Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

The VEGF/VEGFR2 system in ovarian cancer: From functional to pharmacological significance

The vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor regulating a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis and cancer. VEGFR2 is activated by canonical VEGFs and non-canonical ligands, triggering intracellular signaling cascades that mediate its biological activity. Preclinical studies show that VEGFR2 plays a complex yet pivotal role in the progression of ovarian cancer (OC), a deadly disease with a global burden of more than 320,000 women in 2022. Several inhibitors of the VEGF/VEGFR2 axis have been developed and are currently approved or included in clinical trials/preclinical studies for the therapy of different subtypes of OC. Originally developed as anti-angiogenics, anti-VEGF/VEGFR2 drugs are now well-known to also affect tumor cells, immune cells and cancer-associated fibroblasts (CAFs), also in OC. In this review we address the specific role of the VEGF/VEGFR2 axis in OC cells, and, from this perspective, we discuss the therapeutic significance of VEGFR2 targeting. Dissection of the molecular landscape modulated by the VEGF/VEGFR2 system in tumor cells in addition to stromal ones will facilitate ongoing translational efforts directed toward OC therapy. SIGNIFICANCE STATEMENT: Anti-angiogenics blocking the VEGF/VEGFR2 axis are widely used to treat ovarian cancer, although resistance and poor response occur. Recent advances reveal that anti-VEGF/VEGFR2 drugs act on multiple compartments, including ovarian cancer cells. This review discusses the functional and pharmacological significance of the VEGF/VEGFR2 axis in ovarian cancer cells highlighting insights from preclinical and clinical studies. A deeper understanding of this pathway is essential for a safe/efficacious usage of anti-angiogenics targeting the VEGFR2 pathway in ovarian cancer.

Multidimensional technological advances in cervical cancer screening: From standardized processes to precision medicine

Cervical cancer is a common malignancy among women worldwide. To address this significant public health issue, the World Health Organization launched the "Eliminating Cervical Cancer" initiative. Effective screening of cervical cancer is crucial for reducing its morbidity and mortality. With continuous technological advancements, cervical cancer screening has evolved from traditional cytology and human papillomavirus (HPV) testing models to a new era of multidimensional, multilevel, and precise screening. This comprehensive review focuses on the core progress of screening technology in recent years, including the innovation of traditional screening methods, noninvasive optical imaging, molecular diagnosis from the perspective of precision medicine, and the deep integration and empowerment of artificial intelligence in the entire screening process. Cervical liquid-based cytology, combined with automated cell sorting technology and intelligent whole-slide image analysis, has achieved high-throughput identification of abnormal cells. The accuracy and specificity of HPV and multiomic biomarker detection technologies have significantly improved, providing a new basis for the accurate triage of patients with high-risk infections. Noninvasive cervical imaging technology already offers early identification of cervical precancerous lesions at the molecular level, combining ease of use with good patient acceptance. Notably, artificial intelligence technology is being integrated into multiple screening processes, leveraging horizontal integration and cross-platform capabilities in image recognition, risk assessment, auxiliary diagnosis, and automated testing processes, becoming a key driver of innovation in screening systems.

Prospects of nano-theranostic approaches against breast and cervical cancer

The bottleneck on therapeutics and diagnostics is removed by an alternate approach known as theranostics which combines both therapeutics and diagnostics within a single platform. Due to this "all in one" nature of theranostics, it is now extensively applied in the medicinal field mainly in cancer treatment over the conventional therapy. Recently, FDA approval of lutetium 177 (177Lu) DOTATATE and 177Lu-PSMA-based radionuclide theranostics are clinically used and very few theranostics specific to breast cancer are in clinical trials. In this review, we are willing to draw special attention to the application of theranostics in the most relevant cancers in women, the breast and the cervical as these cancers affect women harshly but talked very silently due to the social restrictions and discriminations mainly in rural areas of developing and under developing countries. This approach not only combines therapeutics and diagnostics but targeting moieties can also be accommodated for the precise medication. Herein, our main objective is to enlighten the broader aspects of different kinds of theranostic devices based on radioisotopes, nanoparticles, graphene quantum dots, dendrimers and their fruitful application against breast and cervical cancer. The development of synthetic nano-theranostics was reported by accommodating therapeutic drugs, imaging probes and targeting ligands through conjugation or encapsulation. The imaging modalities like optical fluorescence, photosensitizers and radiotracers are used to get the diagnostic images through NIR, PET, MRI and CT/SPECT to detect the progress of cancer non-invasively and also at the same time targeting ligands such as antibodies, proteins and peptides in attachment with the theranostics enhances the therapeutic efficacy in addition to the clarity in diagnostics. The applications of theranostics from the last decade with their present scenario in clinics and future perspectives, as well as the pitfalls with the hurdles that still leave questions to rethink from the root are also been discussed in this review.

Emerging biomarkers and molecular targets for precision medicine in cervical cancer

Cervical cancer remains a significant global health burden, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Precision medicine has emerged as a promising paradigm, leveraging biomarkers and molecular targets to tailor therapy to individual patients. This review explores the landscape of emerging biomarkers and molecular targets in cervical cancer, highlighting their potential implications for precision medicine. By integrating these biomarkers into comprehensive diagnostic algorithms, clinicians can identify high-risk patients at an earlier stage, enabling timely intervention and improved patient outcomes. Furthermore, the identification of specific molecular targets has paved the way for the development of targeted therapies aimed at disrupting key pathways implicated in cervical carcinogenesis. In conclusion, the evolving landscape of biomarkers and molecular targets presents exciting opportunities for advancing precision medicine in cervical cancer. By harnessing these insights, clinicians can optimize treatment selection, enhance patient outcomes, and ultimately transform the management of this devastating disease.

Lymphatic vasculature in ovarian cancer

Ovarian cancer (OVCA) is the second most common gynecological cancer and one of the leading causes of cancer related mortality among women. Recent studies suggest that among ovarian cancer patients at least 70% of the cases experience the involvement of lymph nodes and metastases through lymphatic vascular network. However, the impact of lymphatic system in the growth, spread and the evolution of ovarian cancer, its contribution towards the landscape of ovarian tissue resident immune cells and their metabolic responses is still a major knowledge gap. In this review first we present the epidemiological aspect of the OVCA, the lymphatic architecture of the ovary, we discuss the role of lymphatic circulation in regulation of ovarian tumor microenvironment, metabolic basis of the upregulation of lymphangiogenesis which is often observed during progression of ovarian metastasis and ascites development. Further we describe the implication of several mediators which influence both lymphatic vasculature as well as ovarian tumor microenvironment and conclude with several therapeutic strategies for targeting lymphatic vasculature in ovarian cancer progression in present day.

Neo-vascularization-based therapeutic perspectives in advanced ovarian cancer

The process of angiogenesis is well described for its potential role in the development of normal ovaries, and physiological functions as well as in the initiation, progression, and metastasis of ovarian cancer (OC). In advanced stages of OC, cancer cells spread outside the ovary to the pelvic, abdomen, lung, or multiple secondary sites. This seriously limits the efficacy of therapeutic options contributing to fatal clinical outcomes. Notably, a variety of angiogenic effectors are produced by the tumor cells to initiate angiogenic processes leading to the development of new blood vessels, which provide essential resources for tumor survival, dissemination, and dormant micro-metastasis of tumor cells. Multiple proangiogenic effectors and their signaling axis have been discovered and functionally characterized for potential clinical utility in OC. In this review, we have provided the current updates on classical and emerging proangiogenic effectors, their signaling axis, and the immune microenvironment contributing to the pathogenesis of OC. Moreover, we have comprehensively reviewed and discussed the significance of the preclinical strategies, drug repurposing, and clinical trials targeting the angiogenic processes that hold promising perspectives for the better management of patients with OC.

Advances and prospects of mRNA vaccines in cancer immunotherapy

Cancer vaccines, designed to activate the body's own immune system to fight against tumors, are a current trend in cancer treatment and receiving increasing attention. Cancer vaccines mainly include oncolytic virus vaccine, cell vaccine, peptide vaccine and nucleic acid vaccine. Over the course of decades of research, oncolytic virus vaccine T-VEC, cellular vaccine sipuleucel-T, various peptide vaccines, and DNA vaccine against HPV positive cervical cancer have brought encouraging results for cancer therapy, but are losing momentum in development due to their respective shortcomings. In contrast, the advantages of mRNA vaccines such as high safety, ease of production, and unmatched efficacy are on full display. In addition, advances in technology such as pseudouridine modification have cracked down the bottleneck for developing mRNA vaccines including instability, innate immunogenicity, and low efficiency of in vivo delivery. Several cancer mRNA vaccines have achieved promising results in clinical trials, and their usage in conjunction with other immune checkpoint inhibitors (ICIs) has further boosted the efficiency of anti-tumor immune response. We expect a rapid development of mRNA vaccines for cancer immunotherapy in the near future. This review provides a brief overview of the current status of mRNA vaccines, highlights the action mechanism of cancer mRNA vaccines, their recent advances in clinical trials, and prospects for their clinical applications.

Evaluating the current status of protein kinase C (PKC)-protein kinase D (PKD) signalling axis as a novel therapeutic target in ovarian cancer

Ovarian cancer, especially high grade serous ovarian cancer is one of the most lethal gynaecological malignancies with high relapse rate and patient death. Notwithstanding development of several targeted treatment and immunotherapeutic approaches, researchers fail to turn ovarian cancer into a manageable disease. Protein kinase C (PKC) and protein kinase D (PKD) are families of evolutionarily conserved serine/threonine kinases that can be activated by a plethora of extracellular stimuli such as hormones, growth factors and G-protein coupled receptor agonists. Recent literature suggests that a signalling cascade initiated by these two protein kinases regulates a battery of cellular and physiological processes involved in tumorigenesis including cell proliferation, migration, invasion and angiogenesis. In an urgent need to discover novel therapeutic interventions against a deadly pathology like ovarian cancer, we have discussed the status quo of PKC/PKD signalling axis in context of this disease. Additionally, apart from discussing the structural properties and activation mechanisms of PKC/PKD, we have provided a comprehensive review of the recent reports on tumor promoting functions of PKC isoforms and discussed the potential of PKC/PKD signalling axis as a novel target in this lethal pathology. Furthermore, in this review, we have discussed the significance of several recent clinical trials and development of small molecule inhibitors that target PKC/PKD signalling axis in ovarian cancer.

Targeting tumor microenvironment in ovarian cancer: Premise and promise

Ovarian cancer is the leading cause of gynecological cancer-related mortality globally. The majority of ovarian cancer patients suffer from relapse after standard of care therapies and the clinical benefits from cancer therapies are not satisfactory owing to drug resistance. Certain novel drugs targeting the components of tumor microenvironment (TME) have been approved by US Food and Drug Administration in solid cancers. As such, the passion is rekindled to exploit the role of TME in ovarian cancer progression and metastasis for discovery of novel therapeutics for this deadly disease. In the current review, we revisit the recent mechanistic insights into the contributions of TME to the development, progression, prognosis prediction and therapeutic efficacy of ovarian cancer via modulating cancer hallmarks. We also explored potentially promising predictive and prognostic biomarkers for ovarian cancer patients.

BRCA1/P53: Two strengths in cancer chemoprevention

Increasing emphasis has been given to prevention as a feasible approach to reduce the cancer burden. However, for its clinical success, further advances are required to identify effective chemopreventive agents. This review affords a critical and up-to-date discussion of issues related to cancer prevention, including an in-depth knowledge on BRCA1 and p53 tumor suppressor proteins as key molecular players. Indeed, it compiles the most recent advances on the topic, highlighting the unique potential of BRCA1 and p53 germline mutations as molecular biomarkers for risk assessment and targets for chemoprevention. Relevant evidences are herein provided supporting the effectiveness of distinct pharmacological agents in cancer prevention, by targeting BRCA1 and p53. Moreover, the rationale for using germline mutant BRCA1- or p53-related cancer syndromes as model systems to investigate effective chemopreventive agents is also addressed. Altogether, this work provides an innovative conception about the dependence on p53 and BRCA1 co-inactivation in tumor formation and development, emphasizing the relationship between these two proteins as an encouraging direction for future personalized pharmacological interventions in cancer prevention.

Gynecological malignancy organoids: A game changer for personalized medicine

Recently, the incidence of gynecological malignancies has increased annually, posing a serious threat to women's health. Historically, the emergence and progression of gynecological cancers have primarily been studied using cell lines and animal models. However, these models often fail to accurately reflect tumor characteristics because genetic mutations frequently occur during long-term cultivation. Also, the complex tumor microenvironment is difficult to replicate. Consequently, these models have limitations in translating research findings into clinical applications. Organoids successfully retain key characteristics of primary tumors, including histological structure, genomic landscape, expression profiles, and intratumor heterogeneity. They provide new solutions to these challenges and have been effectively applied in drug development and personalized therapy. This review describes several common culture systems for organoids of gynecological malignancies. It discusses the latest technologies related to organoids and their applications in gynecological oncology. Despite limitations, organoids are ideal preclinical models and a promising platform for tumor research.

Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: Linkage to ovarian tumour behaviour

Venous thromboembolism (VTE) is a common cardiovascular disease thought to be the outcome of an intricate interplay between acquired and inherited factors that act together to modify disease risk. Over the years, several single-nucleotide polymorphisms (SNPs) in candidate genes have been associated with disease risk, including F5 rs6025, F2 rs1799963, FGG rs2066865, ABO genetic variants, among others less common. More recently, genome-wide association studies (GWAS) have contributed to the identification of novel VTE-associated SNPs, some of them located in novel genes with no clear role in the haemostatic system, such as SLC44A2 rs2288904 and TSPAN15 rs78707713. Given the existence of a tight relationship between VTE and cancer, with both pathologies sharing biological pathways that allow one to promote the other, these SNPs constitute potential prognostic and predictive biomarkers currently needed for better management of cancer patients. Among solid tumours, ovarian cancer (OC) is one of the most frequently associated with VTE. Indeed, haemostatic components might have a significant impact in OC progression, and therefore, the clinical and biological implications of VTE-associated SNPs should be assessed in patients with this neoplasia.

Liquid biopsy for ovarian cancer using circulating tumor cells: Recent advances on the path to precision medicine

Ovarian cancer (OC) is the most lethal gynecologic malignance worldwide. Considering its metastasis nature, oncologists shift focus towards circulating tumor cells (CTCs), a progenitor that originates from primary tumor and undergoes morphologic/genetic alterations to enter bloodstream and invade nearby tissues. Mountains of evidence suggested that CTCs could provide deep insights into genomic, transcriptomic, and proteomic profiling of OC metastatic cascades. To pave the way for precision medicine, researchers exert great efforts to develop isolation/detection methodologies and construct CTCs-derived propagation platforms, including traditional cell cultures, patient-derived xenografts (PDXs), and organoids. From bench to bedside, CTCs provide minimally-invasive means to inform early diagnosis, predict prognosis, and guide treatment decisions. This review shined a spotlight on biology, detection technologies, and propagation platforms for CTCs. Of note, we also reviewed clinical applications of CTCs in liquid biopsy-based personalized cancer treatment and critically appraised limitations in routine clinical practice on the path to precision medicine.

Recent advancements in therapeutic targeting of the Warburg effect in refractory ovarian cancer: A promise towards disease remission

Epithelial ovarian cancer, the most lethal gynecological malignancy, is diagnosed at advanced stage, recurs and displays chemoresistance to standard chemotherapeutic regimen of taxane/platinum drugs. Despite development of recent therapeutic approaches including poly-ADP ribose polymerase inhibitors, this fatal disease is diagnosed at advanced stage and heralds strategies for early detection and improved treatment. Recent literature suggests that high propensity of ovarian cancer cells to consume and metabolize glucose via glycolysis even in the presence of oxygen (the 'Warburg effect') can significantly contribute to disease progression and chemoresistance and hence, it has been exploited as novel drug target. This review focuses on the molecular cues of aberrant glycolysis as drivers of chemo-resistance and aggressiveness of recurrent ovarian cancer. Furthermore, we discuss the status quo of small molecule inhibition of aerobic glycolysis and significance of metabolic coupling between cancer cells and tumor microenvironment as novel therapeutic interventions against this lethal pathology.

Roles of CA125 in diagnosis, prediction, and oncogenesis of ovarian cancer

After it was discovered approximately 40 years ago, carbohydrate antigen 125 (CA125) became the most widely used and concerning biomarker in ovarian cancer screening. However, there is still controversy about its role in clinical practice. CA125 is not sufficiently reliable in diagnosis to screen for early-stage ovarian cancer. On the other hand, CA125 has been a valuable indicator for evaluating chemotherapeutic efficacy and prognosis. We still do not know much about its biological role, and several studies have indicated that this marker participates in the occurrence and development of ovarian cancer. Currently, an increasing number of scholars have begun to pay attention to CA125-targeted treatment strategies. In the interest of better design and development of anticancer therapies, a renewed and systematic understanding of the roles of CA125 in diagnosis, prediction, and tumorigenesis is warranted.

Comprehensive insights into human papillomavirus and cervical cancer: Pathophysiology, screening, and vaccination strategies

This article provides an in-depth review of the Human Papillomavirus (HPV), a predominant etiological factor in cervical cancer, exploring its pathophysiology, epidemiology, and mechanisms of oncogenesis. We examine the role of proteins, DNA methylation markers, and non-coding RNAs as predictive biomarkers in cervical cancer, highlighting their potential in refining diagnostic and prognostic practices. The evolution and efficacy of cervical cancer screening methods, including the Papanicolaou smear, HPV testing, cytology and HPV test, and colposcopy techniques, are critically analyzed. Furthermore, the article delves into the current landscape and future prospects of prophylactic HPV vaccines and therapeutic vaccines, underscoring their significance in the prevention and potential treatment of HPV-related diseases. This comprehensive review aims to synthesize recent advances and ongoing challenges in the field, providing a foundation for future research and clinical strategies in the prevention and management of cervical cancer.

Biomarkers in high grade serous ovarian cancer

High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.

Tertiary lymphoid structures achieve ‘cold’ to ‘hot’ transition by remodeling the cold tumor microenvironment

Overview of splicing variation in ovarian cancer

Ovarian cancer remains one of the deadliest gynecological malignancies, with a persistently high mortality rate despite promising advancements in immunotherapy. Aberrant splicing events play a crucial role in cancer heterogeneity and treatment resistance. Many splicing variants, especially those involving key molecular markers such as BRCA1/2, are closely linked to disease progression and treatment outcomes. These variants and related splicing factors hold significant clinical value as diagnostic and prognostic biomarkers and therapeutic targets. This review provides a comprehensive overview of splicing variants in ovarian cancer, emphasizing their role in metastasis and resistance, and offers insights to advance biomarker development and treatment strategies.

The neoantigens derived from transposable elements – A hidden treasure for cancer immunotherapy

Deciphering the “Rosetta Stone” of ovarian cancer stem cells: Opportunities and challenges

Ovarian cancer stem cells (OCSCs) play a pivotal role in the initiation, maintenance, and progression of ovarian cancer, functioning through complex molecular mechanisms that are closely linked to metastasis and drug resistance. The complexity of these underlying mechanisms contributes to cancer hallmarks such as the high plasticity of OCSCs, leading to chemotherapy resistance; activation of invasion and metastasis, epigenetic reprogramming, and cell death resistance; and deregulation of cellular metabolism. OCSCs are characterized by the expression of markers including ALDH, CD133, CD44, and CD24. They preserve their stemness through intricate molecular mechanisms that involve interactions with the tumor microenvironment and various signaling pathways. To investigate these molecular mechanisms, both in vitro and in vivo models of OCSC have been established. The results of these studies can be applied in clinical practice, facilitating the development of various new therapies. This review aims to provide a deeper understanding of the mechanisms through which OCSCs function, highlighting significant opportunities for future research aimed at improving ovarian cancer treatment.

Roles of miRNAs in regulating ovarian cancer stemness

Ovarian cancer is one of the gynaecology malignancies with the highest mortality rate. Ovarian cancer stem cell (CSC) is a subpopulation of ovarian cancer cells with increased self-renewability, aggression, metastatic potentials, and resistance to conventional anti-cancer therapy. The emergence of ovarian CSC is a critical factor that promotes treatment resistance and frequent relapse among ovarian cancer patients, leading to poor clinical outcomes. MicroRNA (miRNA) is a short, non-protein-coding RNA that regulates ovarian CSC development. Although multiple original research articles have discussed the CSC-regulatory roles of different miRNAs in ovarian cancer, there is a deficiency of a review article that can summarize the findings from different research papers. To narrow the gap in the literature, this review aimed to provide an up-to-date summary of the CSC-regulatory roles of various miRNAs in modulating ovarian cancer cell stemness. This review will begin by giving an overview of ovarian CSC and the pathways responsible for driving its appearance. Next, the CSC-regulatory roles of miRNAs in controlling ovarian CSC development will be discussed. Overall, more than 60 miRNAs have been reported to play CSC-regulatory roles in the development and progression of ovarian cancer. By targeting various downstream targets, these miRNAs can control the signaling activities of PI3K/AKT, EGFR/ERK, WNT/ß-catenin, NF-kß, Notch, Hippo/YAP, EMT, and DNA repair pathways. Hence, these CSC-modulatory miRNAs have the potential to be used as prognostic biomarkers in predicting the clinical outcomes of ovarian cancer patients. Targeting CSC-promoting miRNAs or increasing the expressions of CSC-repressing miRNAs can help slow ovarian cancer progression. However, more in-depth functional and clinical trials must be carried out to evaluate the suitability, safety, sensitivity, and specificity of these CSC-regulating miRNAs as prognostic biomarkers or therapeutic targets.

The high-grade serous ovarian cancer metastasis and chemoresistance in 3D models

High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive type of epithelial ovarian cancer, with high recurrence rate and chemoresistance being the main issues in its clinical management. HGSOC is specifically challenging due to the metastatic dissemination via spheroids in the ascitic fluid. The HGSOC spheroids represent the invasive and chemoresistant cellular fraction, which is impossible to investigate in conventional two-dimensional (2D) monolayer cell cultures lacking critical cell-to-cell and cell-extracellular matrix interactions. Three-dimensional (3D) HGSOC cultures, where cells aggregate and exhibit relevant interactions, offer a promising in vitro model of peritoneal metastasis and multicellular drug resistance. This review summarizes recent studies of HGSOC in 3D culture conditions and highlights the role of multicellular HGSOC spheroids and ascitic environment in HGSOC metastasis and chemoresistance.

Harnessing tumor immunogenomics: Tumor neoantigens in ovarian cancer and beyond

Ovarian cancer is a major cause of death among gynecological cancers due to its highly aggressive nature. Immunotherapy has emerged as a promising avenue for ovarian cancer treatment, offering targeted approaches with reduced off-target effects. With the advent of next-generation sequencing, it has become possible to identify genomic alterations that can serve as potential targets for immunotherapy. Furthermore, immunogenomics research has revealed the importance of genetic alterations in shaping the cancer immune responses. However, the heterogeneity of immunogenicity and the low tumor mutation burden pose challenges for neoantigen-based immunotherapies. Further research is needed to identify neoantigen-specific tumor-infiltrating lymphocytes (TIL) and establish guidelines for patient inclusion criteria in TIL-based therapy. The study of neoantigens and their implications in ovarian cancer immunotherapy holds great promise, and efforts focused on personalized treatment strategies, refined neoantigen selection, and optimized therapeutic combinations will contribute to improving patient outcomes in the future.

Emerging perspectives on metabolic reprogramming in the microenvironment of ovarian cancer metastasis

Ovarian cancer (OC) is one of the most lethal malignancies in females, mainly due to the aggressive metastasis at the late stage and the unsatisfactory of current therapies. OC cells exhibit a special metastatic behavior compared to other common epithelial tumors, primarily spreading within the peritoneal cavity. Due to the complexity of tumor microenvironment, physical factors induce significant metabolic changes in OC cells, thereby enhancing their metastatic ability. Key cellular components, such as cancer-associated fibroblasts and adipocytes, act synergistically to support metastasis through metabolic interactions. Recent efforts in tumor immunometabolism showed that metabolic reprogramming of immune cells can also significantly impact metastatic progression. Moreover, the microbiome and cellular senescence are emerging as important factors that alter the metabolic landscape. This review provides a systematic review of metabolic reprogramming in the OC microenvironment and highlights the most recent clinical trials targeting metabolic pathways. By increasing our understanding of these metabolic interactions, we can develop innovative metabolism-targeting interventions for this devastating gynecological malignancy.

The impact of HPV infection on human glycogen and lipid metabolism – a review

Reinterpretation of the Wartburg effect leads to understanding aerobic glycolysis as a process that provides considerable amount of molecular precursors for the production of lipids, nucleotides and amino acids that are necessary for continuous growth and rapid proliferation characteristic for cancer cells. Human papilloma virus (HPV) is a number one cause of cervical carcinoma with 99% of the cervical cancer patients being HPV positive. This tight link between HPV and cancer raises the question if and how HPV impact cells to reprogram their metabolism? Focusing on early phase proteins E1, E2, E5, E6 and E7 we demonstrate that HPV activates plethora of metabolic pathways and directly influences enzymes of the glycolysis pathway to promote the Warburg effect by increasing glucose uptake, activating glycolysis and pentose phosphate pathway, increasing the level of lactate dehydrogenase A synthesis and inhibiting β-oxidation. Our considerations lead to conclusion that HPV is substantially involved in metabolic cell reprogramming toward neoplastic phenotype and its metabolic activity is the fundamental reason of its oncogenicity.

Exploring the metabolic alterations in cervical cancer induced by HPV oncoproteins: From mechanisms to therapeutic targets

The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer.

PARP inhibitor resistance in ovarian cancer: Underlying mechanisms and therapeutic approaches targeting the ATR/CHK1 pathway

Ovarian cancer (OC) constitutes the most common cause of gynecologic cancer-related death in women worldwide. Despite consistent developments in treatment strategies for OC, the management of advanced-stage disease remains a significant challenge. Recent improvements in targeted treatments based on poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have provided invaluable benefits to patients with OC. Unfortunately, numerous patients do not respond to PARPi due to intrinsic resistance or acquisition of resistance. Here, we discuss mechanisms of resistance to PARPi that have specifically emerged in OC including increased drug efflux, restoration of HR repair, re-establishment of replication fork stability, reduced PARP1 trapping, abnormalities in PARP signaling, and less common pathways associated with alternative DNA sensing and repair pathways. Elucidation of the precise mechanisms is essential for the development of novel strategies to re-sensitize OC cells to PARPi agents. Additionally, novel potential concepts for preventing and combating resistance to PARPi under development and relevant clinical reports on treatment strategies have been reviewed, with emphasis on the exploitation of the ATR/CHK1 kinase pathway in sensitization to PARPi to overcome resistance-induced vulnerability in ovarian cancer.

Extracellular vesicle-based liquid biopsy holds great promise for the management of ovarian cancer

Ovarian cancer is a highly lethal gynecological disease because most patients are diagnosed in advanced stages due to a lack of appropriate markers or methods for early detection. Extracellular vesicles (EVs) are small biological vesicles released by all types of cells and are widely distributed in biofluids. These vesicles and their bioactive contents are involved in various aspects of tumorigenesis and development, and some of them could be detected in biofluids from liquid biopsy and used as markers for cancer management. Liquid biopsy is a recently developed method for disease diagnosis and real-time monitoring by detecting biomolecules in biofluids such as plasma. The operation is minimally invasive and relatively convenient, especially for patients with cancer. In this review, we describe the use of EV-based liquid biopsy in ovarian cancer and summarize recent advances in technologies for EV isolation and detection, as well as biomarkers identified from ovarian cancer-derived EVs, with a focus on their potential roles in diagnosis and progression monitoring. Although the advantages of liquid biopsy make this approach promising, some technological challenges remain, and qualified biomarkers for clinical use are still being explored.

The implication of IL-6 in the invasiveness and chemoresistance of ovarian cancer cells. Systematic review of its potential role as a biomarker in ovarian cancer patients

Interleukin 6 (IL-6) is a pleiotropic cytokine that is strongly implicated in the development and progression of ovarian cancer. The most recognized actions of IL-6 in ovarian cancer (OC) cells are the induction of cell proliferation and inhibition of cell apoptosis. Equally important is its ability to enhance the migratory and invasive potential of OC cells. Moreover, the increased expression and secretion of this cytokine positively correlates with OC cell chemoresistance. Elevated concentrations of IL-6 are observed in the serum and ascites of ovarian cancer patients. Thus, its level is discussed in the literature as a potential biomarker that can help to discriminate malignant and nonmalignant ovarian tumors and allow for the prediction of the chemotherapy response. The importance of IL-6 in ovarian cancer is proved by the fact that this cytokine is a potential target to anti-cancer therapy. This review is divided into two parts. The first summarizes the general biological activity of IL-6, and overviews its impact on OC cells, as well as discusses the current proposition of IL-6 inclusion in combination of anti-OC therapy. The second part is a systematic review of IL-6 as a possible biomarker in ovarian cancer patients.

Long non-coding RNAs: A view to kill ovarian cancer

An emerging role of long non-coding RNAs (lncRNAs) in tumor progression has been revealed in the last decade. Through interactions with nucleic acids and proteins, lncRNAs could act as enhancers, scaffolds or decoys for a number of oncoproteins and tumor suppressors. The aberrant lncRNA expression or mutations are often associated with changes in a variety of cellular processes, including proliferation, stress response and cell death. Here, we will focus on the tumor-associated lncRNAs in ovarian cancer according to their contribution to cancer hallmarks, such as intense proliferation, cell death resistance, altered energy metabolism, invasion and metastasis, and immune evasion. Moreover, the potential clinical implications of lncRNAs and their significance for the diagnosis, prognosis and therapy of ovarian cancer will be discussed.

Emerging strategies to overcome PARP inhibitors' resistance in ovarian cancer

The utilization of PARP inhibitors (PARPis) has significantly improved the prognosis for ovarian cancer patients. However, as the use of PARPis increases, the issue of PARPi resistance has become more prominent. Prolonged usage of PARPis can lead to the development of resistance in ovarian cancer, often mediated by mechanisms such as homologous recombination (HR) recovery, ultimately resulting in cancer relapse. Overcoming PARPi resistance in ovarian cancer is a pressing concern, aiming to enhance the clinical benefits of PARPi treatment and delay disease recurrence. Here, we summarize the mechanisms underlying PARPi resistance, methods for analyzing resistance, and strategies for overcoming it. Our goal is to inspire the development of more cost-effective and convenient methods for analyzing resistance mechanisms, as well as safer and more effective strategies to overcome resistance. These advancements can contribute to developing personalized approaches for treating ovarian cancer.

Pyroptosis and the tumor immune microenvironment: A new battlefield in ovarian cancer treatment

Ovarian cancer is a less common tumor in women compared to cervical or breast cancer, however it is more malignant and has worse outcomes. Ovarian cancer patients still have a five-year survival rate < 50% despite advances in therapy. Due to recent developments in immune checkpoint inhibitors (ICIs), cancer immunotherapy has attracted increased interest. Pyroptosis is a highly inflammatory form of cell death, which is essential for bridging innate and adaptive immunity, and is involved in immune regulation within the tumor microenvironment (TME). Recent research has shown that pyroptosis can promote immunotherapy of ovarian cancer, including treatment with chimeric antigen receptor T-cells (CAR-T) or ICIs. Moreover, inflammasomes, various signaling pathways and lncRNAs can all affect pyroptosis in ovarian cancer. Here we discuss how pyroptosis affects the development and progression of ovarian cancer as well as the TME. We also provide a summary of small molecule drugs that could target pyroptotic cell death processes and may be useful in ovarian cancer therapy.

Snail transcription factors as key regulators of chemoresistance, stemness and metastasis of ovarian cancer cells

Ovarian cancer is one of the deadliest gynecological malignancies among women. The reason for this outcome is the frequent acquisition of cancer cell resistance to platinum-based drugs and unresponsiveness to standard therapy. It has been increasingly recognized that the ability of ovarian cancer cells to adopt more aggressive behavior (mainly through the epithelial-to-mesenchymal transition, EMT), as well as dedifferentiation into cancer stem cells, significantly affects drug resistance acquisition. Transcription factors in the Snail family have been implicated in ovarian cancer chemoresistance and metastasis. In this article, we summarize published data that reveal Snail proteins not only as key inducers of the EMT in ovarian cancer but also as crucial links between the acquisition of ovarian cancer stem properties and spheroid formation. These Snail-related characteristics significantly affect the ovarian cancer cell response to treatment and are related to the acquisition of chemoresistance.

Potential applications of DNA methylation testing technology in female tumors and screening methods

DNA methylation is a common epigenetic modification, and the current commonly used methods for DNA methylation detection include methylation-specific PCR, methylation-sensitive restriction endonuclease-PCR, and methylation-specific sequencing. DNA methylation plays an important role in genomic and epigenomic studies, and combining DNA methylation with other epigenetic modifications, such as histone modifications, may lead to better DNA methylation. DNA methylation also plays an important role in the development of disease, and analyzing changes in individual DNA methylation patterns can provide individualized diagnostic and therapeutic solutions. Liquid biopsy techniques are also increasingly well established in clinical practice and may provide new methods for early cancer screening. It is important to find new screening methods that are easy to perform, minimally invasive, patient-friendly, and affordable. DNA methylation mechanisms are thought to have an important role in cancer and have potential applications in the diagnosis and treatment of female tumors. This review discussed early detection targets and screening methods for common female tumors such as breast, ovarian, and cervical cancers and discussed advances in the study of DNA methylation in these tumors. Although existing screening, diagnostic, and treatment modalities exist, the high morbidity and mortality rates of these tumors remain challenging.

The role of noncoding RNAs in rare gynecological cancers

Gynecological cancers are cancers that begin in the female reproductive organs. Gynecological cancer is the second most common cancer type among women and has become a global health burden for the female population. More than 50 % of all gynecological cancers can be defined as rare cancers. Three main types of noncoding RNAs (ncRNAs), namely, microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play crucial regulatory roles in physiological and pathological processes. Increasing evidence has revealed that ncRNAs closely participate in gynecological cancers. In this review, we focus on the role of ncRNAs in rare gynecological cancers. We first introduce the definitions, classifications, epidemiological characteristics, prognoses and treatments of rare gynecological cancers. Next, we summarize the differentially expressed ncRNAs and the molecular mechanisms underlying ncRNA connections to tumorigenesis, metastasis, chemoresistance, and recurrence. Finally, we highlight the potential applications of ncRNAs as diagnostic and prognostic biomarkers and therapeutic targets.

Artificial intelligence and allied subsets in early detection and preclusion of gynecological cancers

Lyotropic liquid crystalline 2D and 3D mesophases: Advanced materials for multifunctional anticancer nanosystems

Scientific and clinical relevance of non-cellular tumor microenvironment components in ovarian cancer chemotherapy resistance

The tumor microenvironment (TME) components play a crucial role in cancer cells' resistance to chemotherapeutic agents. This phenomenon is exceptionally fundamental in patients with ovarian cancer (OvCa), whose outcome depends mainly on their response to chemotherapy. Until now, most reports have focused on the role of cellular components of the TME, while less attention has been paid to the stroma and other non-cellular elements of the TME, which may play an essential role in the therapy resistance. Inhibiting these components could help define new therapeutic targets and potentially restore chemosensitivity. The aim of the present article is both to summarize the knowledge about non-cellular components of the TME in the development of OvCa chemoresistance and to suggest targeting of non-cellular elements of the TME as a valuable strategy to overcome chemoresistance and to develop new therapeutic strategies in OvCA patients.

Finding the junction between claudins and endometrial carcinoma

Endometrial carcinoma (EC) defines a heterogeneous group of neoplastic diseases originating from the transformation of endometrial cells that constitute the internal lining of the uterus. To date several molecular targets have been analysed to describe the natural course of the disease, claudins being among these. Claudins are the main components of tight junctions (TJs), and their main functions are ascribed to the compartmentalization of tissues and cell-cell communication by means of intracellular ions diffusion: these features are typical of epithelial cells. Their overexpression, mis-localization or loss contribute to the malignancy of EC cells. This review collected all available data regarding the expression, regulation and claudin-related signaling pathways to provide a comprehensive view on the influence of claudin in EC progression. Further, the translational potential of claudin differential expression was explored, indicating that their role in personalized medicine could also contribute to EC therapy besides their employment for diagnosis and prognosis.

The interplay of obesity, microbiome dynamics, and innovative anti-obesity strategies in the context of endometrial cancer progression and therapeutic approaches

Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and its incidence and mortality are rising. Obesity is more tightly associated with EC than any other cancer. Thus, the rising prevalence of obesity and associated risk factors, including diabetes and insulin resistance, cause alarm. The metabolic derangements of obesity increase the bioavailability of estrogen, hyperinsulinemia, and inflammation in a complex system with direct and indirect effects on the endometrium, resulting in proliferation and, ultimately, carcinogenesis. In addition, the gut dysbiosis associated with obesity helps contribute to these metabolic derangements, priming an individual for developing EC and perhaps affecting treatment efficacy. More recent studies are beginning to explore obesity's effect on the local tumor microbiome of EC and its role in carcinogenesis. Significant and sustained weight loss in individuals can considerably decrease the risk of EC, likely through reversal of the altered metabolism and dysbiosis resulting obesity. Bariatric surgery is the gold standard for successful weight loss and highlights how reversing of the systemic effects of obesity can reduce EC risk. However, the current limited availability, knowledge, and imposed stigma of bariatric surgery prohibits population-level reductions in EC. Therefore, effective and maintainable non-surgical dietary and pharmacologic interventions are needed.