Differential microRNA Expression Analysis in Patients with HPV-Infected Ovarian Neoplasms.

This study aimed to identify microRNAs (miRNAs) whose expression levels are altered by high-risk human papillomavirus (HR-HPV) infection in women with epithelial ovarian neoplasms. MiRNA expression was quantified by real-time polymerase chain reaction, while HR-HPV DNA was quantified using digital-droplet PCR. Analysis of 11 miRNAs demonstrated significantly lower hsa-miR-25-5p expression in HPV-infected compared to uninfected ovarian tissues (p = 0.0405), while differences in miRNA expression in corresponding serum were statistically insignificant. The expression of hsa-miR-218-5p in ovarian tumors was significantly higher in high-grade serous ovarian carcinoma (HGSOC) cases than in other neoplasms (p = 0.0166). In addition, hsa-miR-218-5p was significantly upregulated, whereas hsa-miR-191-5p was significantly downregulated in tissues with stage III/IV FIGO (p = 0.0009 and p = 0.0305, respectively). Using unsupervised clustering, we identified three unique patient groups with significantly varied frequencies of HPV16/18-positive samples and varied miRNA expression profiles. In multivariate analysis, high expression of hsa-miR-16-5p was an independent prognostic factor for poor overall survival (p = 0.0068). This preliminary analysis showed the changes in miRNA expression in ovarian neoplasms during HPV infection and those collected from HGSOCs or patients with advanced disease. This prospective study can provide new insights into the pathogenesis of ovarian neoplasms and host-virus interactions.

High-Grade Serous Ovarian Cancer-A Risk Factor Puzzle and Screening Fugitive.

High-grade serous ovarian cancer (HGSOC) is the most lethal tumor of the female genital tract. Despite extensive studies and the identification of some precursor lesions like serous tubal intraepithelial cancer (STIC) or the deviated mutational status of the patients (BRCA germinal mutation), the pathophysiology of HGSOC and the existence of particular risk factors is still a puzzle. Moreover, a lack of screening programs results in delayed diagnosis, which is accompanied by a secondary chemo-resistance of the tumor and usually results in a high recurrence rate after the primary therapy. Therefore, there is an urgent need to identify the substantial risk factors for both predisposed and low-risk populations of women, as well as to create an economically and clinically justified screening program. This paper reviews the classic and novel risk factors for HGSOC and methods of diagnosis and prediction, including serum biomarkers, the liquid biopsy of circulating tumor cells or circulating tumor DNA, epigenetic markers, exosomes, and genomic and proteomic biomarkers. The novel future complex approach to ovarian cancer diagnosis should be devised based on these findings, and the general outcome of such an approach is proposed and discussed in the paper.

miRNA Expression Profiles in Ovarian Endometriosis and Two Types of Ovarian Cancer-Endometriosis-Associated Ovarian Cancer and High-Grade Ovarian Cancer.

Endometriosis-associated ovarian cancer (EOC) consisting of endometrioid cancer and clear-cell ovarian cancer could be promoted by many factors. miRNAs, which are small, non-coding molecules of RNA, are among them. The aim of this study was to detect miRNAs connected with the malignant transformation of endometriosis. FFPE (formalin-fixed, paraffin-embedded) samples of 135 patients operated on for endometriosis and different types of ovarian cancer (EOC and HGSOC-high-grade serous ovarian cancer) were studied. Healthy ovarian tissue was used as a control group. From the expression panel of 754 miRNAs, 7 were chosen for further tests according to their ROC (receiver operating characteristic) curves: miR-1-3p, miR-125b-1-3p, miR-31-3p, miR-200b-3p, miR-502-5p, miR-503-5p and miR-548d-5p. Furthermore, other potentially important clinical data were analysed, which included age, BMI, Ca-125 concentration, miscarriages and deliveries and concomitant diseases such as hypertension, type 2 diabetes and smoking. Among the miRNAs, miR200b-3p had the lowest expression in neoplastic tissues. miR31-3p had the highest expression in women without any lesions in the ovaries. miR-502-5p and miR-548-5p did not differ between the studied groups. The examined miRNA panel generally distinguished significantly normal ovarian tissue and endometriosis, normal ovarian tissue and cancer, and endometriosis and cancer. The malignant transformation of endometriosis is dependent on different factors. miRNA changes are among them. The studied miRNA panel described well the differences between endometriosis and EOC but had no potential to differentiate types of ovarian cancer according to their origin. Therefore, examination of a broader miRNA panel is needed and might prove itself advantageous in clinical practice.

"DEPHENCE" system-a novel regimen of therapy that is urgently needed in the high-grade serous ovarian cancer-a focus on anti-cancer stem cell and anti-tumor microenvironment targeted therapies.

Ovarian cancer, especially high-grade serous type, is the most lethal gynecological malignancy. The lack of screening programs and the scarcity of symptomatology result in the late diagnosis in about 75% of affected women. Despite very demanding and aggressive surgical treatment, multiple-line chemotherapy regimens and both approved and clinically tested targeted therapies, the overall survival of patients is still unsatisfactory and disappointing. Research studies have recently brought some more understanding of the molecular diversity of the ovarian cancer, its unique intraperitoneal biology, the role of cancer stem cells, and the complexity of tumor microenvironment. There is a growing body of evidence that individualization of the treatment adjusted to the molecular and biochemical signature of the tumor as well as to the medical status of the patient should replace or supplement the foregoing therapy. In this review, we have proposed the principles of the novel regimen of the therapy that we called the "DEPHENCE" system, and we have extensively discussed the results of the studies focused on the ovarian cancer stem cells, other components of cancer metastatic niche, and, finally, clinical trials targeting these two environments. Through this, we have tried to present the evolving landscape of treatment options and put flesh on the experimental approach to attack the high-grade serous ovarian cancer multidirectionally, corresponding to the "DEPHENCE" system postulates.

How to Improve Non-Invasive Diagnosis of Endometriosis with Advanced Statistical Methods.

Background and Objectives: Endometriosis is one of the most common gynecological disorders in women of reproductive age. Causing pelvic pain and infertility, it is considered one of the most serious health problems, being responsible for work absences or productivity loss. Its diagnosis is often delayed because of the need for an invasive laparoscopic approach. Despite years of studies, no single marker for endometriosis has been discovered. The aim of this research was to find an algorithm based on symptoms and laboratory tests that could diagnose endometriosis in a non-invasive way. Materials and Methods: The research group consisted of 101 women hospitalized for diagnostic laparoscopy, among which 71 had confirmed endometriosis. Data on reproductive history were collected in detail. CA125 (cancer antigen-125) level and VEGF1(vascular endothelial growth factor 1) were tested in blood samples. Among the used statistical methods, the LASSO regression-a new important statistical tool eliminating the least useful features-was the only method to have significant results. Results: Out of 19 features based on results of LASSO, 7 variables were chosen: body mass index, age of menarche, cycle length, painful periods, information about using contraception, CA125, and VEGF1. After multivariate logistic regression with a backward strategy, the three most significant features were evaluated. The strongest impact on endometriosis prediction had information about painful periods, CA125 over 15 u/mL, and the lowest BMI, with a sensitivity of 0.8800 and a specificity of 0.8000, respectively. Conclusions: Advanced statistical methods are crucial when creating non-invasive tests for endometriosis. An algorithm based on three easy features, including painful menses, BMI level, and CA125 concentration could have an important place in the non-invasive diagnosis of endometriosis. If confirmed in a prospective study, implementing such an algorithm in populations with a high risk of endometriosis will allow us to cover patients suspected of endometriosis with proper treatment.

Deficits of Sensory Integration and Balance as Well as Scoliotic Changes in Young Schoolgirls.

The aim of this study was to assess the relationship between sensory integration and balance deficits as well as scoliotic changes in young schoolgirls. The study comprised 54 girls aged 11 years with scoliotic changes. The Clinical Test of Sensory Integration and Balance of the Biodex Balance System platform were used to analyze the deficits in sensory integration and balance. Scoliotic changes were assessed using the Diers Formetric III 4D optoelectronic method. In the present study, there was a significant relationship between sensory integration and balance deficits as well as spine curvature angle (°) (p = 0.01), vertebral surface rotation (°) (p = 0.03), pelvic tilt (°) (p = 0.02), and lateral deviation (mm) (p = 0.04). The integration of the sensory systems has a positive effect on the structure of the intended and controlled movement as well as body posture and the development of the spine. In the treatment of scoliotic changes, one should also consider exercises that improve sensory integration as well as position and balance reactions.

Microvesicles released from ectopic endometrial foci as a potential biomarker of endometriosis.

OBJECTIVES: Angiogenesis is engaged in endometriosis. It is regulated by regulatory factors and cytokines, transported in microvesicles. The purpose was to investigate the presence of MVs with vascular endothelial growth factor (VEGF) and metalloproteinase-9 (MMP-9) in peripheral blood and peritoneal fluid of women operated on for endometrioma or teratoma Material and methods:Microvesicles (MVs) were determined in blood samples and peritoneal fluid samples collected from women aged 20-60 years operated on for endometriosis (test group) and teratoma (control group). The final investigations were performed on 47 patients, who qualified for the study based on the meticulous inclusion criteria. MVs were analyzed by flow cytometry (FACS) using annexin V, antibodies for molecules characteristic of cells from endometriosis foci (keratin 18 (K18), CD105, CD146), and antibodies for intraepithelial vascular growth factor VEGF and metalloproteinase-9 (MMP-9). The sample was double "reading" using flow cytometry (FACSCantoII). RESULTS: Cytometry analysis confirmed MVs' presence in plasma and peritoneal fluid collected from patients with both endometriosis and teratomas. A statistically significant higher level of AnnexinV (+) MVs were observed in plasma samples of endometriosis patients. In the control group, there was a higher percentage of double-positive VEGF (+)/MMP-9 (+) and single MMP-9 (+) positive MVs in the serum. In the peritoneal fluid higher frequency of double-positive VEGF (+)/MMP-9 (+) MVs were found in the control group. However, the amount of VEGF (+) / MMP-9 (+) MVs object did not enable to differentiate between the test and control groups. The study was the first, in which MVs were confirmed in plasma and peritoneal fluid in benign adnexa tumors. CONCLUSIONS: Microvesicles are present in peripheral blood and peritoneal fluid samples collected from patients with endometriosis and teratomas. Microvesicles with proangiogenic factors (VEGF and MMP-9) are more abundant in blood and peritoneal fluid samples from patients with teratomas.

Prediction of Chemoresistance-How Preclinical Data Could Help to Modify Therapeutic Strategy in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is one of the most lethal tumors generally and the most fatal cancer of the female genital tract. The approved standard therapy consists of surgical cytoreduction and platinum/taxane-based chemotherapy, and of targeted therapy in selected patients. The main therapeutic problem is chemoresistance of recurrent and metastatic HGSOC tumors which results in low survival in the group of FIGO III/IV. Therefore, the prediction and monitoring of chemoresistance seems to be of utmost importance for the improvement of HGSOC management. This type of cancer has genetic heterogeneity with several subtypes being characterized by diverse gene signatures and disturbed peculiar epigenetic regulation. HGSOC develops and metastasizes preferentially in the specific intraperitoneal environment composed mainly of fibroblasts, adipocytes, and immune cells. Different HGSOC subtypes could be sensitive to distinct sets of drugs. Moreover, primary, metastatic, and recurrent tumors are characterized by an individual biology, and thus diverse drug responsibility. Without a precise identification of the tumor and its microenvironment, effective treatment seems to be elusive. This paper reviews tumor-derived genomic, mutational, cellular, and epigenetic biomarkers of HGSOC drug resistance, as well as tumor microenvironment-derived biomarkers of chemoresistance, and discusses their possible use in the novel complex approach to ovarian cancer therapy and monitoring.

Personalization of Therapy in High-Grade Serous Tubo-Ovarian Cancer-The Possibility or the Necessity?

High-grade serous tubo-ovarian cancer (HGSTOC) is the most lethal tumor of the female genital tract. The foregoing therapy consists of cytoreduction followed by standard platinum/taxane chemotherapy; alternatively, for primary unresectable tumors, neo-adjuvant platinum/taxane chemotherapy followed by delayed interval cytoreduction. In patients with suboptimal surgery or advanced disease, different forms of targeted therapy have been accepted or tested in clinical trials. Studies on HGSTOC discovered its genetic and proteomic heterogeneity, epigenetic regulation, and the role of the tumor microenvironment. These findings turned attention to the fact that there are several distinct primary tumor subtypes of HGSTOC and the unique biology of primary, metastatic, and recurrent tumors may result in a differential drug response. This results in both chemo-refractoriness of some primary tumors and, what is significantly more frequent and destructive, secondary chemo-resistance of metastatic and recurrent HGSTOC tumors. Treatment possibilities for platinum-resistant disease include several chemotherapeutics with moderate activity and different targeted drugs with difficult tolerable effects. Therefore, the question appears as to why different subtypes of ovarian cancer are predominantly treated based on the same therapeutic schemes and not in an individualized way, adjusted to the biology of a specific tumor subtype and temporal moment of the disease. The paper reviews the genomic, mutational, and epigenetic signatures of HGSTOC subtypes and the tumor microenvironment. The clinical trials on personalized therapy and the overall results of a new, comprehensive approach to personalized therapy for ovarian cancer have been presented and discussed.

Physiotherapy as a Specific and Purposeful Form of Physical Activity in Children with Idiopathic Body Asymmetry.

The aim of the study was to determine the relationship between idiopathic asymmetry in infants and body posture in children at an early school age. The study included 45 girls aged nine. The Diers Formetric III 4D device was used to assess body posture, which allows photogrammetric registration of the back surface using the raster stereography process. For the purposes of the re-search project, the examination was performed via DiCAM using the "Average measurement" mode. Despite physiotherapy, these children had more postural defects later on compared to the control group due to asymmetry. They mainly concerned pelvic skewness, scoliosis angle, deviation from the vertical line and lateral deviation, as well as surface rotation. Positive correlations were observed between direction of asymmetry and pelvic skewness (r = 0.40), and between the location of asymmetry and the location of curvature (r = 0.39). Significant negative correlations were also found between the age of treatment initiation and trunk length (r = -0.42). There was also a negative correlation between the number of physiotherapeutic appointments and deviation from the vertical line, which means that along with an increase in the number of physiotherapeutic visits, the value of deviation from the vertical line decreased (p = -0.40). For scoliosis angle, the most important predictor was the direction of asymmetry (p = 0.05). For the location of the curvature, the most important predictor was the direction of asymmetry (p = 0.04), as well as the number of physiotherapeutic appointments (p = 0.04). Additionally, regression analysis allowed us to show that the number of physiotherapeutic visits (p = 0.03) was the most important predictor of curvature direction. The applied physiotherapy probably contributed to the occurrence of a smaller number of postural defects in these children at a later age. Physiotherapy as a specific and targeted form of physical activity among infants with idiopathic asymmetry should play a very important role in the prevention of body posture defects.

The Importance of Posture and Body Composition for The Stability and Selected Motor Abilities of Professional Handball Players.

The aim of the research was to analyze body composition, body posture and postural stability of professional male handball players and to determine the differences between players with correct and incorrect body posture, considering power of the lower limbs and agility, speed, and change of direction deficit. The study comprised 16 professional handball players. Body composition analysis was performed using the method of electrical bioimpedance. Body posture was examined using the Diers formetric III 4D optoelectronic method. Postural stability was tested via the Biodex Balance System. Players performed the following fitness tests assessing lower limb muscle power (LP, HS, CMJ), linear speed (SLS 20 m), and COD speed (Zig-Zag test, COD deficit). Only 31.25% of players demonstrated body posture with correct physiological curvatures, while 68.75% showed changes in body asymmetry. The group with correct body posture performed better in SLS 20m than the group with incorrect posture, yet in the Zig-Zag agility test, the difference in the results was not significant and this affected the COD deficit, which was higher. The vast majority of participants demonstrated postural defects and incorrect physiological curvatures of the spine. The occurrence of scoliotic posture was also observed. The body deflection angles indicated that athletes' postural stability was good. However, it is worth noting that the majority demonstrated a tendency towards asymmetrical body deflections to the right or to the left, backwards direction. One-sided sports specialization leads to disturbances in the statics of the body, therefore, it becomes necessary to include postural re-education exercises in training.

The Toll-like Receptor 4 Polymorphism Asp299Gly Is Associated with an Increased Risk of Ovarian Cancer.

Ovarian cancer (OC) is one of the most common cancers threatening women's lives around the world. Epithelial ovarian tumors represent the most common ovarian neoplasms. Most OC patients are diagnosed at the advanced stage, and there is an urgent need to identify novel biomarkers of the disease. Single-nucleotide polymorphisms (SNPs) in TLR genes may serve as crucial markers of cancer susceptibility. We investigated the frequency of TLR polymorphisms in a group of 200 women, including 70 with OC. Four SNPs, two each in TLR4 (rs4986790 and rs4986791) and TLR9 (rs187084 and rs5743836), were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The digested fragments were separated and identified by multicapillary electrophoresis. The load quantification of human papillomavirus (HPV) types 16/18 was determined using a digital droplet PCR method. We found an increased frequency of heterozygous genotype and minor allele of the TLR4 rs4986790 SNP in women with OC compared with healthy controls, and this result remained highly significant after Bonferroni's correction for multiple testing (p < 0.0001). No evidence of linkage disequilibrium was found with any of the examined TLR SNPs. The findings suggest that the TLR4 Asp299Gly polymorphism could be a genetic risk factor for the development of OC.

ERAP/HLA-C and KIR Genetic Profile in Couples with Recurrent Implantation Failure.

Proper embryo implantation depends on the tolerance of the maternal immune system to the fetus and its foreign paternal antigens. During implantation and early pregnancy, the dominant leukocytes in the uterus are uterine NK cells, expressing killer immunoglobulin-like receptors (KIR). KIRs recognize human leukocyte antigens (HLA-C) on the human trophoblast inherited from the father and mother. The antigenic peptides presented by the HLA are formed via their cleavage by endoplasmic reticulum aminopeptidases ERAP1 and ERAP2. The aim of this study was to assess the association of combined KIR genes and their HLA-C ligands, as well as ERAP1 and ERAP2 polymorphisms with recurrent implantation failure after in vitro fertilization (RIF). We tested 491 couples who underwent in vitro fertilization (IVF) and 322 fertile couples. Genotype CC rs27044 ERAP1 in female with a male's HLA-C1C1 or HLA-C1C2 protected from RIF (p/pcorr. = 0.005/0.044, OR = 0.343; p/pcorr. = 0.003/0.027, OR = 0.442, respectively). Genotype TT rs30187 ERAP1 in female with a male's HLA-C1C2 genotype increased the risk of RIF. Summarizing, in the combination of female ERAP1 and an HLA-C partner, the rs30187 C>T and rs27044 C>G polymorphisms play an important role in implantation failure.

Correlation between Endometriosis and Selected Allergic and Autoimmune Diseases and Eating Habits.

Background and Objectives: Endometriosis is a hormone-dependent chronic inflammatory disease with serious reproductive and general health consequences. It is viewed as a multifactorial problem, consisting of matters related to altered immunity and genetics. In this study, we determined the correlation between endometriosis and allergic and autoimmune diseases in patients at reproductive age. Materials and Methods: Online surveys distributed through websites related to gynecological problems. The questionnaire was composed of 63 single and multiple-choice questions concerning the course of endometriosis, diet, and allergic and autoimmune diseases. The obtained data were assessed using statistical tests. Results: 501 female patients (mean age 31.1 SD = 6.8) were included in the study. The control group (n = 155) consisted of healthy females, whereas the study group (n = 346) consisted of female patients with endometriosis; each group was subdivided according to allergy status. There were statistically significant differences between groups for the following: positive family history of endometriosis (p = 0.0002), onset of allergic symptoms (p = 0.0003), frequency and duration of abdominal pain (p = 0.00625), and defecation disorders (p = 0.0006). Asthma was less common in the study group (p = 0.00611). The group of patients with endometriosis and allergies had a high median of consumption of red meat (p = 0.0143), fish (p = 0.0016), and dairy products (p = 0.0001). Conclusions: Endometriosis did not affect autoimmune diseases and their courses. Patients with diagnosed endometriosis presented allergy symptoms much earlier than the healthy patients. The consumption of dietary products such as soya products, red meat, and alcohol had an influence on the occurrence of endometriosis.

miR 31-3p Has the Highest Expression in Cesarean Scar Endometriosis.

Micro-RNAs expression can vary between different forms of endometriosis, but data on miRNA expression in cesarean scar endometriosis is lacking. The present study is comprised of 30 patients with endometriosis in the cesarean scar (scar endometriosis, SE), 14 patients with deep infiltrating endometriosis (DIE), 47 patients with endometrioma (ovarian endometrial cyst, OE), and 33 patients with healthy ovarian tissue as the control group (CG). In the initial experiment to identify possible dysregulated miRNAs, the levels of 754 miRNAs in formalin-fixed paraffin-embedded tissue (FFPE) samples from OE, high-grade ovarian cancer, endometrioid ovarian cancer, and CG were measured. We identified seven potentially dysregulated miRNAs: miR-1-3p, miR-31-3p, miR-125b-1-3p, miR-200b-3p, miR-548d, miR-502, and miR-503. We then examined the expression profiles of each of these miRNAs individually in the SE, DIE, OE, and CG FFPE samples using RT-qPCR. miR-31-3p had significantly higher levels of expression and miR-125b-1-3p had significantly lower levels of expression in SE compared to the controls. Overall, the higher expression levels of miR-31-3p and the lower expression levels of miR-125b-1-3p are consistent with the benign nature of SE. Importantly, the results of the present study demonstrate the possibility of using miRNA to monitor the risk of malignant transformation of endometriosis tissue.

Cancer Stem Cells in Ovarian Cancer-A Source of Tumor Success and a Challenging Target for Novel Therapies.

Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.

Adenomyosis as a Risk Factor for Myometrial or Endometrial Neoplasms-Review.

Adenomyosis is a common benign gynecological condition, defined as an extension of endometrial tissue into the myometrium. Some studies suggest that adenomyosis could be a favorable prediction factor associated with survival outcomes in endometrial cancer. The aim of our systematic review was to investigate the current knowledge regarding adenomyosis and a possible molecular mechanism of carcinogenesis in adenomyotic lesions. In addition, the long-term prognosis for patients with endometrial cancer and coexisting adenomyosis (and endometriosis) was a key point of the research. The current literature was reviewed by searching PubMed, using the following phrases: "adenomyosis and endometrial cancer" and "malignant transformation of adenomyosis". According to the literature, genetic mutations, epigenetic changes, and inactivation of specific tumor suppressor genes in adenomyosis are still poorly understood. Data regarding the influence of adenomyosis on survival outcomes in endometrial cancer seem to be contradictory and require further clinical and molecular investigation.

Cancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors.

Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.

Cancer Stem Cells: An Ever-Hiding Foe.

Cancer stem cells are a population of cells enable to reproduce the original phenotype of the tumor and capable to self-renewal, which is crucial for tumor proliferation, differentiation, recurrence, and metastasis, as well as chemoresistance. Therefore, the cancer stem cells (CSCs) have become one of the main targets for anticancer therapy and many ongoing clinical trials test anti-CSCs efficacy of plenty of drugs. This chapter describes CSCs starting from general description of this cell population, through CSCs markers, signaling pathways, genetic and epigenetic regulation, role of epithelial-mesenchymal transition (EMT) transition and autophagy, cooperation with microenvironment (CSCs niche), and finally role of CSCs in escaping host immunosurveillance against cancer.

Human Papillomaviruses as Infectious Agents in Gynecological Cancers. Oncogenic Properties of Viral Proteins.

Human papillomaviruses (HPVs), which belong to the Papillomaviridae family, constitute a group of small nonenveloped double-stranded DNA viruses. HPV has a small genome that only encodes a few proteins, and it is also responsible for 5% of all human cancers, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. HPV types may be classified as high- and low-risk genotypes (HR-HPVs and LR-HPVs, respectively) according to their oncogenic potential. HR-HPV 16 and 18 are the most common types worldwide and are the primary types that are responsible for most HPV-related cancers. The activity of the viral E6 and E7 oncoproteins, which interfere with critical cell cycle points such as suppressive tumor protein p53 (p53) and retinoblastoma protein (pRB), is the major contributor to HPV-induced neoplastic initiation and progression of carcinogenesis. In addition, the E5 protein might also play a significant role in tumorigenesis. The role of HPV in the pathogenesis of gynecological cancers is still not fully understood, which indicates a wide spectrum of potential research areas. This review focuses on HPV biology, the distribution of HPVs in gynecological cancers, the properties of viral oncoproteins, and the molecular mechanisms of carcinogenesis.