell death, and the combination of Thio and cisplatin led to the highest percentage of dead cells in four cells lines. Thio and the combined modality led to cell apoptosis by inducing G0/G1 arrest. The collapse of mitochondrial membrane potential, activation of caspase 9, upregulation of Bax protein, and downregulation of Bcl-2 protein demonstrated that apoptosis was mitochondria dependent. These data indicated that Thio could be used to modulate cisplatin-based chemotherapeutic regimen in lung and ovary cancers.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/metabolismo , Neoplasias Ovarianas/metabolismo , Tioridazina/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos
13.
Braz J Med Biol Res ; 52(7): e8381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31241714

RESUMO

Experiments were conducted to determine if the follicle-stimulating hormone (FSH) receptor binding inhibitor (FRBI) impacts the expression levels of AT-rich interactive domain-containing protein 1A (ARID1A) and phosphatase and tensin homolog (PTEN) in ovaries and blood, as well as expressions of follicle-stimulating hormone cognate receptor (FSHR) gene and proteins. Mice in FRBI-10, FRBI-20, FRBI-30, and FRBI-40 groups were intramuscularly injected with 10, 20, 30, and 40 mg FRBI/kg, respectively, for five consecutive days. Western blotting and qRT-PCR were utilized to determine expression levels of ARID1A and PTEN proteins and mRNAs. Serum ARID1A and PTEN concentrations of the FRBI-40 group were higher than the control group (CG) and FSH group (P<0.05). FSHR mRNA levels of FRBI-20, FRBI-30, and FRBI-40 groups were lower than that of CG and FSH groups on day 15 (P<0.05 or P<0.01). Expression levels of FSHR proteins of FRBI-30 and FRBI-40 groups were lower than those of CG and FSH groups (P<0.05). Levels of ARID1A and PTEN proteins of the FRBI-30 group were greater than CG on days 20 and 30 (P<0.05). FRBI doses had significant positive correlations to levels of ARID1A and PTEN proteins. Additionally, ARID1A and PTEN had negative correlations to FSHR mRNAs and proteins. A high dose of FRBI could promote the expression levels of ARID1A and PTEN proteins in ovarian tissues. FRBI increased serum concentrations of ARID1A and PTEN. However, FRBI depressed expression levels of FSHR mRNAs and proteins in mouse ovaries.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Hormônio Foliculoestimulante/metabolismo , Proteínas Nucleares/sangue , Neoplasias Ovarianas/metabolismo , PTEN Fosfo-Hidrolase/sangue , Receptores do FSH/antagonistas & inibidores , Animais , Western Blotting , Proteínas de Ligação a DNA/sangue , Feminino , Camundongos , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Ativação Transcricional/genética , Regulação para Cima
14.
Gen Physiol Biophys ; 38(4): 353-363, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241042

RESUMO

Intracellular calcium concentration ([Ca2+]i) may have an important role in the development of chemoresistance, which is an essential problem in cancer chemotherapy. Cisplatin (DDP), which modulates the intracellular calcium concentration by different mechanisms, is an antineoplastic agent with high success rate in cancer therapies. We investigated the regulatory role of [Ca2+] in cisplatin resistance in epithelial ovarian cancer cell line, in MDAH-2774, and its chemoresistant subclone MDAH-2774/DDP. The measurement of [Ca2+]i using fluorescence microscope, and flow cytometry revealed that the amount of intracellular calcium decreased in cisplatin resistant cells compared to the amounts in parental cells. mRNA expression profiles of calcium homeostasis-associated major genes (IP3R1/2/3, RYR1/2, SERCA1/2/3, NCX1/2/3, PMCA1/2/3, and PMCA4) decreased in cisplatin resistant cell line in comparison to the expression profiles in parental cells. Owing to the changes in the expression of genes involved in calcium regulation, these results show, drug resistance may be prevented by introducing a new perspective on the use of inhibitors and activators of these genes, and thus of cytostatic treatment strategies, due to changes in the expression of genes involved in calcium regulation.


Assuntos
Antineoplásicos/farmacologia , Cálcio/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Homeostase , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Homeostase/efeitos dos fármacos , Humanos , Neoplasias Ovarianas/tratamento farmacológico
15.
Cancer Sci ; 110(8): 2658-2666, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199029

RESUMO

Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.


Assuntos
Fibrina/metabolismo , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Ascite/metabolismo , Ascite/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Peritônio/metabolismo , Peritônio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Anticancer Res ; 39(6): 2883-2889, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177126

RESUMO

BACKGROUND/AIM: High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian carcinoma. Somatic mutation of tumor protein 53 (TP53) is a hallmark of tubo-ovarian HGSC and is observed in almost all such cases. Highly sensitive targeted genomic sequencing can be used to identify novel mutations that may become potential druggable targets and aid in therapeutic decisions. The aim of this study was to describe the clinicopathological and molecular characteristics of HGSCs with novel somatic TP53 mutations identified by next-generation sequencing (NGS). MATERIALS AND METHODS: A commercial NGS panel comprising 170 genes, including TP53, was used to analyze the genetic profiles of 132 ovarian carcinoma cases. The clinicopathological characteristics and p53 immunostaining results of two HGSCs exhibiting novel TP53 mutations were investigated. RESULTS: Eighty-eight (66.7%) out of 132 ovarian carcinoma cases were diagnosed as HGSC. Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each. Both patients were postmenopausal women. Imaging and laboratory studies revealed peritoneal carcinomatosis and elevated levels of serum tumor markers. The patients underwent primary debulking surgery and were diagnosed as having stage IIIC HGSC. In both cases, p53 immunostaining revealed uniform nuclear immunoreactivity in 90% or more of tumor cells at a very strong intensity. CONCLUSION: Targeted genomic sequencing revealed novel in-frame deletion mutations of TP53 leading to p53 overexpression in tubo-ovarian HGSC. This discovery of previously unreported somatic TP53 mutations provides insight into the translation of NGS technology into personalized medicine and identifies new potential targets for therapeutic applications.


Assuntos
Cistadenocarcinoma Seroso/cirurgia , Neoplasias das Tubas Uterinas/cirurgia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/cirurgia , Deleção de Sequência , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Núcleo Celular/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Pós-Menopausa , Medicina de Precisão , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/metabolismo
17.
Nat Commun ; 10(1): 2406, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160622

RESUMO

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.


Assuntos
Líquido Ascítico , Carcinoma/secundário , Adesão Celular , Hidrodinâmica , Células-Tronco Neoplásicas/metabolismo , Oligossacarídeos/metabolismo , Neoplasias Ovarianas/patologia , Selectina-P/metabolismo , Neoplasias Peritoneais/secundário , Animais , Carcinoma/metabolismo , Linhagem Celular Tumoral , Epitélio/metabolismo , Feminino , Fucosiltransferases/metabolismo , Células HEK293 , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Peritônio/metabolismo , Receptor IGF Tipo 1/metabolismo , Estresse Mecânico
18.
Gynecol Oncol ; 154(3): 531-538, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31227223

RESUMO

OBJECTIVE: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. METHODS: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6 months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. CONCLUSIONS: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.


Assuntos
Anastrozol/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Pós-Menopausa , Intervalo Livre de Progressão , Estudos Prospectivos , Qualidade de Vida , Receptores de Progesterona/metabolismo , Adulto Jovem
19.
J Ovarian Res ; 12(1): 37, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039792

RESUMO

BACKGROUND: The expression of PD-L1 has been reported in ovarian cancer. However, the prognostic role of PD-L1 expression in ovarian carcinoma remained controversial. This study was performed to assess the prognostic value of PD-L1 expression on ovarian cancer. METHODS: The PubMed, Embase, EBSCO, and Cochrane Library databases were searched to identify available publications. The pooled odds ratio (OR) or hazard ratios (HRs: multivariate analysis) with their 95% confidence intervals (95% CIs) were calculated in this analysis. A bioinformatics study based on The Cancer Genome Atlas (TCGA) sequencing and microarray datasets was used to further validate the results of PD-L1 mRNA expression. Kaplan-Meier (KM) survival curves were performed to evaluate the prognostic effect of PD-L1 mRNA expression. RESULTS: Twelve studies with 1630 ovarian cancers regarding PD-L1 immunohistochemical expression were identified. Meta-analysis showed that PD-L1 protein expression was not associated with tumor grade, clinical stage, lymph node status, tumor histology, overall survival (OS), and progression-free survival (PFS). TCGA data showed no association between PD-L1 mRNA expression and ovarian cancer. Further validation using microarray data suggested that no association between PD-L1 mRNA expression and OS was found in large independent patient cohorts (1310 cases). PD-L1 mRNA expression was significantly linked to worse PFS in 1228 patients with ovarian cancer (227458_at: HR = 1.55, 95% CI = 1.28-1.88, P < 0.001; 223834_at: HR = 1.41, 95% CI = 1.14-1.75, P = 0.0015). CONCLUSIONS: Meta-analysis showed that PD-L1 may not be a prognostic factor for ovarian cancer. But a bioinformatics study showed that PD-L1 expression was significantly associated with worse PFS of ovarian cancer. More clinical studies are needed to further validate these findings.


Assuntos
Antígeno B7-H1/genética , Biologia Computacional/métodos , Neoplasias Ovarianas/genética , Antígeno B7-H1/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico
20.
Methods Mol Biol ; 1966: 27-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041737

RESUMO

Immunohistochemistry using formalin-fixed, paraffin-embedded tissue, chromogen label, and light microscopy has traditionally been used to semiquantify estrogen receptor (ER) to guide diagnosis and management of breast cancer. Quantitation of ER for this purpose currently only assesses levels of the ER-alpha subtype. Considerable variability in results reported has been due to protocol and fixation variability, intraobserver and interobserver variability, and different scoring systems and thresholds for scoring ER positivity. Results can also vary with low expression levels of ER. ER-beta expression is reduced in breast and ovarian cancers and requires quantitation.Herein we describe a novel approach to quantifying ERß using older mouse ovarian surface epithelium, where ERß is expressed at lower levels than ERα and is therefore harder to detect. We use an antibody highly specific to the ERß1 isoform, together with immunofluorescence, confocal microscopy, and imaging and statistical software to achieve clear, reproducible, and unbiased quantitation of ERß.


Assuntos
Receptor beta de Estrogênio/análise , Regulação da Expressão Gênica , Imuno-Histoquímica/métodos , Microscopia Confocal/métodos , Ovário/metabolismo , Epitélio/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Microscopia Intravital/métodos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo
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