Circulating Expressions of Gonadotropin Releasing Hormones and Risk of Ovarian Cancer

Background: Ovarian cancer (OC) is a worst type of malignancy in the field of gynecology. This is because ovarian tumors diagnosed at advanced stage of disease. The exact mechanism for its development is still unknown. Aim: The aim of this study is to measure the levels of steroidal hormones and their function in ovarian cancer progression. Methods: In the present study, fifty ovarian cancer patients and fifty control individuals were taken and serum was separated from their blood samples. The levels of steroid hormones were measured by ELISA kit methods. Results: Result of the current study determined the levels of E2, progesterone, testosterone, FSH, LH, 17-β-HSD-I, 17-β-HSD-II, cortisol and aromatase were extensively higher in patient group in comparison with healthy individuals. Conclusion: Current study concluded the Study concluded that overexpression of steroid hormones may lead to enhance tumor survival in ovarian cancer through various signaling mechanisms. Keywords: Ovarian cancer, Estradiol, FSH, LH, progesterone

Hymenialdisine is Cytotoxic against Cisplatin-Sensitive but not against Cisplatin-Resistant Cell Lines

New compounds are needed to overcome the resistance to commonly used cytotoxic chemotherapy for epithelial ovarian cancer. Marine sponges are a rich source of diverse chemical compounds, and hymenialdisine has been found to have antiproliferative effects. We investigated the cytotoxic effect of hymenialdisine in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. Methods: The anti-cancer effects of hymenialdisine or cisplatin were assessed by treating cells with different concentrations of hymenialdisine and cisplatin. Cell viability was determined using the AlamarBlue® Assay. Results: The IC50 of cisplatin was estimated at 31.4 μM for A2780S and 76.9 μM for A2780CP, whereas the IC50 of hymenialdisine was evaluated at 146.8 μM for A2780S cells. Despite the higher concentrations of hymenialdisine (up to 300 μM), IC50 could not be determined for the A2780CP cell line. Conclusion: When compared to cisplatin, hymenialdisine was less toxic against both A2780S and A2780CP ovarian cancer cell lines. Keywords: Ovarian Cancer, Marine compounds, Cisplatin, Hymenialdisine, Oman

Ovarian Cancer and Pregnancy—A Current Problem in Perinatal Medicine: A Comprehensive Review

The frequency of concomitant adnexal tumors in pregnancy is reported to be at 0.15–5.7%, while ovarian cancer complicates 1 in 15,000 to 1 in 32,000 pregnancies, being the second most common gynecologic cancer diagnosed during pregnancy. The aim of this review is to discuss the problem of ovarian cancer complicating pregnancy and the current recommendations for diagnostics and treatment, with an emphasis on the risk to the fetus. A detailed analysis of the literature found in the PubMed and MEDLINE databases using the keywords “ovarian cancer”, “ovarian malignancy”, “adnexal masses”, “ovarian tumor” and “pregnancy” was performed. There were no studies on a large series of pregnant women treated for ovarian malignancies and the management has not been well established. The diagnostics and therapeutic procedures need to be individualized with respect to the histopathology of the tumor, its progression, the gestational age at the time of diagnosis and the mother’s decisions regarding pregnancy preservation. The multidisciplinary cooperation of specialists in perinatal medicine, gynecological oncology, chemotherapy, neonatology and psychology seems crucial in order to obtain the best possible maternal and neonatal outcomes.

Manejo del cáncer de ovario durante el embarazo

The most common gynecological malignancies during pregnancy are cervical cancer, followed by malignant ovarian tumors. During pregnancy, gynecological examination is limited and the rate of misdiagnosis is higher. Although the appearance of ovarian tumors during pregnancy is relatively common, most of them are functional and resolve spontaneously. Treatment during pregnancy is related to factors such as tumor size, histological type, gestational age, lymph node involvement and willingness of women to continue the pregnancy. In early-stage malignant tumors, surgery should be planned preferably after 16 weeks of pregnancy and chemotherapy can be administered from the second trimester as in non-pregnant patients. Prognosis is not affected by pregnancy. The result of pregnant woman with ovarian cancer is similar to non-pregnant patients. Keywords: Ovarian cancer, Pregnancy, Management, Diagnosis, Treatment. 332

ROLE OF CANCER STEM CELLS IN OVARIAN CARCINOGENESIS

Ovarian cancer (OC) is an aggressive malignant tumor (MT) with a relapsing course and a low 5-year survival rate. Most cases are diagnosed at advanced stages, while treatment options for OC are limited. Thus, the development of primary or secondary resistance to standard chemotherapy is often fatal for patients. MT heterogeneity contributes to the survival of the most adapted cells during the selection; such cells need high tumorigenicity in the site of a disease for further expansion of the surviving clone and fixation of a stable phenotype in the focus. Cancer stem cells (CSCs) combine these characteristics and are at the top of the hierarchical tumor structure. Their biological properties, such as the ability to self-renewal, and multilinear differentiation, are similar to those of normal human stem cells. Phenotypic plasticity and interaction with other parenchyma components, tumor stroma, and extra-tumor elements allow CSCs to withstand unfavorable conditions, such as chemotherapy, immunological surveillance, physical damaging factors and anoikis in the blood and lymphatic bed, and unusual microenvironment of targeted metastasis organs in the case of distant metastasis. More and more research articles are devoted to finding ways to use CSCs as a predictive and prognostic biomarker and as a target for therapy. However, unambiguous identification of CSCs, their counting, and specific elimination are a difficult problem. Currently, science is at the stage of accumulating data on this topic. The review summarizes current advances in understanding CSC biology and their impact on OC clinical progression. The literature search was carried out in PubMed, Google Scholar, and eLibrary databases. Keywords: ovarian cancer, cancer stem cells, chemotherapy, carcinogenesis, drug resistance. Рак яичников (РЯ) – агрессивная злокачественная опухоль (ЗО) с рецидивирующим течением и низкой 5-летней выживаемостью пациенток. Большинство случаев диагностируется на распространенных стадиях, а терапевтические опции при РЯ ограничены, поэтому развитие первичной или вторичной резистентности к стандартной химиотерапии часто является фатальным для больной. Гетерогенность ЗО приводит к тому, что в ходе селекции выживают наиболее адаптированные клетки; для дальнейшей экспансии выжившего клона и закрепления устойчивого фенотипа в очаге им необходима высокая туморогенность. Стволовые опухолевые клетки (СОК) сочетают в себе эти характеристики и стоят на вершине иерархической структуры опухоли. Их биологические свойства, такие как способность к самообновлению, мультилинейная дифференцировка, схожи со свойствами нормальных стволовых клеток человека. Пластичность фенотипа и взаимодействие с иными составляющими паренхимы, стромы опухоли, а также внеопухолевыми элементами позволяют СОК противостоять неблагоприятным условиям: воздействию химиопрепаратов, иммунологическому надзору, физическим повреждающим факторам и аноикису в кровеносном и лимфатическом русле, непривычному микроокружению таргетных органов при отдаленном метастазировании. Все больше работ посвящается поиску путей использования СОК как предиктивного и прогностического биомаркера и как мишени для терапии, однако их однозначная идентификация, подсчет и специфическая элиминация представляют сложную проблему. В настоящее время наука находится на этапе накопления данных по этой тематике. В обзоре суммированы современные достижения в понимании биологии СОК и их влияния на клиническое течение РЯ. Поиск литературы осуществлялся по базам данных PubMed, Google Scholar, eLibrary. Ключевые слова: рак яичников, стволовые опухолевые клетки, химиотерапия, канцерогенез, лекарственная устойчивость.

Identification of a gene set correlated with immune status in ovarian cancer by transcriptome-wide data mining

Background : Ovarian cancer (OC) is a serious tumor disease in gynecology. Many papers have reported that high tumor mutational burden (TMB) can generate many neoantigens to result in a higher degree of tumor immune infiltration, so our study aims to predict the key molecules in OC immunotherapy by combined TMB with immunoactivity-related gene. Method: We divided OC cases into two groups: the low & high TMB group hinged on the somatic mutation data from the Cancer Genome Atlas (TCGA). We also used single-sample gene set enrichment analysis (ssGSEA) scores of immune cell types to conduct unsupervised clustering of OC patients in the TCGA cohort and some of them were defined as the low & high immunity group. Besides, to further understand the function of these genes, we conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, protein-protein interaction network, survival prognosis analysis and immune infiltration analysis. Finally, the effects on prognosis and immunotherapy in OC patients were explored by the Group on Earth Observations verification the patients' responses to immunotherapy. Results: We found that the higher the TMB was associated with the higher OC grades. Moreover, both high TMB and high immunity were significantly correlated with a good prognosis of OC. Then, 14 up-regulated differential expression genes (Up-DEGs) that were closely related to the prognosis of OC patients were screened according to the high TMB group and the high immunity group. Next, pathway analysis revealed that Up-DGEs were mainly involved in immune response and T cell proliferation. Finally, four genes had a good prognosis and were validated in the GEO dataset which included CXCL13, FCRLA, PLA2G2D, and MS4A1. We also identified that four genes had a good prognosis in melanoma patients treated with anti-PD-L1 and anti-CTLA-4 in the TIDE database. Conclusion: High TMB can promote immune cell infiltration and increases immune activity. And our analysis also demonstrated that the higher the TMB, the higher the immune activity, the better the prognosis of OC. Altogether, we found that CXCL13, FCRLA, PLA2G2D, and MS4A1 may be biomarkers for OC immunotherapy. Keywords: ovarian cancer, TMB, immune cells infiltration, survival prognosis.

Identifying Potential Markers for Monitoring Progression to Ovarian Cancer Using Plasma Label-free Proteomics

PurposeCancer antigen 125 (CA125) is considered to have high sensitivity but poor specificity for ovarian cancer. New biomarkers utilized to early detect and monitor the progression of ovarian cancer patients are critically needed. Methods A total of 80 patients including 16 early stage, and matched with 17 late stage, 23 benign ovarian tumor (BOT) and 24 uterine fibroid (UF) patients were utilized to perform plasma proteomics analysis using isobaric tag for relative and absolute quantitation (iTRAQ) method to identify differential diagnostic proteins of ovarian cancer patients. A validation set of 9 early stage, 11 late stage, 17 BOT and 16 UF collected by an independent cohort of samples with the same matching principles was examined to confirm the expressed levels of differential expression proteins by ELISA analysis. Results CRP and ARHGEF 11 were identified as potential diagnostic biomarkers of ovarian cancer. Results of area under the curve (AUC) analysis suggested that combination of diagnostic proteins and CA125 achieved a much higher diagnostic accuracy compared with CA125 alone (AUC values: 0.98 versus 0.80), especially improved the specificity (0.97 versus 0.77). In addition, elevated plasma CRP levels were associated with increased risk of ovarian cancer. Conclusions Current study found that plasma protein CRP was an indicator for monitoring the progression of ovarian cancer. Combination of plasma protein biomarkers with CA125 could be utilized to early diagnose of ovarian cancer patients. Keywords ovarian cancer, proteomics, diagnosis, progression, CRP

EXPRESSION LEVEL OF DRUG RESISTANCE GENES IN THE TUMOR OF OVARIAN CANCER PATIENTS AFTER NEOADJUVANT CHEMOTHERAPY

The purpose of the paper is to evaluate the relationship between the expression of drug resistance genes in the tumor tissue of patients with ovarian cancer after neoadjuvant chemotherapy (NAChT) with clinical and pathological disease parameters. Materials and Methods. The study included 26 patients with ovarian cancer who had undergone NAChT according to the AP scheme. The authors used paired samples of normal and tumor ovatian tissue as material for their study. The expression level of ABCB1, ERCC1, and TOP2A genes was evaluated by real-time PCR. Results. It was found out that in patients under 60 years of age, the level of ABCB1 expression is higher than in patients over 60. ERCC1 and TOP2A expression in different age groups was the same. The linkage between the studied genes, tumor size and metastasis was not discovered. TOP2A and ABCB1 expression levels in patients with and without relapses did not differ significantly. In patients with relapses, the level of ERCC1 expression is higher than in patients without relapses. In patients with a normal CA-125 value, the level of ERCC1 expression is lower than in patients with a high CA-125 value. An analysis of the linkage between the expression of the studied genes and the general and relapse-free patient survival did not give significant results. Conclusion. The level of ABCB1expression is associated with the patients’ age, while the level of ERCC1expression is connected with disease recurrence and CA-125. In general, the expression of the studied genes weakly correlates with the main clinical and pathological disease parameters. Keywords: ovarian cancer, neoadjuvant chemotherapy, expression, drug resistance genes ABCB1, ERCC1, TOP2A. Цель работы – оценка связи экспрессии генов лекарственной устойчивости в опухолевой ткани больных раком яичников после проведения неоадъювантной химиотерапии (НАХТ) с клинико-патологическими параметрами заболевания. Материалы и методы. В исследование вошли 26 больных раком яичников после НАХТ по схеме АР. Материал для исследования – парные образцы нормальной и опухолевой ткани яичников. Уровень экспрессии генов ABCB1, ERCC1 и TOP2A оценивали при помощи ПЦР в реальном времени. Результаты. Выявлено, что у больных до 60 лет уровень экспрессии гена ABCB1 выше, чем у больных старше 60 лет. Экспрессия ERCC1 и TOP2A в разных возрастных группах не отличалась. Не установлена связь изучаемых генов с размером опухоли и метастазированием. Уровень экспрессии генов TOP2A и ABCB1 у больных с рецидивами и без них достоверно не отличался. У больных с рецидивами уровень экспрессии ERCC1 выше, чем у больных без рецидивов. У больных с нормальным значением СА-125 уровень экспрессии ERCC1 ниже, чем у больных с высоким показателем. Анализ связи экспрессии исследуемых генов с общей и безрецидивной выживаемостью больных не дал значимых результатов. Выводы. Уровень экспрессии гена ABCB1 связан с возрастом пациентов, а уровень экспрессии ERCC1 – с рецидивом заболевания и СА-125. В целом экспрессия изучаемых генов слабо коррелирует с основными клинико-патологическими параметрами заболевания. Ключевые слова: рак яичников, неоадъювантная химиотерапия, экспрессия, гены лекарственной устойчивости ABCB1, ERCC1, ТОР2А.

BLOOD SERUM CYTOKINE STATUS IN OVARIAN CANCER PATIENTS WITH DIFFERENT LEVELS OF CIRCULATING TUMOR CELLS

Circulating tumor cells (CTCs) are essential for hematogenous metastasis. In 2003, it was found out that such cells were present in the blood of patients diagnosed with ovarian cancer (OC). It is known that inflammation plays an important role in tumor progression. There are CSCs with a large number of components in the blood, e.g. cytokines that can modulate the metastatic potential of a tumor cell. The aim of the study is to assess the blood serum cytokine status in ovarian cancer patients with different levels of circulating tumor cells. Materials and Methods. Untreated primary patients (n=24) with histologically or cytologically verified ovarian cancer, stage II–IV according to FIGO classification, were the trial subjects. Flow cytometry was used to detect the number of circulating tumor cells in the blood from the patients; the authors also determined IL-6, IL-17A, IL-1β, TGF-α, IL-4, VEGF, TNF-α, HGF, IL-18, IL-10, IL-8 levels. The results were processed using the Statistica Windows software package. Results. The authors determined that TNF-α, HGF, IL-10, IL-18 cytokine level in the blood serum from OC patients significantly increased, and IL-8 level decreased with CTC increase. Conclusion. The obtained results suggest a correlation of CTC level with TNF-α, HGF, IL-10, IL-18, IL-8 cytokine serum level in patients diagnosed with advanced ovarian cancer. At the same time, a sharp and significant increase in TNF-α level accompanied with CTC increase may indicate a change in the phenotypes of TNF-producing cells in OC. Keywords: ovarian cancer, cytokines, circulating tumor cells. Циркулирующие опухолевые клетки (ЦОК) представляют собой основу гематогенного метастазирования. В 2003 г. было продемонстрировано их существование в крови больных раком яичников (РЯ). Известно, что воспаление играет важную роль в прогрессировании опухолей. В крови ЦОК встречаются с большим количеством компонентов, в т.ч. с цитокинами, которые способны модулировать метастатический потенциал опухолевой клетки. Целью данного исследования была оценка цитокинового статуса сыворотки крови больных раком яичников с различным уровнем циркулирующих опухолевых клеток. Материалы и методы. Объектом исследования явились первичные больные с верифицированным (гистологически либо цитологически) раком яичников II–IV степеней по FIGO (n=24) до лечения. В крови пациенток определяли число циркулирующих опухолевых клеток методом проточной цитофлюориметрии и уровни IL-6, IL-17A, IL-1β, TGF-α, IL-4, VEGF, TNF-α, HGF, IL-18, IL-10, IL-8. Обработку результатов проводили с использованием пакета программ Statistica Windows. Результаты. Было установлено, что уровень цитокинов TNF-α, HGF, IL-10, IL-18 в сыворотке крови больных РЯ статистически значимо повышался, а уровень IL-8 снижался с увеличением количества ЦОК. Выводы. Полученные результаты позволяют предполагать корреляцию уровня ЦОК с сывороточным уровнем цитокинов TNF-α, HGF, IL-10, IL-18, IL-8 у больных распространенным РЯ. При этом резкое и значимое возрастание уровня TNF-α при увеличении числа ЦОК может свидетельствовать о смене фенотипов TNF-продуцирующих клеток при РЯ. Ключевые слова: рак яичников, цитокины, циркулирующие опухолевые клетки.

The Regulatory Roles of Long Non-Coding RNA in the Chemoresistance Process of Ovarian cancer

Background: Ovarian cancer is the most malignant tumor in gynecological tumors, with low five-year survival rate. The main reasons are diagnosis at advanced stages (the early symptoms are uncharacteristic, and most are diagnosedlate.), relapse, and resistance to existing chemotherapy drugs. Methods: Search strategy was performed in the following steps. Firstly, LncRNA related to ovarian cancer was retrieved by using the LncRNA Disease database, and articles were searched by searching keywords: ovarian cancer, drug resistance, and LncRNA retrieved from the LncRNA Disease database. Results/Conclusion: With the development of the study on drug resistance of ovarian cancer, the role of LncRNAs as sensitive biomarker and therapeutic target has emerged, providing a direction for precision medicine of ovarian cancer resistance.