Overexpression of Fut 2, 4, and 8, and nuclear localization of Fut 4 in ovarian cancer cell lines induced by ascitic fluids from epithelial ovarian cancer patients.

Fucosyltransferases (Fut) regulate the fucosylation process associated with tumorogenesis in different cancer types. Ascitic fluid (AF) from patients diagnosed with advanced stage of epithelial ovarian cancer (EOC) is considered as a dynamic tumor microenvironment associated with poor prognosis. Previous studies from our laboratory showed increased fucosylation in SKOV-3 and OVCAR-3, cancer-derived cell lines, when these cells were incubated with AFs derived from patients diagnosed with EOC. In the present work we studied three fucosyltransferases (Fut 2, Fut 4, and Fut 8) in SKOV-3, OVCAR-3 and CAOV-3 cell lines in combination with five different AFs from patients diagnosed with this disease, confirming that all tested AFs increased fucosylation. Then, we demonstrate that mRNAs of these three enzymes were overexpressed in the three cell lines under treatment with AFs. SKOV-3 showed the higher overexpression of Fut 2, Fut 4, and Fut 8 in comparison with the control condition. We further confirmed, in the SKOV-3 cell line, by endpoint PCR, WB, and confocal microscopy, that the three enzymes were overexpressed, being Fut 4 the most overexpressed enzyme compared to Fut 2 and Fut 8. These enzymes were concentrated in vesicular structures with a homogeneous distribution pattern throughout the cytoplasm. Moreover, we found that among the three enzymes, only Fut 4 was located inside the nuclei. The nuclear location of Fut 4 was confirmed for the three cell lines. These results allow to propose Fut 2, Fut 4, and Fut 8 as potential targets for EOC treatment or as diagnostic tools for this disease.

Body Composition and Metabolic Dysfunction Really Matter for the Achievement of Better Outcomes in High-Grade Serous Ovarian Cancer.

Although obesity-associated metabolic disorders have a negative impact on various cancers, such evidence remains controversial for ovarian cancer. Here, we aimed to evaluate the impact of body composition (BC) and metabolism disorders on outcomes in high-grade serous ovarian cancer (HGSOC). METHODS: We analyzed clinical/genomic data from two cohorts (PUC n = 123/TCGA-OV n = 415). BC was estimated using the measurement of adiposity/muscle mass by a CT scan. A list of 425 genes linked to obesity/lipid metabolism was used to cluster patients using non-negative matrix factorization. Differential expression, gene set enrichment analyses, and Ecotyper were performed. Survival curves and Cox-regression models were also built-up. RESULTS: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival. High adiposity and sarcopenia were associated with worse outcomes. We also found that recovery of a normal BC and drug interventions to correct metabolism disorders had a positive impact on outcomes. Additionally, we showed that immune-cell-depleted microenvironments predominate in HGSOC, which was more evident among the BC types and the obesity/lipid metabolism cluster with worse prognosis. CONCLUSIONS: We have demonstrated the relevance of BC and metabolism disorders as determinants of outcomes in HGSOC. We have shone a spotlight on the relevance of incorporating corrective measures addressing these disorders to obtain better results.

Role of magnetic resonance imaging in the differentiation of mucinous ovarian carcinoma and mucinous borderline ovarian tumors

SUMMARY OBJECTIVE: This study was carried out to investigate the differentiation of mucinous borderline ovarian tumor from mucinous ovarian carcinoma using magnetic resonance imaging. METHODS: We evaluated 77 women patients who underwent abdominal magnetic resonance imaging due to pelvic mass. magnetic resonance imaging was reviewed by an experienced radiologist. A total of 70 women patients were included in the study. The magnetic resonance imaging features were retrospectively evaluated and compared between the two pathologies. RESULTS: There was no difference between the two groups in terms of maximum tumor size. Age at diagnosis was 56.29±11.92 in the mucinous ovarian carcinoma group and 44.74±13.60 in the mucinous borderline ovarian tumor group (p<0.05). A significant difference was found between the two groups, and it was observed that mucinous borderline ovarian tumors appeared in the younger age group compared to mucinous ovarian carcinomas. Presence of ascites, peritoneal dissemination, lymphadenopathy, and mural nodules was found significantly more frequently in mucinous ovarian carcinomas than in mucinous borderline ovarian tumors. Honeycomb appearance was found more frequently in mucinous borderline ovarian tumor patients than in mucinous ovarian carcinoma patients. CONCLUSION: magnetic resonance imaging findings of these two pathologies overlapped considerably. Compared with mucinous borderline ovarian tumors, mucinous ovarian carcinomas frequently had mural nodules larger than 5 mm, larger tumor size, peritoneal dissemination, and abnormal ascites.

Estrategias terapéuticas actuales en el tratamiento del cáncer de ovario

Introducción: El cáncer de ovario es uno de los tumores más frecuentes y letales entre las mujeres. Esto se debe a su detección en estados tardíos y al desarrollo de quimiorresistencia a la terapia estándar. El desarrollo de terapias dirigidas contra las propiedades distintivas de las células cancerosas y sus características habilitadoras ha surgido como una alternativa promisoria para el tratamiento de estos tumores. Objetivo: Describir las actuales estrategias terapéuticas dirigidas contra las distintas capacidades de las células tumorales en el tratamiento del cáncer de ovario. Método: Se realizó una búsqueda en las bases de datos ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL´s CLIN, Registro Público Cubano de Ensayos Clínicos, entre enero y abril de 2023. Se seleccionaron 50 artículos referentes al cáncer de ovario y las alternativas para su tratamiento. Desarrollo: Se mencionaron los diversos factores que influyen en la elección de terapias contra el cáncer de ovario. Se describieron las actuales dianas terapéuticas utilizadas en el tratamiento de esta neoplasia, así como el empleo de múltiples fármacos aprobados y en fases de estudio, y las combinaciones sinérgicas de los mismos. Consideraciones finales: Actualmente existen disímiles opciones de tratamiento del cáncer de ovario. A pesar de que la eficacia clínica de los agentes dirigidos todavía está restringida a subtipos moleculares específicos y ningún ensayo ilustra un beneficio en la supervivencia general, son notorios los resultados alcanzados en el desarrollo de fármacos específicamente dirigidos contra la inestabilidad del genoma y angiogénesis sostenida.

Introduction: Ovarian cancer is one of the most common and lethal tumor in women. This happens as a result of late-stage cancer detention and an increased chemoresistance to standard therapy. The current development in therapies to kill the cancer cells and its spread tendencies has emerged as a key alternative to treat tumors. Objective: To describe the current therapeutic strategies lead to confront different capabilities of tumor cells found in the ovarian cancer treatment. Method: A search of literuture was carried out in the following databases ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL's CLIN, Cuban Public Registry of Clinical Trials, from January to April 2023. A total of 50 text concerning ovarian cancer subject and alternative for treatment were selected. Development: The driving factors that promoted the use of ovarian cancer therapies were pointed out. The current therapeutic targets used in the treatment of this neoplasia were described, as well as the use of multiple approved drugs or in process of approval, including the synergistic drug combinations. Final considerations: There are a lot of options currently being implemented in ovarian cancer treatment. Despite clinical efficacy of targeted therapy, it´s presented still restricted to specific molecular subtypes and none of the assays illustrated survival benefit in general; the results obtained in the process of drugs development specifically targeting genome instability and sustained angiogenesis have been remarkable.

Introdução: O câncer de ovário é um dos tumores mais frequentes e letais entre as mulheres. Isso se deve à sua detecção em estágios tardios e ao desenvolvimento de quimiorresistência à terapia padrão. O desenvolvimento de terapias direcionadas contra as propriedades distintas das células cancerígenas e suas características facilitadoras surgiu como uma alternativa promissora para o tratamento desses tumores. Objetivo: Descrever as atuais estratégias terapêuticas dirigidas contra as diferentes capacidades das células tumorais no tratamento do câncer de ovário. Método: Foi realizada uma busca nas bases de dados ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL's CLIN, Registro Público Cubano de Ensaios Clínicos, entre janeiro e abril de 2023. 50 artigos referentes ao câncer de ovário e as alternativas para o seu tratamento. Desenvolvimento: Foram mencionados os vários fatores que influenciam a escolha das terapias contra o câncer de ovário. Foram descritos os atuais alvos terapêuticos utilizados no tratamento desta neoplasia, bem como o uso de múltiplas drogas aprovadas e em fase de estudo, e suas combinações sinérgicas. Considerações finais: Atualmente existem opções de tratamento dissimilares para o câncer de ovário. Apesar de a eficácia clínica dos agentes direcionados ainda estar restrita a subtipos moleculares específicos e nenhum ensaio mostrar benefício na sobrevida global, são notáveis os resultados alcançados no desenvolvimento de fármacos direcionados especificamente contra a instabilidade do genoma e a angiogênese sustentada.

IL-6 secretion of CD4+ T cells stimulated by LC3-positive extracellular vesicles in human epithelial ovarian cancer.

BACKGROUND: Ovarian cancer (OC) as the most fatal gynecological malignancy worldwide, with epithelial ovarian cancer (EOC) being the predominant and most lethal form, poses a serious threat to human health. LC3-positive extracellular vesicles (LC3+ EVs) promote tumorigenesis by educating CD4+ T cells in a murine melanoma model. However, regulation of LC3+ EVs in human EOC remains largely unknown.  METHODS: Differential analysis of Rab8a, Hsp90α and Il6 expression was performed using GEPIA2. The number of LC3+ EVs and the frequency of Heat shock protein 90α+ LC3+ EVs (HSP90α+ LC3+ EVs) in the ascites of EOC patients were tested by flow cytometry. IL-6, IL-10, IFN-γ, IL-4 and TGF-ß were measured by ELISA. CD4+ T cells were isolated from peripheral blood of healthy human donors using MACS magnetic bead technology.  RESULTS: Higher Rab8a, Hsp90a and Il6 expression of cancer tissues compared with normal adjacent tissues in OC were found. The level of IL-6 was positively correlated with LC3+ EVs number, HSP90α+ LC3+ EVs percentage in the ascites, and ROMA index of the patient. In addition, elevated IL-6 production by CD4+ T cells induced by LC3+ EVs was observed, which was suppressed by anti-HSP90α or anti-TLR2.  CONCLUSIONS: LC3+ EVs level and HSP90α+ LC3+ EVs percentage were associated with elevated IL-6 in the ascites of EOC patients. HSP90α on LC3+ EVs from human EOC could stimulate CD4+ T cell production of IL-6 via TLR2.

Clinical Benefits of Olaparib in Mexican Ovarian Cancer Patients With Founder Mutation BRCA1-Del ex9-12.

Background: Ovarian cancer (OC) is gynecologic cancer with the highest mortality rate. It is estimated that 13-17% of ovarian cancers are due to heritable mutations in BRCA1 and BRCA2. The BRCA1 (BRCA1-Del ex9-12) Mexican founder mutation is responsible for 28-35% of the cases with ovarian cancer. The aim was to describe the PFS of OC patients treated with olaparib, emphasizing patients carrying the Mexican founder mutation (BRCA1-Del ex9-12). Methods: In this observational study, of 107 patients with BRCAm, 35 patients were treated with olaparib from November 2016 to May 2021 at the Ovarian Cancer Program (COE) of Mexico; patient information was extracted from electronic medical records. Results: Of 311 patients, 107 (34.4%) were with BRCAm; 71.9% (77/107) were with BRCA1, of which 27.3% (21/77) were with BRCA1-Del ex9-12, and 28.1% (30/107) were with BRCA2 mutations. Only 35 patients received olaparib treatment, and the median follow-up was 12.87 months. The PFS of BRCA1-Del ex9-12 was NR (non-reach); however, 73% of the patients received the treatment at 36 vs. 11.59 months (95% CI; 10.43-12.75) in patients with other BRCAm (p = 0.008). Almost 50% of patients required dose reduction due to toxicity; the most frequent adverse events were hematological in 76.5% and gastrointestinal in 4%. Conclusion: Mexican OC BRCA1-Del ex9-12 patients treated with olaparib had a significant increase in PFS regardless of the line of treatment compared to other mutations in BRCA.

Value of fertility-sparing surgery for young females with epithelial ovarian cancer: a comparative study / Valor de la cirugía de preservación de la fertilidad en mujeres jóvenes con cáncer de ovario epitelial: un estudio comparativo

Resumen OBJETIVO: Comparar la cirugía radical con la cirugía conservadora de la fertilidad en mujeres con cáncer de ovario epitelial en estadio 1A-C con respecto a la tasa de recurrencia y las tasas de supervivencia. Además, evaluar los desenlaces reproductivos y obstétricos para las mujeres con cáncer de ovario epitelial en estadio I tratadas con una conducta conservadora de la fertilidad. PACIENTES Y MÉTODOS: Estudio prospectivo efectuado en pacientes con cáncer de ovario epitelial, estadio I, con edad ≤ 40 años. A las pacientes del grupo de preservación de la fertilidad se les practicó salpingooforectomía del lado del ovario afectado y una biopsia por incisión o escisión en cuña del ovario contralateral. A las pacientes del grupo de cirugía radical se les practicó la histerectomía total y salpingooforectomía bilateral. Para evaluar los desenlaces reproductivos y oncológicos se dio seguimiento a todas las pacientes durante cinco años. RESULTADOS: Se estudiaron 60 pacientes; las del grupo de cirugía de preservación de la fertilidad eran significativamente más jóvenes (30 ± 4 en comparación con 35 ± 5) (p < 0.001), el tamaño de sus tumores era más pequeño 3.4 ± 1.3 en comparación con 6.0 ± 2,6 (p < 0.001), de menor grado (p < 0.001). = 0.011), estadio más precoz (p < 0.001) y con más histología mucinosa que las pacientes del grupo de cirugía radical. No hubo diferencias estadísticamente significativas entre ambos grupos en cuanto a la recurrencia tumoral o las tasas de supervivencia. De 25 pacientes operadas para preservación de la fertilidad 18 de 25 intentaron quedar embarazadas. Se registraron 15 de 18 embarazos, incluidos 13 nacidos vivos, 1 aborto espontáneo y 1 muerte fetal intrauterina. CONCLUSIÓN: La cirugía conservadora de la fertilidad podría ser una alternativa adecuada a la cirugía radical para mujeres jóvenes con cáncer epitelial de ovario en estadio I.

Abstract OBJECTIVE: In the current study, we aimed to compare between radical surgery and fertility saving surgery in females with stage 1A-C EOC regarding recurrence rate and patients survival rates in addition to evaluating reproductive and obstetric outcomes for stage I EOC females who were managed by fertility saving surgery. PATIENTS AND METHODS: We prospectively identified 60 patients diagnosed with stage I EOC aged ≤ 40 years. Patients in the fertility-preservation group underwent salpingo-oophorectomy on the side of the affected ovary in addition to incisional biopsy or wedge excision of the ovary on the other side. Patients in the radical surgery group underwent total hysterectomy and bilateral salpingo-oophorectomy. We followed up all patients for 5 years to assess their reproductive and oncological outcomes. RESULTS: Patients in the fertility preservation surgery group were significantly younger (30 ± 4 versus 35 ± 5) (p < 0.001), their tumor sizes were smaller 3.4 ± 1.3 versus 6.0 ± 2.6 (p < 0.001), of lower grade (p = 0.011), earlier stage (p < 0.001) and has more mucinous histology than patients in the radical surgery group. There were no statistically significant differences between both groups regarding tumor recurrence or survival rates. Of 25 patients underwent fertility preservation surgery, 18/25 (72%) tried to get pregnant. 15/18 (83%) pregnancies were recorded, including 13 live births, 1 miscarriage, and 1 intrauterine fetal death. CONCLUSION: Fertility sparing surgery could be adequate alternative to radical surgery for young females with stage I EOC.

Tumor de células de Sertoli-Leydig: a propósito de un caso y revisión de la literatura reciente / Ovarian Sertoli-Leydig cell tumour: a clinical case and recent basic literature review

INTRODUCCIÓN: Los tumores de células de Sertoli-Leydig son neoplasias de ovario infrecuentes, lo que dificulta su diagnóstico y tratamiento. OBJETIVO: Revisar y sintetizar el manejo actual de los tumores de células de Sertoli-Leydig. MÉTODO: Se realizó una revisión de la literatura reciente sobre tumores de células de Sertoli-Leydig, a propósito de un caso en nuestro centro. RESULTADOS: Los tumores de las células de Sertoli-Leydig son infrecuentes, con mayor incidencia en edades tempranas. Ante una paciente joven con una lesión anexial unilateral y signos de virilización deberán considerarse estos tumores dentro del diagnóstico diferencial. En los estadios iniciales y en pacientes jóvenes podrá plantearse un tratamiento quirúrgico que preserve la fertilidad, y la asociación de tratamiento adyuvante dependerá de la diferenciación y del estadiaje del tumor.

INTRODUCTION: Sertoli-Leydig cell tumors are infrequent ovarian neoplasms, which difficults their diagnosis and treatment. Objective: To review and synthesize the current management of the Sertoli-Leydig cell tumor. METHOD: A review of the recent literature regarding the Sertoli-Leydig cell tumor was carried out, regarding a case in our center. RESULTS: Sertoli-Leydig cell tumors are an infrequent entity, with a higher incidence in early ages. In a young patient with a unilateral adnexal lesion and signs of virilization, these tumors should be considered within the differential diagnosis. In early stages and young patients, a surgical treatment that preserves fertility may be considered, and the association of adjuvant treatment will depend on the differentiation and staging of the tumor.

Current Treatments and New Possible Complementary Therapies for Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) is one of the deadliest gynaecological malignancies. The late diagnosis is frequent due to the absence of specific symptomatology and the molecular complexity of the disease, which includes a high angiogenesis potential. The first-line treatment is based on optimal debulking surgery following chemotherapy with platinum/gemcitabine and taxane compounds. During the last years, anti-angiogenic therapy and poly adenosine diphosphate-ribose polymerases (PARP)-inhibitors were introduced in therapeutic schemes. Several studies have shown that these drugs increase the progression-free survival and overall survival of patients with ovarian cancer, but the identification of patients who have the greatest benefits is still under investigation. In the present review, we discuss about the molecular characteristics of the disease, the recent evidence of approved treatments and the new possible complementary approaches, focusing on drug repurposing, non-coding RNAs, and nanomedicine as a new method for drug delivery.

Role of Mitochondria in Interplay between NGF/TRKA, miR-145 and Possible Therapeutic Strategies for Epithelial Ovarian Cancer.

Ovarian cancer is the most lethal gynecological neoplasm, and epithelial ovarian cancer (EOC) accounts for 90% of ovarian malignancies. The 5-year survival is less than 45%, and, unlike other types of cancer, the proportion of women who die from this disease has not improved in recent decades. Nerve growth factor (NGF) and tropomyosin kinase A (TRKA), its high-affinity receptor, play a crucial role in pathogenesis through cell proliferation, angiogenesis, invasion, and migration. NGF/TRKA increase their expression during the progression of EOC by upregulation of oncogenic proteins as vascular endothelial growth factor (VEGF) and c-Myc. Otherwise, the expression of most oncoproteins is regulated by microRNAs (miRs). Our laboratory group reported that the tumoral effect of NGF/TRKA depends on the regulation of miR-145 levels in EOC. Currently, mitochondria have been proposed as new therapeutic targets to activate the apoptotic pathway in the cancer cell. The mitochondria are involved in a myriad of functions as energy production, redox control, homeostasis of Ca+2, and cell death. We demonstrated that NGF stimulation produces an augment in the Bcl-2/BAX ratio, which supports the anti-apoptotic effects of NGF in EOC cells. The review aimed to discuss the role of mitochondria in the interplay between NGF/TRKA and miR-145 and possible therapeutic strategies that may decrease mortality due to EOC.

Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells.

Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, ß-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.

NGF/TRKA Decrease miR-145-5p Levels in Epithelial Ovarian Cancer Cells.

Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The expression of these proteins is controlled by microRNAs (miRs), such as miR-145, whose dysregulation has been related to cancer. The aims of this work were to evaluate in EOC cells whether NGF/TRKA decreases miR-145 levels, and the effect of miR-145 upregulation. The levels of miR-145-5p were assessed by qPCR in ovarian biopsies and ovarian cell lines (human ovarian surface epithelial cells (HOSE), A2780 and SKOV3) stimulated with NGF. Overexpression of miR-145 in ovarian cells was used to evaluate cell proliferation, migration, invasion, c-MYC and VEGF protein levels, as well as tumor formation and metastasis in vivo. In EOC samples, miR-145-5p levels were lower than in epithelial ovarian tumors. Overexpression of miR-145 decreased cell proliferation, migration and invasion of EOC cells, changes that were concomitant with the decrease in c-MYC and VEGF protein levels. We observed decreased tumor formation and suppressed metastasis behavior in mice injected with EOC cells that overexpressed miR-145. As expected, ovarian cell lines stimulated with NGF diminished miR-145-5p transcription and abundance. These results suggest that the tumoral effects of NGF/TRKA depend on the regulation of miR-145-5p levels in EOC cells, and that its upregulation could be used as a possible therapeutic strategy for EOC.

Fertility-sparing treatment for epithelial ovarian cancer: a literature review.

Epithelial ovarian cancer is more common in postmenopausal women, with a mean age at diagnosis of 65 years; however, it has been documented that 3% to 17% of epithelial ovarian cancer cases are diagnosed in women younger than 40 years, with an overall survival of up to 90% when diagnosed in early-stage disease. The development of fertility-sparing approaches represents one of the most significant advances in the gynecologic oncology field. These approaches can have satisfactory outcomes on fertility with excellent oncological results in premenopausal women with early-stage epithelial ovarian cancer and the desire to preserve fertility. Because of the low occurrence of this specific population, randomized trials have not been performed. However, several retrospective series suggest that in certain cases, fertility-sparing surgery is safe, with low rates of recurrence and favorable reproductive outcomes in accordance to the new techniques in reproductive biology; therefore, fertility-sparing approaches must be discussed with young female patients with epithelial ovarian cancer or in patients that desire to preserve fertility or to maintain ovarian function and to improve quality of life in this particular group of individuals. In this review, we present the published evidence, including oncologic and reproductive results, as well as fertility-sparing surgical options, in the field in the last 10 years.

NGF-Enhanced Vasculogenic Properties of Epithelial Ovarian Cancer Cells Is Reduced by Inhibition of the COX-2/PGE2 Signaling Axis.

Epithelial ovarian cancer (EOC) is a lethal gynecological neoplasia characterized by extensive angiogenesis and overexpression of nerve growth factor (NGF). Here, we investigated the mechanism by which NGF increases vascular endothelial growth factor (VEGF) expression and the vasculogenic potential of EOC cells, as well as the contribution of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) signaling axis to these events. EOC biopsies and ovarian cell lines were used to determine COX-2 and PGE2 levels, as well as those of the potentially pro-angiogenic proteins c-MYC (a member of the Myc transcription factors family), survivin, and ß-catenin. We observed that COX-2 and survivin protein levels increased during EOC progression. In the EOC cell lines, NGF increased the COX-2 and PGE2 levels. In addition, NGF increased survivin, c-MYC, and VEGF protein levels, as well as the transcriptional activity of c-MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef) in a Tropomyosin receptor kinase A (TRKA)-dependent manner. Also, COX-2 inhibition prevented the NGF-induced increases in these proteins and reduced the angiogenic score of endothelial cells stimulated with conditioned media from EOC cells. In summary, we show here that the pro-angiogenic effect of NGF in EOC depends on the COX-2/PGE2 signaling axis. Thus, inhibition COX-2/PGE2 signaling will likely be beneficial in the treatment of EOC.

Identification of High-affinity Novel Targeted Peptides for the Treatment of Human Ovarian Cancer

Background: To investigate the potential of the phage display-identified tumor cellbinding peptide as a biomarker of epithelial ovarian cancer using phage display technology. Method: The Ph.D.-7 Phage Display Peptide Library was used to identify the specific conjugated phages with SKOV3 epithelial ovarian cancer cells, while Chinese hamster ovary cells formed the basis. After employing the rapid differential screening method invitro, the enzyme-linked immunosorbent assay (ELISA), DNA sequencing, immunohistochemistry, immunofluorescence, and the competitive inhibition test of synthetic peptides were used to determine the affinity and specificity of the phages with SKOV3 cells. Results: Using bio panning, we screened the phages, showing a 3590-fold increase after the third round. A total of 61 titers of the phage were randomly selected for ELISA and 10 kinds of the phages with an optical density >0.5 were used for DNA sequencing. Clones of the phage TRRNIPN were derived from DNA sequencing based on ELISA, exhibiting both the brown granular phenomenon and green fluorescence. The specific targeted peptide TRRNIPN was incorporated in tumor cells through the competitive inhibition test. Conclusion: The results of our study indicate that the phage display identified polypeptide TRRNIPN may be an effective biomarker for the early diagnosis and targeted therapy of ovarian cancer

Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer.

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II - versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II - versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

Surgery in ovarian cancer - Brazilian Society of Surgical Oncology consensus.

Surgical management in epithelial ovarian cancer (EOC) has a significant impact in overall survival and progression-free survival. The Brazilian Society of Surgical Oncology (BSSO) supported a taskforce of experts to reach a consensus: experienced and specialised trained surgeons, in cancer centres, provide the best EOC surgery. Laparoscopic and/or radiological staging prognosticates the possibility of complete cytoreduction (CC0) and helps to reduce unnecessary laparotomies. Surgical techniques were reviewed. Multidisciplinary input is essential for treatment planning. Quality assurance criteria are proposed and require national consensus. Genetic testing is mandatory. This consensus states the final recommendations from BSSO for management of EOC. TWEETABLE ABSTRACT: Brazilian Society of Surgical Oncology consensus for surgery in epithelial ovarian cancer patients.

Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma.

Anterior gradient 2 protein belongs to a family of chaperone-like proteins, namely protein disulfide isomerase. Generally, AGR2 is highly expressed in mucus-secreting cells and endocrine organs, and in this study, we aimed to evaluate AGR2 and cell cycle molecules in epithelial ovarian cancer and its implications on prognosis. One hundred seventy-five patient's samples that were diagnosed with primary epithelial ovarian carcinoma were selected. All the patients were treated with platinum-taxane standard chemotherapy after surgery and CA125 serum levels were routinely determined. Four-micrometer-thick sections were processed by immunohistochemistry using an automated immunostainer, Ventana BenchMark AutoStainer with AGR2, cyclin D1, p21WAF1, and p53. Forty-nine of 167 cases (29.3%) showed strong to moderate cytoplasmic marking of AGR2, and 118 (70.7%) had weak to negative expression. The absence of the AGR2 protein was observed in high-grade serous carcinoma (P < .001) and significantly associated with disease-free survival (DFS; P = .034). The expression of G1-S phase-regulatory proteins showed loss of p21 in high-grade serous carcinoma (P < .001) and was related with poor DFS (P = .003). Strong and diffuse immunoexpression of p53 plus complete absence of p53 staining was interpreted as likely indicating a TP53 gene mutation. This result showed worse DFS alone (P = .012) and combined with low levels of AGR2 (P = .005). The expression profile of AGR2 and cell cycle proteins here presented was showed as good prognosis marker in epithelial ovarian cancer. This finding suggests AGR2 and as putative biomarker of disease progression in chemotherapy-treated high-grade serous carcinoma patients.

Effect of ovarian cancer ascites on SKOV-3 cells proteome: new proteins associated with aggressive phenotype in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can be found in all clinical stages, however in advanced disease stages IIIC and IV it is more frequent and could be massive, associated with worse prognosis. Due to the above, it was our interest to understanding how the ascites of ovarian cancer patients induces the mechanisms by which the cells present in it acquire a more aggressive phenotype and to know new proteins associated to this process. METHODS: A proteomic analysis of SKOV-3 cells treated with five different EOC ascites was performed by two-dimensional electrophoresis coupled to MALDI-TOF. The level of expression of the proteins of interest was validated by RT-PCR because several of these proteins have only been reported at the messenger level. RESULTS: Among the proteins identified that increased their expression in ascites-treated SKOV-3 cells, were Ran GTPase, ZNF268, and Synaptotagmin like-3. On the other hand, proteins that were negatively regulated by ascites were HLA-I, HSPB1, ARF1, Synaptotagmin 1, and hnRNPH1, among others. Furthermore, an interactome for every one of these proteins was done in order to identify biological processes, molecular actions, and cellular components in which they may participate. CONCLUSIONS: Identified proteins participate in cellular processes highly relevant to the aggressive phenotype such as nuclear transport, regulation of gene expression, vesicular trafficking, evasion of the immune response, invasion, metastasis, and in resistance to chemotherapy. These proteins may represent a source of information which has the potential to be evaluated for the design of therapies directed against these malignant cells that reside on ovarian cancer ascites.

Aspectos anatómicos y técnicos de la cirugia de citorredución de cáncer de ovario en abdomen superior / Anatomical and technical aspects of debulking surgery for ovarian cancer in the upper abdomen

RESUMEN El Cáncer de Ovario Epitelial es la novena causa de cáncer en la mujer y la neoplasia ginecológica más letal en países desarrollados. La mayoría de las pacientes son diagnosticadas en etapa avanzada de la enfermedad debido a la ausencia de síntomas específicos. La cirugía y la quimioterapia cumplen un rol fundamental en el tratamiento de esta enfermedad. En pacientes con enfermedad avanzada (estadios III - IV) al momento del diagnóstico, la extirpación de todo tumor macroscópico (citorreducción óptima) ha demostrado ser el factor pronóstico más importante, demostrando un beneficio tanto en tiempo libre de enfermedad como en sobrevida global. Nuestro objetivo es describir, desde una perspectiva multidisciplinaria, los aspectos técnicos más relevantes de la citorreducción del abdomen superior para aquellas pacientes con neoplasias de origen ginecológico.

ABSTRACT Epithelial Ovarian cancer is the ninth most frequent cancer in women and the most lethal gynecologic malignancy in developed countries. The majority of patients are diagnosed in advanced stage of the disease due to the lack of specific symptoms. Surgery and systemic treatment play a key role in the treatment of this disease. For those patients with advanced stage at the time of diagnosis (III - IV), removal of all macroscopic disease (optimal cytoreduction) has been shown as the most important prognostic factor, demonstrating improvement not only in progression free survival but also in overall survival. Our aim is to describe, in a multidisciplinary fashion, the most relevant aspect about oncological debulking procedures in the upper abdominal cavity for women with gynecological malignancies.