Advances in Experimental Medicine and Biology

Endometrial Carcinoma and its Precursors

This chapter focuses on premalignant and malignant diseases of the endometrium (lining of the uterus). Endometrial carcinoma is the most common gynecologic cancer in the United States. Women have a 1 in 40 lifetime risk of being diagnosed with endometrial cancer, the fourth most common malignancy among women. An estimated 61,880 new diagnoses of uterine cancer and 12,160 deaths from the disease occurred in 2019 in the United States (American Cancer Society, Facts & Figures, https://www.cdc.gov/cancer/uterine/statistics/index.htm , 2019).

Endometrial Tumour Microenvironment

Endometrial cancer (EC) is the most common gynaecological tumour in developed countries, and its incidence is increasing in part due to the prevalence of obesity and its related hormone dysregulation. As described in this chapter, the tumour microenvironment plays a principal role in unopposed oestrogen stimulation promoting tumour cell proliferation. Factors and cytokines secreted by the different cell types defining the reactive tumour stroma also determine the invasive abilities of the tumour cells. Cancer-associated fibroblasts and tumour-associated macrophages actively participate through SDF-1, TGF-b or HGF to promote epithelial-to-mesenchymal transition or to generate an appropriate tumour niche. Likewise, endothelial cells facilitate lymph node and vascular infiltration through VEGF. Finally, the possibility to balance the immunosuppressive phenotypes in advanced endometrial cancer through the tumour microenvironment will probably represent a main therapeutic strategy in the near future.

The Many Microenvironments of Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most common and deadly subtype of ovarian cancer as it is commonly diagnosed after substantial metastasis has already occurred. The past two decades have been an active era in HGSOC research, with new information on the origin and genomic signature of the tumor cell. Additionally, studies have begun to characterize changes in the HGSOC microenvironment and examine the impact of these changes on tumor progression and response to therapies. While this knowledge may provide valuable insight into better prognosis and treatments for HGSOCs, its collection, synthesis, and application are complicated by the number of unique microenvironments in the disease-the initiating site (fallopian tube), first metastasis (ovary), distal metastases (peritoneum), and recurrent/platinum-resistant setting. Here, we review the state of our understanding of these diverse sites and highlight remaining questions.

Ovarian Cancer Biomarkers: Moving Forward in Early Detection

Ovarian cancer is a silent cancer which rate survival mainly relays in early stage detection. The discovery of reliable ovarian cancer biomarkers plays a crucial role in the disease management and strongly impact in patient's prognosis and survival. Although having many limitations CA125 is a classical ovarian cancer biomarker, but current research using proteomic or metabolomic methodologies struggles to find alternative biomarkers, using non-invasive our relatively non-invasive sources such as urine, serum, plasma, tissue, ascites or exosomes. Metabolism and metabolites are key players in cancer biology and its importance in biomarkers discovery cannot be neglected. In this chapter we overview the state of art and the challenges facing the use and discovery of biomarkers and focus on ovarian cancer early detection.

Cathepsin D in the Tumor Microenvironment of Breast and Ovarian Cancers

Cancer remains a major and leading health problem worldwide. Lack of early diagnosis, chemoresistance, and recurrence of cancer means vast research and development are required in this area. The complexity of the tumor microenvironment in the biological milieu poses greater challenges in having safer, selective, and targeted therapies. Existing strategies such as chemotherapy, radiotherapy, and antiangiogenic therapies moderately improve progression-free survival; however, they come with side effects that reduce quality of life. Thus, targeting potential candidates in the microenvironment, such as extracellular cathepsin D (CathD) which has been known to play major pro-tumorigenic roles in breast and ovarian cancers, could be a breakthrough in cancer treatment, specially using novel treatment modalities such as immunotherapy and nanotechnology-based therapy. This chapter discusses CathD as a pro-cancerous, more specifically a proangiogenic factor, that acts bi-functionally in the tumor microenvironment, and possible ways of targeting the protein therapeutically.

Endometriosis and Endometriosis-Associated Ovarian Cancer (EAOC)

Endometriosis is a gynecologic disease that affects over 10% of women of reproductive age causing pelvic pain, dysmenorrhea, and infertility, resulting in significant disability and reduced quality of life. Very recent genetic studies have suggested that endometriosis is a clonal disease in the epithelium and its development is independent of stroma, providing new insight into the genesis of endometriosis. The endometrioid tissue lining may also react by epithelial atypical hyperplasia and even neoplasia, in a manner somehow similar to that in the uterine cavity and under the same hormonal influences.

DNA Damage Repair Inhibitor for Breast Cancer Treatment

Cancer has been defined as a genetic disorder caused by the accumulation of genetic alterations, which result from various internal and external DNA damage that is left unrepaired. One of the main characteristics of cancer is a partial loss of DNA damage repair (DDR) pathway, resulting in increased DNA damage levels and replication stress. DDR inhibitors have been suggested as a new anticancer strategy, under the concept of synthetic lethality. The poly-(ADP-ribose) polymerase (PARP) inhibitor is the first DDR inhibitor to be used in clinical practice. PARP inhibitors have been tested in patients with BRCA1/2 germline mutations (gBRCA1/2mt) and shown robust clinical benefits in breast cancer with gBRCA1/2mt and serous ovarian cancer patients. The concept of synthetic lethality is not limited to gBRCAmt for PARP inhibitor, and discovering homologous recombination deficiency (HRD) markers beyond BRCA1/2 and identifying best candidates for DDR inhibitors are the active research areas. At the same time, various combinations of DDR inhibitors and other anticancer drugs are being tested in both preclinical and clinical studies. In addition, based on recent evidence of the immune-modulatory effect of PARP inhibitors, the combination of DDR inhibitors and immune checkpoint inhibitors is being actively investigated. Acquired resistance mechanism of DDR inhibitors, as well as defining best candidates and best combinations, would be future research topics for DDR inhibitors. Furthermore, it would also be crucial to establish a clinically relevant standardized method to detect HRD for future clinical use.

Human Papillomavirus-Associated Cancers

Human Papillomavirus (HPV) is the causative agent in the majority of anal, head and neck, oral, oropharyngeal, penile, vaginal, vulvar, and cervical cancers. Cervical cancer is the fourth most common cancer among women worldwide. Of all diagnosed human malignant neoplasms, approximately 4.5% are attributable to HPV, including cervical, anal cancers, vaginal, vulvar, penile, and oropharyngeal cancers. Over 182 HPV types have been identified and sequenced to date however, only certain types of HPV are more frequent in malignant lesions and considered to be a major risk factor in the development of some cancers. Because most HPV infections are transient, and an individual's immunocompetent may clear the infection, HPV infection has received little attention from clinicians, the general public, or policy makers. This lack of attention may underpin a deadly and increasing problem because each newly acquired infection has the potential to persist and become an incurable, lifelong affliction. In addition, no successful treatment of HPV infection currently exists despite the great strides toward understanding the mechanisms underlying HPV pathogenesis. Moreover, ample research has proven that the use of prophylactic vaccines, such as Gardasil and Cervarix, have led to documented progress in decreasing the burden of HPV infection, however not all countries introduced a government-funded National HPV Vaccination Program to protect young men and women. This chapter summarizes the HPV infection, detection and prevention. We also shed light on non-cervical HPV-related cancers, which is rapidly increasing in more developed countries toward cervical cancer.

Single-Cell RNA Sequencing of Ovarian Cancer: Promises and Challenges

Ovarian cancer remains the leading cause of death from gynecologic malignancy in the Western world. Tumors are comprised of heterogeneous populations of various cancer, immune, and stromal cells; it is hypothesized that rare cancer stem cells within these subpopulations lead to disease recurrence and treatment resistance. Technological advances now allow for the analysis of tumor genomes and transcriptomes at the single-cell level, which provides the resolution to potentially identify these rare cancer stem cells within the larger tumor.In this chapter, we review the evolution of next-generation RNA sequencing techniques, the methodology of single-cell isolation and sequencing, sequencing data analysis, and the potential applications in ovarian cancer. We also summarize the current published work using single-cell sequencing in ovarian cancer.By utilizing this novel technique to characterize the gene expression of rare subpopulations, new targets and treatment pathways may be identified in ovarian cancer to change treatment paradigms.

Epithelial Ovarian Cancer and Cancer Stem Cells

Epithelial ovarian cancer is a lethal gynecological cancer. It is related to high mortality because the majority of the patients present in advanced stage and because of the high recurrence rates of the disease. Recurrent ovarian cancer is classified according to the time interval between the last platinum-based chemotherapy and the occurrence of recurrence, to platinum-sensitive and platinum-resistant. Many theories tried to explain development of resistance to platinum-based therapy. "Cancer stem cells" is one of these theories and is being currently under investigation by many groups. This chapter will demonstrate the suggested contribution of cancer stem cells to the development of recurrent ovarian cancer.

Enforced Expression of METCAM/MUC18 Decreases In Vitro Motility and Invasiveness and Tumorigenesis and In Vivo Tumorigenesis of Human Ovarian Cancer BG-1 Cells

We tested if METCAM/MUC18 overexpression also plays a suppressor role in another human ovarian cancer cell line, BG-1, in addition to the SK-OV3 cell line. Human ovarian cancer BG-1 cells were transfected with METCAM/MUC18 cDNA and G418-resistant clones expressing different levels of METCAM/MUC18 were isolated. These clones were used to test the effects of enforced expression of METCAM/MUC18 on in vitro motility, invasiveness, and anchorage-independent colony formation (in vitro tumorigenesis), and in vivo tumorigenesis after SC injection and after IP injection in female athymic nude mice. Overexpression of METCAM/MUC18 reduced in vitro motility and invasiveness of BG-1 cells and anchorage-independent colony formation (in vitro tumor formation). Higher expression of METCAM/MUC18 in BG-1 cells significantly reduced in vivo tumor proliferation of the BG-1 cells after IP injection (orthotopic route) of the clones in female nude mice, though it did not significantly affect in vivo tumor proliferation after SC injection (non-orthotopic route). Similar to SK-OV3 cells, METCAM/MUC18 also plays a suppressor role in the progression of BG-1 cells in a xenograft mouse model.

Ovarian Cancer: Therapeutic Strategies to Overcome Immune Suppression

Ovarian cancer generally escapes diagnosis until the advanced stages. High-grade serous ovarian cancer (HGSOC) is the most frequently occurring form of this malaise and is a disease which has the highest mortality rate of gynecologic cancers. Over recent years it has been revealed that the course of such cancers can be significantly influenced by the nature of immune cells in tumors at the time of diagnosis and by immune cells induced by therapy. Numerous investigators have since focused on disease biology to identify biomarkers or therapeutic targets. Yet, while over the past decade there have been significant improvements in state-of-the-art surgery for ovarian cancer as frontline therapy, there have been limited advancements in the development of novel curative or management drugs for this disease. This chapter discusses the major elements of immune suppression in HGSOC from a biological viewpoint, mechanisms of overcoming resistance to therapies, and recent therapy aimed at improving patient care and survival.

Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity

The majority of ovarian cancer patients present clinically with wide-spread metastases throughout the peritoneal cavity, metastasizing to the mesothelium-lined peritoneum and visceral adipose depots within the abdomen. This unique metastatic tumor microenvironment is comprised of multiple cell types, including mesothelial cells, fibroblasts, adipocytes, macrophages, neutrophils, and T lymphocytes. Modeling advancements, including complex 3D systems and organoids, coupled with 2D cocultures, in vivo mouse models, and ex vivo human tissue cultures have greatly enhanced our understanding of the tumor-stroma interactions that are required for successful metastasis of ovarian cancer cells. However, advanced multifaceted model systems that incorporate frequency and spatial distribution of all cell types present in the tumor microenvironment of ovarian cancer are needed to enhance our knowledge of ovarian cancer biology in order to identify methods for preventing and treating metastatic disease. This review highlights the utility of recently developed modeling approaches, summarizes some of the resulting progress using these techniques, and suggests how these strategies may be implemented to elucidate signaling processes among cell types of the tumor microenvironment that promote ovarian cancer metastasis.

Ovarian Cancer Stem Cells: Characterization and Role in Tumorigenesis

Ovarian cancer is a heterogenous disease with variable clinicopathological and molecular mechanisms being responsible for tumorigenesis. Despite substantial technological improvement, lack of early diagnosis contributes to its highest mortality. Ovarian cancer is considered to be the most lethal female gynaecological cancer across the world. Conventional treatment modules with platinum- and Taxane-based chemotherapy can cause an initial satisfactory improvement in ovarian cancer patients. However, approximately 75-80% patients of advanced stage ovarian cancer, experience relapse and nearly 40% have overall poor survival rate. It has been observed that a subpopulation of cells referred as cancer stem cells (CSCs), having self renewal property, escape the conventional chemotherapy because of their quiescent nature. Later, these CSCs following its interaction with microenvironment and release of various inflammatory cytokines, chemokines and matrix metalloproteinases, induce invasion and propagation to distant organs of the body mainly peritoneal cavity. These CSCs can be enriched by their specific surface markers such as CD44, CD117, CD133 and intracellular enzyme such as aldehyde dehydrogenase. This tumorigenicity is further aggravated by the epithelial to mesenchymal transition of CSCs and neovascularisation via epigenetic reprogramming and over-expression of various signalling cascades such as Wnt/β-catenin, NOTCH, Hedgehog, etc. to name a few. Hence, a comprehensive understanding of various cellular events involving interaction between cancer cells and cancer stem cells as well as its surrounding micro environmental components would be of unmet need to achieve the ultimate goal of better management of ovarian cancer patients. This chapter deals with the impact of ovarian cancer stem cells in tumorigenesis which would help in the implementation of basic research into the clinical field in the form of translational research in order to reduce the morbidity and mortality in ovarian cancer patients through amelioration of diagnosis and impoverishment of therapeutic resistance.

PAX8, an Emerging Player in Ovarian Cancer

Ovarian Cancer is one of the most lethal and widespread gynecological malignancies. It is the seventh leading cause of all cancer deaths worldwide. High-Grade Serous Cancer (HGSC), the most commonly occurring subtype, alone contributes to 70% of all ovarian cancer deaths. This is mainly attributed to the complete lack of symptoms during the early stages of the disease and absence of an early diagnostic marker.PAX8 is emerging as an important histological marker for most of the epithelial ovarian cancers, as it is expressed in about 90% of malignant ovarian cancers, specifically in HGSC. PAX8 is a member of the Paired-Box gene family (PAX1-9) of transcription factors whose expression is tightly controlled temporally and spatially. The PAX genes are well known for their role in embryonic development and their expression continues to persist in some adult tissues. PAX8 is required for the normal development of Müllerian duct that includes Fallopian tube, uterus, cervix, and upper part of vagina. In adults, it is expressed in the Fallopian tube and uterine epithelium and not in the ovarian epithelium. Considering the recent studies that predict the events preceding the tumorigenesis of HGSC from the Fallopian tube, PAX8 appears to have an important role in the development of ovarian cancer.In this chapter, we review some of the published findings to highlight the significance of PAX8 as an important marker and an emerging player in the pathogenesis of ovarian cancer. We also discuss regarding the future perspectives of PAX8 wherein it could contribute to the betterment of ovarian cancer diagnosis and treatment.

Pharmacological Effects of Natural Components Against Ovarian Cancer and Mechanisms

Ovarian cancer, one of the three leading malignancies in women, has high incidence and mortality worldwide. It is hard to diagnose until very late stages and the 5-year survival rate is very low, due mostly to its distant metastasis. Chemotherapy is currently the most common treatment to inhibit cancer growth, but long-term use could result in resistance and tumor recurrence in addition to damages to normal tissues and functions of the patients. In order to achieve safe and curative effects against cancers, many investigators have focused their attention on traditional Chinese herbal medicines. Paclitaxel, a natural antitumor agent, has significant effects on advanced malignancies including ovarian cancer and is in the standard front-line treatment. Additional natural anticancer substances have continually been discovered for their high effectiveness and low side-effects in ovarian cancer prevention and therapy. In this chapter, we summarize recent work on a selected group of natural components, including lignans, ellagic acid, luteolin, mangiferin, and Acanthopanax senticosus, which have all been demonstrated to reduce the progress of epithelial ovarian cancer in a dose-depend manner, by both in vitro and in vivo experiments. The mechanisms of the anticancer activities by these natural components involve expression suppression of MMP2 and MMP9.

3D Models for Ovarian Cancer

The main reasons for the slow progress in improving survival outcomes for ovarian cancer are the 'one-size-fits-all' therapy and lack of clinically relevant experimental models that represent the advanced stages of the human disease. The interaction of tumour cells with their surrounding niche, the tumour microenvironment, influences the spread of ovarian cancer cells within the peritoneum and their responses to therapeutics. Scientists are increasingly using 3D cell culture models to dissect the role of the tumour microenvironment in cancer development and progression and the treatment of this disease. In this chapter, we will briefly describe the tumour microenvironment of ovarian cancer. Then, we will review some of the clinically relevant experimental approaches, such as spheroid, organoid and organotypic models, that have been developed for the 3D culture of ovarian cancer cells using different tools, including hydrogels, scaffolds and cancer-on-a-chip devices, to mimic selected components of the tumour microenvironment.

Current and Futuristic Roadmap of Ovarian Cancer Management: An Overview

Ovarian cancer (OC) is the most lethal gynecological malignancy among women worldwide. In most cases, it is diagnosed late at an advanced stage and does not respond well to existing therapies leading to its poor prognosis. In addition, other factors including epidemiological, complex histological diversity, multiple molecular alterations, and overlapping signaling pathways are also important contributors to poor disease outcome. Efforts have continued to develop a deeper understanding of the molecular pathogenesis and altered signaling nodes that provide hope for better clinical management through the development of novel approaches for early diagnosis, disease subtyping, prognosis, and therapy. In this chapter, we provide a detailed overview of OC and its histological subtypes and discuss prevalent molecular aberrations and active signaling pathways that drive OC progression. We also summarize various diagnostic and prognostic markers and therapeutic approaches currently being employed and discuss emerging findings that hold the potential to change the future course of OC management.

IL-10 Signaling in the Tumor Microenvironment of Ovarian Cancer

Unlike other malignancies, ovarian cancer (OC) creates a complex tumor microenvironment with distinctive peritoneal ascites consisting of a mixture of several immunosuppressive cells which impair the ability of the patient's immune system to fight the disease. The poor survival rates observed in advanced stage OC patients and the lack of effective conventional therapeutic options have been attributed in large part to the immature dendritic cells (DCs), IL-10 secreting regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer stem cells that secrete inhibitory cytokines. This review highlights the critical role played by the intraperitoneal presence of IL-10 in the generation of an immunosuppressive tumor microenvironment. Further, the effect of antibody neutralization of IL-10 on the efficacy of DC and chimeric antigen receptor T-cell vaccines will be discussed. Moreover, we will review the influence of IL-10 in the promotion of cancer stemness in concert with the NF-κB signaling pathway with regard to OC progression. Finally, understanding the role of IL-10 and its crosstalk with various cells in the ascitic fluid may contribute to the development of novel immunotherapeutic approaches with the potential to kill drug-resistant OC cells while minimizing toxic side effects.

Human Papillomavirus (HPV) Entry Inhibitors

Chronic or persistent human papillomavirus (HPV) infection is essential for the development of many types of carcinomas, such as cervical carcinoma. Developing new diagnostic and prognostic biomarkers and designing more effective targeted therapeutics and treatment strategies remains urgent. Numerous efforts have been made to design new drugs and vaccines to treat HPV infections. Due to the special HPV infection pathway, entry inhibitors to block viral entry into target cells have been extensively and deeply studied. This chapter reviews the basic characteristics of HPV infection and the various types of HPV entry inhibitors, which were found to have high safety, potent antiviral effects, and broad-spectrum activity against multiple HPV subtypes. Together with the use of prophylactic vaccines, the development and application of these entry inhibitors will reduce the incidence of HPV infection and associated cancers in the future.

Targeting Oestrogen Receptor Signalling in Breast Cancer Therapy

Hormone Signaling in Breast Development and Cancer

Tubulin Complexity in Cancer and Metastasis

Tubulin plays a fundamental role in cellular function and as the subject for microtubule-active agents in the treatment of ovarian cancer. Microtubule-binding proteins (e.g., tau, MAP1/2/4, EB1, CLIP, TOG, survivin, stathmin) and posttranslational modifications (e.g., tyrosination, deglutamylation, acetylation, glycation, phosphorylation, polyamination) further diversify tubulin functionality and may permit additional opportunities to understand microtubule behavior in disease and to develop microtubule-modifying approaches to combat ovarian cancer. Tubulin-based structures that project from suspended ovarian cancer cells known as microtentacles may contribute to metastatic potential of ovarian cancer cells and could represent an exciting novel therapeutic target.

Notch and Endometrial Cancer

The human endometrium is a unique, highly dynamic tissue that undergoes cyclic changes of cell proliferation, differentiation, and death. Endometrial cancer is the most common malignancy among women in developed countries. Importantly, the incidence of endometrial cancer is rising in high-income countries. Currently histological classification is used for subtyping of endometrial cancer, while ongoing research is evaluating markers for more accurate molecular classification. Evolutionary conserved Notch signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and cell invasion. Accumulating evidence links aberrant Notch signaling with diseases such as hyperplasia and endometrial cancer. This chapter summarizes the current state of Notch signaling investigations in the endometrium, endometriosis, and endometrial cancer.

BRCA and Breast Cancer-Related High-Penetrance Genes

Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.

The Impact of Mitochondria in Ovarian Cancer Cell Metabolism, Proliferation, and Metastasis

Mitochondrial dysfunctions are significantly implicated in cancer initiation, progression, and metastasis, which have been shown for several cancers including ovarian cancer.An increase in mitochondrial dysfunction is also associated with drug resistance along with cancer progression, which in part is related to its specific microenvironment that is characterized by ascites, low glucose levels, and hypoxia that causes ovarian cancer cells to switch to mitochondrial respiration to enable their survival. Peritoneal ascitic fluid accumulation is a specific feature of ovarian cancer, and it is a major cause of its metastatic spread that also presents challenges for effective treatment. Among the treatment difficulties for ovarian cancer is the mutation rate and frequency of mtDNA in ovarian cancer tissue that can affect the efficiency of chemotherapeutic drugs. The varied and multiple mutations of different types enable metabolic reprogramming, cancer cell proliferation, and drug resistance.New specific information on mechanisms underlying several of the mitochondrial dysfunctions has led to proposing various mitochondrial determinants as targets for ovarian cancer therapy, which include targeting specific mitochondrial proteins and phosphoproteins as well as reactive oxygen species (ROS) that accumulate abnormally in cancer cells. Because of the genetically and histologically heterogeneous nature of the disease, combination therapy approaches will be necessary to combat the disease and achieve progress in effective treatment of ovarian cancer. This chapter will address (1) mitochondrial vulnerabilities underlying dysfunction and disease; (2) mitochondrial dysfunction in ovarian cancer; (3) present treatment difficulties for ovarian cancer and new potential treatment strategies to target ovarian cancer mitochondrial metabolism; and (4) biobehavioral factors influencing ovarian cancer development.

The Role of the Human Microbiome in Epithelial Ovarian Cancer

Ovarian cancer is the fifth-leading cause of cancer deaths among women due to the absence of available screening methods to identify early disease. Thus, prevention and early disease detection investigations are of high priority, surrounding a critical window of opportunity to better understand important pathogenic mechanisms of disease progression. Microorganisms modulate molecular interactions in humans that can influence states of health and disease, including ovarian cancer. While the mechanisms of infectious microbial invasion that trigger the immune-inflammatory axis are well studied in cancer research, the complex interactions that promote the transition of noninfectious healthy microbes to pathobiont expansion are less understood. As traditional research has focused on the influences of infectious pathogens on ovarian cancer development and progression, the impact of noninfectious microbes has gained scientific attention. The objective of this chapter is to summarize current evidence on the role of microbiota in epithelial ovarian cancer throughout disease.

The Impact of Centrosome Pathologies on Ovarian Cancer Development and Progression with a Focus on Centrosomes as Therapeutic Target

The impact of centrosome abnormalities on cancer cell proliferation has been recognized as early as 1914 (Boveri, Zur Frage der Entstehung maligner Tumoren. Jena: G. Fisher, 1914), but vigorous research on molecular levels has only recently started when it became fully apparent that centrosomes can be targeted for new cancer therapies. While best known for their microtubule-organizing capabilities as MTOC (microtubule organizing center) in interphase and mitosis, centrosomes are now further well known for a variety of different functions, some of which are related to microtubule organization and consequential activities such as cell division, migration, maintenance of cell shape, and vesicle transport powered by motor proteins, while other functions include essential roles in cell cycle regulation, metabolic activities, signal transduction, proteolytic activity, and several others that are now heavily being investigated for their role in diseases and disorders (reviewed in Schatten and Sun, Histochem Cell Biol 150:303-325, 2018; Schatten, Adv Anat Embryol Cell Biol 235:43-50, 2022a; Schatten, Adv Anat Embryol Cell Biol 235:17-35, 2022b).Cancer cell centrosomes differ from centrosomes in noncancer cells in displaying specific abnormalities that include phosphorylation abnormalities, overexpression of specific centrosomal proteins, abnormalities in centriole and centrosome duplication, formation of multipolar spindles that play a role in aneuploidy and genomic instability, and several others that are highlighted in the present review on ovarian cancer. Ovarian cancer cell centrosomes, like those in other cancers, display complex abnormalities that in part are based on the heterogeneity of cells in the cancer tissues resulting from different etiologies of individual cancer cells that will be discussed in more detail in this chapter.Because of the critical role of centrosomes in cancer cell proliferation, several lines of research are being pursued to target centrosomes for therapeutic intervention to inhibit abnormal cancer cell proliferation and control tumor progression. Specific centrosome abnormalities observed in ovarian cancer will be addressed in this chapter with a focus on targeting such aberrations for ovarian cancer-specific therapies.

Insights into the Microbial Composition of Intratumoral, Reproductive Tract, and Gut Microbiota in Ovarian Cancer Patients

According to the latest global cancer data, ovarian cancer is the deadliest among all gynecological malignant tumors and ranks fifth in terms of mortality. Its etiology and pathogenesis are unknown, and the 5-year survival rate of patients with advanced ovarian cancer is only 40% (Sung et al. CA Cancer J Clin 71:209-49, 2021). Recent research has shown that the human microbiota plays a crucial role in the development and progression of tumors, including ovarian cancer. Numerous studies have highlighted the complex connections between the reproductive tract microbiota, intestinal microbiota, and ovarian cancer (Jacobson et al. PeerJ 9:e11574, 2021). Therefore, this chapter will delve into composition, function, and the correlation between microbiota and immunity in the field of ovarian cancer microbiota, as well as the potential of bacteria in therapeutics and diagnostics of ovarian cancer.

Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy

Microtubules are dynamic polymers composed of α- and β-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

Melanoma Cell Adhesion Molecule (CD 146) in Endometrial Physiology and Disorder

The human endometrium, the innermost lining of the uterus, is the anatomic prerequisite for pregnancy. It is the only dynamic tissue that undergoes more than 400 cycles of regeneration throughout the reproductive life of women. Key to this function are endometrial stem cells as well as cell adhesion molecules. Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a membrane glycoprotein of the mucin family and a key cell adhesion protein, highly expressed by endometrial cells. CD146 is a significant molecule pivotal in endometrial physiology, assisting tissue regeneration and angiogenesis. Endometrium also acts as a culprit in causing several endometrial dysfunctions, such as endometriosis, endometrial hyperplasia, and endometrial carcinoma, due to interrupted molecular and functional mechanisms. Though most of the endometrial dysfunctions arise as a result of endocrine disturbance, it has a major pathological role associated with angiogenesis. It has already been proven that CD146 is a potential marker for the diagnosis of angiogenic dysfunctions and malignancy, including endometrial cancer. However, its mechanistic role in causing the pathology is a mystery. This chapter explores the role of CD146 in normal and pathological endometrial conditions and the therapeutic implications of CD146.