The Role and Applications of Exosomes in Gynecological Cancer: A Review.

Exosomes are phospholipid bilayer vesicles that are released by all types of cells, containing proteins, lipids, and nucleic acids such as DNAs and RNAs. Exosomes can be transferred between cells and play a variety of physiological and pathological regulatory functions. Noncoding RNAs, including micro RNAs, long noncoding RNAs, and circular RNAs, are the most studied biomolecules from exosomes and more and more studies found that noncoding RNAs play an important role in the diagnosis, prognosis, and treatment of diseases, including various types of cancer. Gynecological malignancies such as ovarian, endometrial, and cervical cancer seriously threaten women's life. Therefore, this article reviews the roles and applications of exosomes in gynecological malignancies, including the promotion or inhibition of tumor progression and regulation of tumor microenvironments, and as potential therapeutic targets for treating gynecological cancers.

Role of microRNAs in glycolysis in gynecological tumors (Review).

Gynecological malignancies are a leading cause of mortality among females worldwide, and difficulties in early diagnosis and acquired drug resistance constitute obstacles to effective therapies. Ovarian cancer causes more deaths than any other cancer of the female reproductive system. Specifically, in females aged 20 to 39 years, cervical cancer is the third leading cause of cancer­related mortality, and the incidence rates of cervical adenocarcinoma are increasing. Endometrial carcinoma is the most common gynecological cancer in developed countries, such as the United States. Vulvar cancer and uterine sarcomas are considered rare, and therefore require further investigation. Notably, the development of novel treatment options is critical. Previous research has revealed metabolic reprogramming as a distinct feature of tumor cells, which includes aerobic glycolysis. In this instance, cells produce adenosine triphosphate and various precursor molecules through glycolysis, despite oxygen levels being sufficient. This is to meet the energy required for rapid DNA replication. This phenomenon is also known as the Warburg effect. The Warburg effect results in an increased glucose uptake, lactate production and reduced pH values in tumor cells. The results of previous studies have demonstrated that microRNAs (miRNAs/miRs) regulate glycolysis, and participate in tumorigenesis and tumor progression via interactions with glucose transporters, essential enzymes, tumor suppressor genes, transcription factors and multiple cellular signaling pathways that play critical roles in glycolysis. Notably, miRNAs affect the levels of glycolysis in ovarian, cervical and endometrial cancers. The present review article provides a comprehensive overview of the literature surrounding miRNAs in the glycolysis of gynecological malignant cells. The present review also aimed to determine the role of miRNAs as potential therapeutic options rather than diagnostic markers.

Network Medicine-Based Analysis of Association Between Gynecological Cancers and Metabolic and Hormonal Disorders.

Different metabolic and hormonal disorders like type 2 diabetes mellitus (T2DM), obesity, and polycystic ovary syndrome (PCOS) have tangible socio-economic impact. Prevalence of these metabolic and hormonal disorders is steadily increasing among women. There are clinical evidences that these physiological conditions are related to the manifestation of different gynecological cancers and their poor prognosis. The relationship between metabolic and hormonal disorders with gynecological cancers is quite complex. The need for gene level association study is extremely important to find markers and predicting risk factors. In the current work, we have selected metabolic disorders like T2DM and obesity, hormonal disorder PCOS, and 4 different gynecological cancers like endometrial, uterine, cervical, and triple negative breast cancer (TNBC). The gene list was downloaded from DisGeNET database (v 6.0). The protein interaction network was constructed using HIPPIE (v 2.2) and shared proteins were identified. Molecular comorbidity index and Jaccard coefficient (degree of similarity) between the diseases were determined. Pathway enrichment analysis was done using ReactomePA and significant modules (clusters in a network) of the constructed network was analyzed by MCODE plugin of Cytoscape. The comorbid conditions like PCOS-obesity found to increase the risk factor of ovarian and triple negative breast cancers whereas PCOS alone has highest contribution to the endometrial cancer. Different gynecological cancers were found to be differentially related to the metabolic/hormonal disorders and comorbid condition.

The Relevant Participation of Prolactin in the Genesis and Progression of Gynecological Cancers.

Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hormone's modulation in cancer cells. This work aims to review the most important findings regarding the PRL/PRLR axis in cervical, ovarian, and endometrial cancers and its molecular mechanisms to support carcinogenesis.

Phase I evaluation of lenvatinib and weekly paclitaxel in patients with recurrent endometrial, ovarian, fallopian tube, or primary peritoneal Cancer.

OBJECTIVES: To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer. METHODS: Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria. RESULTS: 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months. CONCLUSIONS: The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.

The Microbiome and Gynecologic Cancer: Current Evidence and Future Opportunities.

PURPOSE OF REVIEW: We review the emerging evidence regarding the relationship between the microbiota of the gastrointestinal and female reproductive tracts and gynecologic cancer. RECENT FINDINGS: The microbiome has essential roles in maintaining health. In recent years, the microbiota of the gastrointestinal and female reproductive tracts have been linked to many diseases, including gynecologic cancer. Alterations to the bacterial populations in a microbiota, or dysbiosis, have been shown to favor a pro-carcinogenic state through altered immune responses, dysregulated hormone metabolism, and modulation of the cell cycle. Pre-clinical and clinical studies have emerged, demonstrating that specific bacteria or microbial communities may be associated with increased risk for uterine, ovarian, and cervical cancers. Notably, numerous studies have linked a non-Lactobacillus-dominant vaginal microbiota, composed of anaerobic bacteria, with HPV infection, persistence, and development of invasive cervical cancer. Similarly, next-generation high-throughput sequencing techniques have enabled the characterization of unique microbiotas in patients with malignant and benign gynecologic conditions, shedding light on new associations between bacterial species and gynecologic cancers. Harnessing the power of the microbiome for early diagnosis, therapeutic intervention and modulation creates tremendous potential to optimize gynecologic cancer outcomes in the future.

An emerging role for BAG3 in gynaecological malignancies.

BAG3, a member of the BAG family of co-chaperones, is a multidomain protein with a role in several cellular processes, including the control of apoptosis, autophagy and cytoskeletal dynamics. The expression of bag3 is negligible in most cells but can be induced by stress stimuli or malignant transformation. In some tumours, BAG3 has been reported to promote cell survival and resistance to therapy. The expression of BAG3 has been documented in ovarian, endometrial and cervical cancers, and studies have revealed biochemical and functional connections of BAG3 with proteins involved in the survival, invasion and resistance to therapy of these malignancies. BAG3 expression has also been shown to correlate with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix. Some aspects of BAG3 activity, such as its biochemical and functional interaction with the human papillomavirus proteins, could help in our understanding of the mechanisms of oncogenesis induced by the virus. This review aims to highlight the potential value of BAG3 studies in the field of gynaecological tumours.

Decoupling epithelial-mesenchymal transitions from stromal profiles by integrative expression analysis.

Epithelial-to-mesenchymal transition (EMT) is the most commonly cited mechanism for cancer metastasis, but it is difficult to distinguish from profiles of normal stromal cells in the tumour microenvironment. In this study we use published single cell RNA-seq data to directly compare mesenchymal signatures from cancer and stromal cells. Informed by these comparisons, we developed a computational framework to decouple these two sources of mesenchymal expression profiles using bulk RNA-seq datasets. This deconvolution offers the opportunity to characterise EMT across hundreds of tumours and examine its association with metastasis and other clinical features. With this approach, we find three distinct patterns of EMT, associated with squamous, gynaecological and gastrointestinal cancer types. Surprisingly, in most cancer types, EMT patterns are not associated with increased chance of metastasis, suggesting that other steps in the metastatic cascade may represent the main bottleneck. This work provides a comprehensive evaluation of EMT profiles and their functional significance across hundreds of tumours while circumventing the confounding effect of stromal cells.

Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review).

Cancers of the urinary tract, as well as those of the female and male reproductive systems, account for a large percentage of malignancies worldwide. Mortality is frequently affected by late diagnosis or therapeutic difficulties. The Sonic Hedgehog (SHH) pathway is an evolutionary conserved molecular cascade, which is mainly associated with the development of the central nervous system in fetal life. The present review aimed to provide an in­depth summary of the SHH signaling pathway, including the characterization of its major components, the mechanism of its upstream regulation and non­canonical activation, as well as its interactions with other cellular pathways. In addition, the three possible mechanisms of the cellular SHH cascade in cancer tissue are discussed. The aim of the present review was to summarize significant findings with regards to the expression of the SHH pathway components in kidney, bladder, ovarian, cervical and prostate cancer. Reports associated with common deficits and de­regulations of the SHH pathway were summarized, despite the differences in molecular and histological patterns among these malignancies. However, currently, neither are SHH pathway elements included in panels of prognostic/therapeutic molecular patterns in any of the discussed cancers, nor have the drugs targeting SMO or GLIs been approved for therapy. The findings of the present review may support future studies on the treatment of and/or molecular targets for gynecological and genitourinary cancers.

Melatonin and its mechanism of action in the female reproductive system and related malignancies.

Melatonin (N-acetyl-5-methoxytryptamine), the main product of pineal gland in vertebrates, is well known for its multifunctional role which has great influences on the reproductive system. Recent studies documented that melatonin is a powerful free radical scavenger that affects the reproductive system function and female infertility by MT1 and MT2 receptors. Furthermore, cancer researches indicate the influence of melatonin on the modulation of tumor cell signaling pathways resulting in growth inhibitor of the both in vivo/in vitro models. Cancer adjuvant therapy can also benefit from melatonin through therapeutic impact and decreasing the side effects of radiation and chemotherapy. This article reviews the scientific evidence about the influence of melatonin and its mechanism of action on the fertility potential, physiological alteration, and anticancer efficacy, during experimental and clinical studies.

Autophagy signals orchestrate chemoresistance of gynecological cancers.

Gynecological cancers are characterized by a high mortality rate when chemoresistance develops. Autophagy collaborates with apoptosis and participates in homeostasis of chemoresistance. Recent findings supported that crosstalk of necrotic, apoptotic and autophagic factors, and chemotherapy-driven hypoxia, oxidative stress and ER stress play critical roles in chemoresistance in gynecological cancers. Meanwhile, current studies have shown that autophagy could be regulated by and cooperate with metabolic regulator, survival factors, stemness factors and specific post-translation modification in chemoresistant tumor cells. Meanwhile, non-coding RNA and autophagy crosstalk also contribute to the chemoresistance. Until now, analysis of individual autophagy factors towards the clinical significance and chemoresistance in gynecological cancer is still lacking. We suggest comprehensive integrated analysis of cellular homeostasis and tumor microenvironment to clarify the role of autophagy and the associated factors in cancer progression and chemoresistance. Panel screening of pan-autophagic factors will pioneer the development of risk models for predicting efficacy of chemotherapy and guidelines for systematic treatment and precision medicine.

Long Non-coding RNA NEAT1 as an Emerging Biomarker in Breast and Gynecologic Cancers: a Systematic Overview.

Long non-coding RNAs (lncRNAs) are emerging regulators of cellular pathways, especially in cancer development. Among the lncRNAs, nuclear paraspeckle assembly transcript 1 (NEAT1) forms a scaffold for a nuclear body; the paraspeckle and aberrant expression of NEAT1 have been reported in breast and gynecologic cancers (ovarian, cervical, endometrial, and vulvar). Abundantly expressed NEAT1 in breast and gynecologic cancers generally contribute to tumor development by sponging its corresponding tumor-suppressive microRNAs or interacting with various regulatory proteins. The distinct expression of NEAT1 and its contribution to tumorigenic pathways make it a promising therapeutic target in breast and gynecologic cancers. Herein, we summarize the functions and molecular mechanisms of NEAT1 in human breast, ovarian, cervical, endometrial, and vulvar cancers. Furthermore, we emphasize its critical role in the formation of paraspeckle development and its functions. Conclusively, NEAT1 is a considerable biomarker with a bright prospect and can be therapeutically targeted to manage breast and gynecologic cancers.

Exosomal microRNAs and exosomal long non-coding RNAs in gynecologic cancers.

Gynecologic cancer is a group of any malignancies affecting reproductive tissues and organs of women, including ovaries, uterine, cervix, vagina, vulva, and endometrium. Several types of molecular mechanisms are associated with the progression of gynecologic cancers. Among it can be referred to the most widely studied non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long ncRNAs (lncRNAs). As yet, lncRNAs are known to serve key biological roles via various mechanisms, such as splicing regulation, chromatin rearrangement, translation regulation, cell-cycle control, genetic imprinting and mRNA decay. Besides, miRNAs govern gene expression by modulation of mRNAs and lncRNAs degradation, suggestive of needing more research in this field. Generally, driving gynecological cancers pathways by miRNAs and lncRNAs lead to the current improvement in cancer-related technologies. Exosomes are extracellular microvesicles which can carry cargo molecules among cells. In recent years, more studies have been focused on exosomal non-coding RNAs (exo-ncRNAs) and exosomal microRNAs (exo-miRs) because of being natural carriers of lnc RNAs and microRNAs via programmed process. In this review we summarized recent reports concerning the function of exosomal microRNAs and exosomal long non-coding RNAs in gynecological cancers.

Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer.

We investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.

Loss of ARID1B and SMARCB1 expression are specific for the diagnosis of dedifferentiated/undifferentiated carcinoma in tumours of the upper gynaecological tract and cervix.

AIMS: Genomic inactivation of ARID1B in ARID1A-inactivated tumour and genomic inactivation of SMARCB1 represent two recurrent mechanisms, core SWItch/sucrose non-fermentable (SWI/SNF) complex inactivation, that are associated with de-differentiation in endometrial carcinoma. Approximately one-third of dedifferentiated/undifferentiated endometrial carcinomas (DDEC/UEC) show loss of ARID1B expression with a minor subset showing loss of SMARCB1 expression, but little is known regarding the specificity of ARID1B or SMARCB1 loss in gynaecological tract tumours in general. The aim of this study was to examine the frequency of ARID1B and SMARCB1 loss by immunohistochemistry in a series of gynaecological tract epithelial/mesenchymal neoplasms. METHODS AND RESULTS: We evaluated 1849 tumours that included 748 endometrial carcinomas, 101 uterine carcinosarcomas/adenosarcomas, 64 uterine sarcomas, 221 cervical carcinomas and 715 ovarian carcinomas/borderline tumours by tissue microarrays (TMA). We observed ARID1B loss in 35 of 86 (41%) and SMARCB1 loss in three of 86 (3%) DDEC/UEC, but not in any other uterine tumour types examined. ARID1B-deficient DDEC/UEC also showed concurrent loss of ARID1A expression. All SMARCB1-deficient tumours showed loss of MLH1 and PMS2, while 29 of 35 ARID1B-deficient tumours showed loss of MLH1 and PMS2 or loss of MSH6. All ovarian carcinomas/borderline tumours and cervical carcinomas showed intact expression of ARID1B and SMARCB1. CONCLUSION: Our findings indicate that the loss of expression of ARID1B or SMARCB1 by immunohistochemistry is highly specific for undifferentiated carcinoma among tumours of the upper gynaecological tract and cervix, and therefore can be used to identify these highly aggressive malignant tumours.

Determining the significance of psammoma bodies in pelvic washings: A 10-year retrospective review.

BACKGROUND: Pelvic washing specimens are relatively common and are submitted for patients undergoing gynecologic surgery to evaluate them for metastatic or occult disease. Psammoma bodies are a relatively uncommon finding in these specimens. To date, large-scale studies of their cytologic-histologic correlates and thus clinical significance have been limited. METHODS: A 10-year retrospective search for all pelvic washing specimens was performed, and all cases were reviewed for the presence of psammoma bodies. The findings for the corresponding surgical pathology specimens were then catalogued. RESULTS: Psammoma bodies were present in 138 cases (3.6% of 3840 total pelvic washings). More than half of the cases (n = 73 [53%]) were associated with benign processes, including mesothelial hyperplasia (n = 44), endosalpingiosis (n = 11), endometriosis (n = 11), and ovarian cystadenoma/cystadenofibroma (n = 7). Nineteen cases (14%) were associated with serous borderline tumors. Malignancies were noted in a third of the cases (n = 46 [33%]) and were most frequently low-grade serous adenocarcinomas (n = 15), high-grade serous adenocarcinomas (n = 11), or endometrioid endometrial carcinomas (n = 8). Patients found to have benign processes (median age, 50 years) or borderline disease (median age, 56 years) were significantly younger than patients with malignancies (median age, 65 years; P < .0001). In addition, the correlation of cytologic interpretation categories with concurrent histopathologic findings showed that cytologic analysis was highly sensitive and specific in determining the nature of underlying processes. CONCLUSIONS: The majority of psammoma bodies noted in pelvic washings were associated with benign processes or borderline tumors, with approximately a third of the cases associated with malignancies. Psammoma bodies in pelvic washings from younger patients were significantly more likely to be associated with benign processes or borderline tumors.

DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing.

Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of "new" morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1-associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

The Role of Zinc and Copper in Gynecological Malignancies.

Zinc (Zn) and copper (Cu) are essential microelements, which take part in cellular metabolism, feature in enzymatic systems, and regulate enzyme activity. Homeostasis of these micronutrients is tightly regulated by multiple compensatory mechanisms that balance their concentrations including transporters, importers, and metallothioneins. An altered intake of only one of these trace elements may cause an imbalance in their levels and result in their competition for absorption. Relatively low levels of zinc and increased levels of copper may result in an increased level of oxidative stress and impair the antioxidant properties of multiple enzymes. Altered levels of trace elements were discovered in various pathologies including immunological, degenerative, and inflammatory diseases. Moreover, due to the role of Zn and Cu in oxidative stress and chronic inflammation, they were found to influence cancerogenesis. We review the roles of zinc and copper and their mechanisms in tumor growth, metastasis potential, microenvironment remodeling, and drug resistance. We highlight their role as potential biomarkers for cancer diagnosis, treatment, and prognosis, concentrating on their impact on gynecological malignancies.