Pathogenesis Of Endometrial Cancer Research Articles

A phase 2, two-stage study of avelumab and axitinib in patients with mismatch repair–proficient (MMR-P) recurrent or persistent endometrial cancer (EC).

TPS5628 Background: Despite significant strides in understanding the molecular pathogenesis of EC, there remain few effective therapies for recurrent disease. Deeper insight into the roles of disordered tumor vasculature and HIF1α- and VEGF-mediated immunosuppressive effects on myeloid-derived suppressor cells, T-cells, and PD-L1 expression contributed to the development of new targeted regimens. By inhibiting VEGF receptor (VEGFR) and PD-L1 signaling, immunologically “cold” tumors may become inflamed. The combination of the anti-PD-L1 antibody avelumab with axitinib, an inhibitor of VEGFR 1-3 and PDGFR with more potent IC50 inhibitory activity than lenvatinib, has also shown synergistic activity and is FDA approved as first line treatment for patients with renal cell cancer. We therefore hypothesized that this combination would be well tolerated and efficacious in recurrent MMR-P EC. Objectives:This is a non-randomized two-stage phase 2 study in patients with MMR-P EC evaluating the activity of combined avelumab and axitinib, as assessed by the co-primary endpoints of (1) frequency of patients surviving progression-free for at least 6 months (PFS6), and (2) the objective response rate (ORR) as measured by RECIST 1.1. Methods: Patients must have MMR-P EC and have received at least one chemotherapeutic regimen, with no upper limit on the number of prior lines received. Prior use of immune checkpoint inhibitors (ICI) is excluded. Eligible patients received avelumab 800 mg IV every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. In the first stage of the study, 16 patients were enrolled; if there were ≥2 objective responses or ≥2 PFS6 responses, accrual continued to the second stage with enrollment of an additional 19 patients. The combination of avelumab/axitinib would be considered worthy of further study if overall there were ≥4 objective responses or ≥8 PFS6 responses. Results: As of the data-cutoff in September 2022, a total of 28 patients had received study treatment; one patient withdrew from the study due to toxicity, prior to her first radiographic assessment. The median number of prior lines was 1 (range 1-4). Median follow-up was 12.7 months. Of the 28 patients receiving study treatment, eleven patients (39.3%, 95% CI 21.5%-59.4%) achieved a PR [11/28; 8 confirmed PR (28.6%) and 3 unconfirmed PR (10.7%)]. An additional 39.3% (11/28) had stable disease as best response. Median PFS was 7.3 months (95% CI 3.9-9.0). PFS6 was 59.3% (95% CI 35.7%-76.7%) and at 6 months, 10 patients were still alive and progression-free. Updated efficacy data and safety data will be reported at the time of the meeting. Conclusions: With 8 confirmed PRs and 10 PFS6 responses, the co-primary endpoints were met and the combination of avelumab/axitinib is considered worthy of further study in this population of MMR-P EC. Clinical trial information: NCT02912572 .

FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways.

Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 (FGFR2) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis. Differential transcriptomic analysis and two-step quantitative real-time PCR (qRT-PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2. Candidate genes and target signalling pathways were investigated by qRT-PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D-orthotypic co-culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR/Cas9-based loss-of-function and pharmacological approaches as well as luciferase reporter techniques, cell-based ectodomain shedding assays and bioinformatics analysis. We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7-mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10-mediated Notch signalling in an ADAM17-dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway components, resulting in ADAM17-dependent oncogenic growth. These findings highlight a pivotal role of ADAM17 in the pathogenesis of EC and provide a compelling rationale for targeting ADAM17 protease activity in FGFR2-driven cancers.

Abstract 4236: Obesity-associated endometrial cancer: Identifying the contributions of TMEM205 expression to the pathogenesis of disease

Abstract Background & Objective: Endometrial cancer (EC) is the most common gynecologic malignancy in the US. EC is more strongly associated with obesity than any other cancer type, with 57% of cases linked to obesity. As rates of obesity increase, the incidence of EC is also rising with worsening prognosis. The objective of this study is to identify the molecular mechanisms of TMEM205 expression that regulate exosome secretion, and the oncogenic proteins that underlie this transformation. Our findings are critical to understanding the pathways of obesity mediated EC and essential for developing novel strategies for preventing and treating EC. Methods: The exosomes were then quantified using nanoparticle tracking analyzer (NTA) and their size measured by Transmission electron microscopy (TEM). TMEM205, STAT5, FAS and PIAS3 expression was confirmed by IHC, WB and RT-PCR in patient and high fat diet treated mouse tissue. Endometrial hyperplasia was developed in immunocompetent mice using high fat diet (HFD; 45 kcal% fat diet) for 16 weeks. Results: To examine the effect of a continuous HFD (45 kcal% fat diet) on adipose, uterine and endometrial tissue, we first investigated body weight and uterine morphology in mice after 24 weeks of treatment. As expected, mice fed a HFD had a significantly higher body weight and increased adipose tissue when compared to control. In addition, mice in the HFD group showed marked enlargement in uterine horn size (hyperplasia) and inflammation with increased cell proliferation in the endometrial layer. The HFD treated mice were associated with increased exosome secretion and expression of the oncogenic proteins TMEM205 and STAT5. Expression of the tumor suppressor gene PIAS3 wasdownregulated in adipose and uterine tissues. L-2265 is a small molecule inhibitor that selectively inhibits TMEM205 and exosome secretion in EC cancer cells. To examine the effect of L-2263 in the context of obesity, we fed mice a HFD and treatment with L-2263 (2mg/kg/) weekly for 3 doses. L-2263 treatment resulted in significantly decreased body weight (BW) and decreased accumulation of adipose tissue relative to control HFD treated mice. Mice in the HFD group showed marked enlargement in uterine horn size (hyperplasia), whereas mice that received L-2263 treatment had normal uterine morphology of mouse age. L-2263 treated mice also demonstrated a significant decrease in the expression of proteins involved in exosome secretion (e.g., TMEM205 and STAT5) and those found in exosomes. Conclusion: This study provides fundamental insight into the mechanism of obesity-mediated TMEM205 expression and exosome secretion and their contribution to the pathogenesis of EC. This study is also provides pre-clinical evidence for the development of the first in-human studies of exosome-targeted therapies to prevent obesity-mediated EC. Citation Format: Takahiko Sakaue, Roman Zingarelli, Wafa Khadraoui, Uksha Saini, John Wallbillich, Muralidharan Anbazhakan, Ross Warner, Kalpana Deepa Priya Dorayappan, Deepika Kalaiyarasan, Molly Morton, Casey Cosgrove, Adrian Suarez, Larry J. Maxwell, David O'Malley, David E. Cohn, Karuppaiyah Selvendiran. Obesity-associated endometrial cancer: Identifying the contributions of TMEM205 expression to the pathogenesis of disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4236.

Abstract P015: Mechanisms of mitochondrial dysfunction in development of mismatch repair-deficient endometrial cancer

Abstract Background: Lynch syndrome (LS) is a hereditary cancer syndrome carrying roughly 60% lifetime risk of endometrial cancer (EC) development. LS-EC is caused by mutations in mismatch repair genes (most commonly MSH2), which lead to DNA repair deficiency and hypermutability. Identifying mechanisms that impact cancer development could provide novel opportunities for EC prevention. Our recent studies in Msh2-deficient mice identified mitochondrial dysfunction in EC pathogenesis. The objective of this study is to define the impact of MSH2 loss on mitochondrial function and oxidative DNA damage to identify targets for EC prevention. We hypothesized that MSH2 loss disrupts mitochondrial function and increases oxidative DNA damage in EC cells. Methods: The effects of MSH2 loss on EC pathogenesis were evaluated using our novel mouse model for EC development (PR-Cre+Msh2flox/flox, abbreviated Msh2KO) and primary cell lines derived from this model. Mitochondrial stress tests (MSTs) compared mitochondrial function in murine and human MSH2-deficient and -intact EC cell lines. Western blots compared mitochondrial protein expression between cell lines. Transcriptomic data of human ECs from The Cancer Genome Atlas (TCGA) were probed using cBioPortal. To examine direct effects of MSH2 loss on oxidative stress and mitochondrial function, we performed lentiviral shRNA knockdown (KD) of MSH2 in two human EC cell lines (KLE, Hec1a) and MSH2 overexpression (MSH2++) in MFE280 cells. MSTs and Western blots were utilized as above. Immunofluorescent staining compared oxidative DNA damage in MSH2-KD, MSH2++, and control cell lines after pharmacologically induced oxidative stress via H2O2. RESULTS Transcriptomic signatures of histologically normal endometrium and EC from Msh2KO mice versus control mice reveal mitochondrial dysfunction as a key aberrant pathway. MSTs show reduced baseline and induced mitochondrial function in murine and human MSH2-deficient EC cells compared to MSH2-intact (p<0.0001). Western blots show that MSH2-deficient EC cells exhibit loss of mitochondrial complex II compared to MSH2-intact cells (p<0.05). TCGA data confirm MSH2-deficient human ECs have reduced complex II subunits (p<0.05). Isogenic in vitro studies show MSH2-KD reduces complex II expression yet has variable effects on mitochondrial function. MSH2 overexpression increases complex II expression and mitochondrial function. Oxidative DNA damage did not differ at baseline, but H2O2-induced DNA damage increased after MSH2-KD in one of two cell lines. Conclusions: MSH2 and complex II loss are strongly associated in EC. Further studies on the downstream effects of complex II loss are necessary to determine the contribution to LS-EC development. Complex II loss could result in disruptions to oxidative phosphorylation, the citric acid cycle, metabolic reprogramming, and oncometabolite production. Defining direct effects of MSH2 loss on these potential cancer susceptibility mechanisms will open new avenues for LS-associated EC prevention. Citation Format: Diana L. Moreno, Mikayla S. Borthwick, Leah Peralta, Wai Kin Chan, Brenda Melendez, Qian Zhang, Nisha Gokul, Melinda S. Yates. Mechanisms of mitochondrial dysfunction in development of mismatch repair-deficient endometrial cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P015.

Chasing Uterine Cancer with NK Cell-Based Immunotherapies

Gynecological cancers, including endometrial adenocarcinoma, significantly contribute to cancer incidence and mortality worldwide. The immune system plays a significant role in endometrial cancer pathogenesis. NK cells, a component of innate immunity, are among the critical innate immune cells in the uterus crucial in menstruation, embryonic development, and fighting infections. NK cell number and function influence endometrial cancer development and progression. Hence, it becomes crucial to understand the role of local (uterine) NK cells in uterine cancer. Uterine NK (uNK) cells behave differently than their peripheral counterparts; for example, uNK cells are more regulated by sex hormones than peripheral NK cells. A deeper understanding of NK cells in uterine cancer may facilitate the development of NK cell-targeted therapies. This review synthesizes current knowledge on the uterine immune microenvironment and NK cell-targeted uterine cancer therapeutics.

RNA m6A methylation regulators in endometrial cancer (Review).

As one of the three major malignant tumor types of the female reproductive system, endometrial cancer (EC) is the most prevalent gynecologic cancer in developed countries. In recent years, the incidence of EC has increased worldwide, threatening the health and well‑being of women. Recent research has indicated that the expression of multiple N6‑methyladenosine (m6A) regulators is up‑ or downregulated in EC and that abnormalities in m6A methylation and the expression of associated regulators are critical to the pathogenesis and progression of EC. m6A is the most abundant internal modification of mRNA. Several studies have demonstrated a close association between the development and progression of malignant tumors and the epigenetic phenomenon of m6A methylation. In the present study, the current status of research on m6A methylation in EC was reviewed. The mechanisms of methyltransferase, demethylase and m6A binding protein in regulating the development and progression of EC by modifying mRNA were introduced. The related research results will provide novel methods and approaches for the prevention and treatment of EC.

Beyond Serous: Treatment Options for Rare Endometrial Cancers.

Rare endometrial cancers are high-grade, aggressive malignancies which are often diagnosed at an advanced stage, and account for disproportionately more deaths than their more common low-grade counterparts. Standard of care includes a combination of surgery, radiation, and chemotherapy. Surgery consists of complete hysterectomy, and more recent evidence supports replacing a full lymphadenectomy with sentinel node mapping. Paclitaxel and carboplatin remain the mainstays of chemotherapy, while current studies incorporating immunotherapy will inform future practice. Whether and how to incorporate radiation remains controversial, and certain histologic subtypes, such as carcinosarcomas, may benefit from radiation more than others. Owing to their relative rarity, it is difficult to conduct clinical trials in this patient population, which has hindered the development of effective therapies for rare malignancies. Molecular profiling has offered insight into the pathogenesis of rare endometrial cancers, providing actionable targets for personalized therapy.

Advances in Exosomes as Diagnostic and Therapeutic Biomarkers for Gynaecological Malignancies.

Simple SummaryThe three major gynaecological cancers are ovarian cancer, endometrial cancer, and cervical cancer, which endanger women’s health worldwide. Significant progress has been made in the study of exosomes, which have been proven to be an important form of intercellular communication, as well as an important carrier for the uptake, transport, and release of cargo. Exosomes may also be promising diagnostic or prognostic markers for gynaecologic malignancies, which may improve the level of treatment of gynaecologic malignancies. This article reviews the latest research progress and systematic knowledge of exosomes in gynaecological malignant tumours in recent years, in order to provide a new perspective for the treatment of gynaecological tumours and promote the clinical application of exosomes in gynaecological malignancies.Background: Exosomes are extracellular vesicles that can be released by practically all types of cells. They have a diameter of 30–150 nm. Exosomes control the exchange of materials and information between cells. This function is based on its special cargo-carrying and transporting functions, which can load a variety of useful components and guarantee their preservation. Recently, exosomes have been confirmed to play a significant role in the pathogenesis, diagnosis, treatment, and prognosis of gynaecological malignancies. Particularly, participation in liquid biopsy was studied extensively in gynaecological cancer, which holds the advantages of noninvasiveness and individualization. Literature Review: This article reviews the latest research progress of exosomes in gynaecological malignancies and discusses the involvement of humoral and cell-derived exosomes in the pathogenesis, progression, metastasis, drug resistance and treatment of ovarian cancer, cervical cancer, and endometrial cancer. Advances in the clinical application of exosomes in diagnostic technology, drug delivery, and overcoming tumour resistance are also presented. Conclusion: Exosomes are potentially diagnostic and prognostic biomarkers in gynaecological malignancies, and also provide new directions for the treatment of gynaecological tumours, showing great clinical potential.

Single cell sequencing analysis and transcriptome analysis constructed the liquid-liquid phase separation(LLPS)-related prognostic model for endometrial cancer.

BackgroundEndometrial cancer is one of the most common gynecological tumors in developed countries. Our understanding of the pathogenesis of endometrial cancer and the changes in the immune microenvironment are still unclear. It is necessary to explore new biomarkers to guide the diagnosis and treatment of endometrial cancer.MethodsThe GEO database was used to download the endometrial cancer single cell sequencing dataset GSE173682. The UCSC database was used to download transcriptome sequencing data. The validation set was the transcriptome dataset GSE119041, which was retrieved from the GEO database. On the DrLLPS website, liquid-liquid phase separation-related genes can be downloaded. Relevant hub genes were found using weighted co-expression network analysis and dimension reduction clustering analysis. Prognostic models were built using Lasso regression and univariate COX regression. Analyses of immune infiltration were employed to investigate the endometrial cancer immunological microenvironment. The expression of model genes in endometrial cancer was confirmed using a PCR test.ResultsWe created an LLPS-related predictive model for endometrial cancer by extensive study, and it consists of four genes: EIF2S2, SNRPC, PRELID1, and NDUFB9. Patients with endometrial cancer may be classified into high-risk and low-risk groups based on their risk scores, and those in the high-risk group had significantly worse prognoses (P<0.05). Additionally, there were notable variations in the immunological milieu between the groups at high and low risk. EIF2S2, SNRPC, PRELID1, and NDUFB9 were all up-regulated in endometrial cancer tissues, according to PCR results.ConclusionsOur study can provide a certain reference for the diagnosis and treatment of endometrial cancer.

Prognostic value of angiogenic markers of endometrial cancer (literature review)

Endometrial cancer is the most common cancer of the female reproductive organs. The purpose of the study was to summarize the available data on the role of angiogenic markers in the development, progression and prognosis of endometrial cancer. Material and methods. A literature search was conducted using Medline and Pubmed databases using the key words: “endometrial cancer”, “endometrial hyperplasia” and others. 56 publications were selected to write this review. Results. Currently, there is a variety of different data on the relationship between molecular markers of angiogenesis in endometrial cancer and the prognosis of endometrial cancer. The article summarizes the results of the most recent studies devoted to the study of angiogenic markers of endometrial cancer, as well as the characteristics of the microvasculature. We focused on the prognostic and diagnostic values of these morphological and molecular changes. particular attention was paid to the inactivation of the oncosuppressive protein PTEN, an inhibitor of the PI3K/Akt/mTOR-signaling pathway, which plays an important role in the pathogenesis and prognosis of endometrial cancer. Conclusion. Many of the markers of angiogenesis can be used to assess the development and prognosis of endometrial cancer. However, conflicting research results with respect to some markers require further study, their validation, and subsequent implementation into practice.

The Exploration of Chemokines Importance in the Pathogenesis and Development of Endometrial Cancer.

Endometrial cancer (EC) is one of the most frequent female malignancies. Because of a characteristic symptom, vaginal bleeding, EC is often diagnosed in an early stage. Despite that, some EC cases present an atypical course with rapid progression and poor prognosis. There have been multiple studies conducted on molecular profiling of EC in order to improve diagnostics and introduce personalized treatment. Chemokines—a protein family that contributes to inflammatory processes that may promote carcinogenesis—constitute an area of interest. Some chemokines and their receptors present alterations in expression in tumor microenvironment. CXCL12, which binds the receptors CXCR4 and CXCR7, is known for its impact on neoplastic cell proliferation, neovascularization and promotion of epidermal–mesenchymal transition. The CCL2–CCR2 axis additionally plays a pivotal role in EC with mutations in the LKB1 gene and activates tumor-associated macrophages. CCL20 and CCR6 are influenced by the RANK/RANKL pathway and alter the function of lymphocytes and dendritic cells. Another axis, CXCL10–CXCR3, affects the function of NK-cells and, interestingly, presents different roles in various types of tumors. This review article consists of analysis of studies that included the roles of the aforementioned chemokines in EC pathogenesis. Alterations in chemokine expression are described, and possible applications of drugs targeting chemokines are reviewed.

TPX2 Serves as a Cancer Susceptibility Gene and Is Closely Associated with the Poor Prognosis of Endometrial Cancer.

Background Endometrial cancer (EC) is a common tumor of the genital tract that affects the female reproductive system but with only limited treatment options. We aimed to discover new prognostic biomarkers for EC. Methods We used mRNA-seq data to detect differentially expressed genes (DEGs) between EC and control tissues. Detailed clinicopathological information was collected, and changes in the mRNA and protein levels of hub DEGs were analyzed in EC. Copy number variation (CNV) was also evaluated for its association with the pathogenesis of EC. Gene set enrichment analysis (GSEA) was conducted to enrich significant pathways driven by the hub genes. Cox regression analysis was used to select variables to create a nomogram. The nomogram was calibrated by applying the concordance index (C-index), and net benefits of the nomogram at different threshold probabilities were quantified using decision curve analysis (DCA). Results Differential expression analysis identified 24 DEGs as potential risk factors for EC. Survival analysis revealed that TPX2 expression was related to worsening overall survival in patients with advanced EC. A high CNV was associated with the overexpression of TPX2; this suggested that modifications in the cell-cycle pathway might be crucial in the advancement of EC. Moreover, an individualized nomogram was developed for TPX2 incorporating clinical factors; this was also evaluated for its ability to predict EC. Calibration and DCA analyses confirmed the robustness and clinical usefulness of the nomogram. Conclusion We offer novel insights into the pathogenesis and molecular mechanisms of EC. The overexpression of TPX2 was related to a poorer prognosis and could serve as a biomarker for predicting prognostic outcomes in EC patients.

Endometrioid Cancer Associated With Endometriosis: From the Seed and Soil Theory to Clinical Practice.

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. It is still debated whether endometriosis is a disease that can predispose to the pathogenesis of endometrial cancer outside the uterus. Deficiencies in mismatch repair (MMR) genes are a known risk factor for developing endometrioid cancer. Starting from two cases of patients with abnormal MMR endometrioid carcinoma of the uterus and synchronous endometrioid carcinoma in non-ovarian and ovarian endometriosis, we performed a somatic mutation profile and phylogenetic analysis of the lesions in order to identify if they were metastasis or primary de novo tumors. In the first case, we identified de novo activating mutations in PIK3CA and KRAS in endometrioid cancer lesions but not in endometriosis. Although the acquisition of a de novo mutation in ESR1 and a decrease in mutant allele fraction (MAF) from the endometrial tumor to the localizations in the endometriosis lesions, the clonal relationship was confirmed by the limited number of heteroplasmic mutations in D-loop mitochondrial DNA region. In the other case, the clonal behavior was demonstrated by the overlap of MAF at each site. Our data support the hypothesis of a retrograde dissemination of tumor cells, moving from the primary carcinoma in the endometrium to ectopic sites of endometriosis where localizations of tumor arise.

Differences in the microbial profiles of early stage endometrial cancers between Black and White women

ObjectiveBlack women suffer a higher mortality from endometrial cancer (EC) than White women. Potential biological causes for this disparity include a higher prevalence of obesity and more lethal histologic/molecular subtypes. We hypothesize that another biological factor driving this racial disparity could be the EC microbiome. MethodsBanked tumor specimens of postmenopausal, Black and White women undergoing hysterectomy for early stage endometrioid EC were identified. The microbiota of the tumors were characterized by bacterial 16S rRNA sequencing. The microbial component of endometrioid ECs in The Cancer Genome Atlas (TCGA) database were assessed for comparison. Results95 early stage ECs were evaluated: 23 Black (24%) and 72 White (76%). Microbial diversity was increased (p < 0.001), and Firmicutes, Cyanobacteria and OD1 phyla abundance was higher in tumors from Black versus White women (p < 0.001). Genus level abundance of Dietzia and Geobacillus were found to be lower in tumors of obese Black versus obese White women (p < 0.001). Analysis of early stage ECs in TCGA found that microbial diversity was higher in ECs from Black versus White women (p < 0.05). When comparing ECs from obese Black versus obese White women, 5 bacteria distributions were distinct, with higher abundance of Lactobacillus acidophilus in ECs from Black women being the most striking difference. Similarly in TCGA, Dietzia and Geobacillus were more common in ECs from White women compared to Black. ConclusionIncreased microbial diversity and the distinct microbial profiles between ECs of obese Black versus obese White women suggests that intra-tumoral bacteria may contribute to EC disparities and pathogenesis.

Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies.

Endometrial cancer (EC) is the sixth most prevalent type of cancer among women. Kinases, enzymes mediating the transfer of adenosine triphosphate (ATP) in several signaling pathways, play a significant role in carcinogenesis and cancer cells’ survival and proliferation. Cyclin-dependent kinases (CDKs) are involved in EC pathogenesis; therefore, CDK inhibitors (CDKin) have a noteworthy therapeutic potential in this type of cancer, particularly in EC type 1. Natural compounds have been used for decades in the treatment of cancer serving as a source of anticancer bioactive molecules. Many phenolic and non-phenolic natural compounds covering flavonoids, stilbenoids, coumarins, biphenyl compounds, alkaloids, glycosides, terpenes, and terpenoids have shown moderate to high effectiveness against CDKin-mediated carcinogenic signaling pathways (PI3K, ERK1/2, Akt, ATM, mTOR, TP53). Pharmaceutical regimens based on two natural compounds, trabectedin and ixabepilone, have been investigated in humans showing short and midterm efficacy as second-line treatments in phase II clinical trials. The purpose of this review is twofold: the authors first provide an overview of the involvement of kinases and kinase inhibitors in the pathogenesis and treatment of EC and then discuss the existing evidence about natural products’ derived kinase inhibitors in the management of the disease and outline relevant future research.

Bone Marrow-Derived Cells in Endometrial Cancer Pathogenesis: Insights from Breast Cancer.

Endometrial cancer is the most common gynecological cancer, representing 3.5% of all new cancer cases in the United States. Abnormal stem cell-like cells, referred to as cancer stem cells (CSCs), reside in the endometrium and possess the capacity to self-renew and differentiate into cancer progenitors, leading to tumor progression. Herein we review the role of the endometrial microenvironment and sex hormone signaling in sustaining EC progenitors and potentially promoting dormancy, a cellular state characterized by cell cycle quiescence and resistance to conventional treatments. We offer perspective on mechanisms by which bone marrow-derived cells (BMDCs) within the endometrial microenvironment could promote endometrial CSC (eCSC) survival and/or dormancy. Our perspective relies on the well-established example of another sex hormone-driven cancer, breast cancer, in which the BM microenvironment plays a crucial role in acquisition of CSC phenotype and dormancy. Our previous studies demonstrate that BMDCs migrate to the endometrium and express sex hormone (estrogen and progesterone) receptors. Whether the BM is a source of eCSCs is unknown; alternatively, crosstalk between BMDCs and CSCs within the endometrial microenvironment could be an additional mechanism supporting eCSCs and tumorigenesis. Elucidating these mechanisms will provide avenues to develop novel therapeutic interventions for EC.

Integrated Analysis of Microbiome and Transcriptome Data Reveals the Interplay Between Commensal Bacteria and Fibrin Degradation in Endometrial Cancer.

The gut-uterus axis plays a pivotal role in the pathogenesis of endometrial cancer (EC). However, the correlations between the endometrial microbiome and endometrial tumor transcriptome in patients with EC and the impact of the endometrial microbiota on hematological indicators have not been thoroughly clarified. In this prospective study, endometrial tissue samples collected from EC patients (n = 30) and healthy volunteers (n = 10) were subjected to 16S rRNA sequencing of the microbiome. The 30 paired tumor and adjacent nontumor endometrial tissues from the EC group were subjected to RNAseq. We found that Pelomonas and Prevotella were enriched in the EC group with a high tumor burden. By integrating the microbiome and hematological indicators, a correlation was observed between Prevotella and elevated serum D-dimer (DD) and fibrin degradation products (FDPs). Further transcriptome analysis identified 8 robust associations between Prevotella and fibrin degradation-related genes expressed within ECs. Finally, the microbial marker of Prevotella along with DD and FDPs showed a high potential to predict the onset of EC (AUC = 0.86). Our results suggest that the increasing abundance of Prevotella in endometrial tissue combined with high serum DD and FDP contents may be important factors associated with tumor burden. The microbe-associated transcripts of host tumors can partly explain how Prevotella promotes DD and FDPs.

Towards Personalized Medicine: Non-Coding RNAs and Endometrial Cancer.

Endometrial cancer (EC) is the most frequent female cancer associated with excellent prognosis if diagnosed at an early stage. The risk factors on which clinical staging is based are constantly updated and genetic and epigenetic characteristics have recently been emerging as prognostic markers. The evidence shows that non-coding RNAs (ncRNAs) play a fundamental role in various biological processes associated with the pathogenesis of EC and many of them also have a prognosis prediction function, of remarkable importance in defining the therapeutic and surveillance path of EC patients. Personalized medicine focuses on the continuous updating of risk factors that are identifiable early during the EC staging to tailor treatments to patients. This review aims to show a summary of the current classification systems and to encourage the integration of various risk factors, introducing the prognostic role of non-coding RNAs, to avoid aggressive therapies where not necessary and to treat and strictly monitor subjects at greater risk of relapse.

Patient-derived organoids reflect the genetic profile of endometrial tumors and predict patient prognosis

BackgroundA major hurdle in translational endometrial cancer (EC) research is the lack of robust preclinical models that capture both inter- and intra-tumor heterogeneity. This has hampered the development of new treatment strategies for people with EC.MethodsEC organoids were derived from resected patient tumor tissue and expanded in a chemically defined medium. Established EC organoids were orthotopically implanted into female NSG mice. Patient tissue and corresponding models were characterized by morphological evaluation, biomarker and gene expression and by whole exome sequencing. A gene signature was defined and its prognostic value was assessed in multiple EC cohorts using Mantel-Cox (log-rank) test. Response to carboplatin and/or paclitaxel was measured in vitro and evaluated in vivo. Statistical difference between groups was calculated using paired t-test.ResultsWe report EC organoids established from EC patient tissue, and orthotopic organoid-based patient-derived xenograft models (O-PDXs). The EC organoids and O-PDX models mimic the tissue architecture, protein biomarker expression and genetic profile of the original tissue. Organoids show heterogenous sensitivity to conventional chemotherapy, and drug response is reproduced in vivo. The relevance of these models is further supported by the identification of an organoid-derived prognostic gene signature. This signature is validated as prognostic both in our local patient cohorts and in the TCGA endometrial cancer cohort.ConclusionsWe establish robust model systems that capture both the diversity of endometrial tumors and intra-tumor heterogeneity. These models are highly relevant preclinical tools for the elucidation of the molecular pathogenesis of EC and identification of potential treatment strategies.

Development and validation of m6A regulators' prognostic significance for endometrial cancer.

Background:Endometrial cancer (EC) is the sixth most common cancer in women globally. It has been found that the expression levels of m6A regulators can be potentially used for prognostic stratification in some cancers, but the role of m6A regulators in EC prognosis remains unclear.Methods:The data of 584 EC samples were downloaded from The Cancer Genome Atlas and the mRNA expression profiles of 20 m6A regulators were analyzed, followed by functional enrichment analysis, immune infiltration analysis, and least absolute shrinkage and selection operator method-COX regression analysis.Results:The mRNA expression levels of 20 m6A regulators were significantly different between cancer samples across different grades. The 548 EC samples could be clearly divided into 2 clusters. Kaplan-Meier survival analysis proved that these two groups had highly different overall survival probabilities. Besides, the univariate regression analysis further reserved eight genes related to overall survival from the 20 m6A regulators. We established a prognostic signature including two genes, that is, IGF2BP1 and YTHDF3, that showed a strong ability for stratifying prognostically different EC patients. We identified 3239 differentially expressed genes between the high- and low-risk groups, involving in multiple biological processes and signaling pathways. Meanwhile, 6 differentially infiltrated immune cell types between the high- and low-risk groups could effectively distinguish the high- and low-risk EC groups. The expressions of immune checkpoints were different between high- and low-risk EC patients.Conclusion:We first report the prognostic role of m6A regulators in EC, which should contribute to a better understanding of the underlying mechanisms of EC pathogenesis and progression.