Uterine Endometrial Cancer Research Articles

P38\u03b2 - MAPK11 and its role in female cancers

BackgroundThe p38MAPK family of Mitogen Activated Protein Kinases are a group of signalling molecules involved in cell growth, survival, proliferation and differentiation. The widely studied p38α isoform is ubiquitously expressed and is implicated in a number of cancer pathologies, as are p38γ and p38δ. However, the mechanistic role of the isoform, p38β, remains fairly elusive. Recent studies suggest a possible role of p38β in both breast and endometrial cancer with research suggesting involvement in bone metastasis and cancer cell survival. Female tissue specific cancers such as breast, endometrial, uterine and ovary account for over 3,000,000 cancer related incidents annually; advancements in therapeutics and treatment however require a deeper understanding of the molecular aetiology associated with these diseases. This study provides an overview of the MAPK signalling molecule p38β (MAPK11) in female cancers using an in-silico approach.MethodsA detailed gene expression and methylation analysis was performed using datasets from cBioportal, CanSar and MEXPRESS. Breast, Uterine Endometrial, Cervical, Ovarian and Uterine Carcinosarcoma TCGA cancer datasets were used and analysed.ResultsData using cBioportal and CanSAR suggest that expression of p38β is lower in cancers: BRCA, UCEC, UCS, CESC and OV compared to normal tissue. Methylation data from SMART and MEXPRESS indicate significant probe level variation of CpG island methylation status of the gene MAPK11. Analysis of the genes’ two CpG islands shows that the gene was hypermethylated in the CpG1 with increased methylation seen in BRCA, CESC and UCEC cancer data sets with a slight increase of expression recorded in cancer samples. CpG2 exhibited hypomethylation with no significant difference between samples and high levels of expression. Further analysis from MEXPRESS revealed no significance between probe methylation and altered levels of expression. In addition, no difference in the expression of BRCA oestrogen/progesterone/HER2 status was seen.ConclusionThis data provides an overview of the expression of p38β in female tissue specific cancers, showing a decrease in expression of the gene in BRCA, UCEC, CESC, UCS and OV, increasing the understanding of p38β MAPK expression and offering insight for future in-vitro investigation and therapeutic application.

Testing methods for surgical treatment of endometrial cancer

Annotation. The urgency of the study is due to an increase in the incidence (more than 50%) of newly diagnosed uterine endometrial cancer, especially among young people. The main method of treatment for stage I-II endometrial cancer remains surgery. The study aimed to identify possible cytological conversion during laparoscopic procedures. The main method of research was a non-randomized, prospective cohort study with subsequent observation of the duration of hospitalization and 30 days after discharge for the period from 2010 to 2019. The duration of hospitalization was estimated, while in the perioperative period and within 30 days after discharge – the presence of postoperative complications. A total of 812 patients with stage I-IV endometrial cancer were analyzed, with a mean age of 52±5 years (25 to 75 years). The first group included patients who underwent laparotomy, the second – laparoscopic surgery. The presence of metastases and recurrences was confirmed by morphological, radiological, echoscopic and clinical methods. Standard methods of descriptive statistics were used for data processing; in particular, the average values were calculated with their standard errors when using the standard Student’s t-test at p<0.05 using Microsoft Excel software packages. Conclusions were made about the volume and type of surgery, taking into account the histological type of tumor, lymphovascular invasion, clinical stage, presence or absence of obesity and other comorbidities that may affect metabolism, life history and the presence of surgery. The obtained data confirm the safety of laparoscopic hysterectomy for women with stage I endometrial cancer. However, there are no data on whether laparoscopy can lead to intra-abdominal dissemination of tumor cells.

Characteristics of local inflammation in patients with uterine fibroids and endometrial cancer.

e17561 Background: Contribution of local inflammation to the course of endometrial cancer (EC) is of interest since it may aggravate the disease. Methods: The study included 25 women aged 62+1.6 years with histologically verified EC (group 1a), 29 women aged 48+8.4 years with uterine fibroids (UF) (group 1b) and 13 non-cancer women aged 42+2.3 years (group 2, controls). Vaginal swabs were taken prior to antitumor treatment. Relative expression of genes encoding the synthesis of IL1B, IL10, IL18, TNFA, TLR4, GATA3, and CD68 in comparison with the reference gene B2M was determined by Real-time PCR using the ImmunoQuantex kit (Russia). An integral parameter of an inflammation index was calculated using binary logistics, and the ratios of the listed indicators were also calculated. 12 parameters were analyzed in total. Groups Ia and Ib were compared with healthy people (p1) and with each other (p2). Results: 4 of 12 studied parameters in EC patients differed from control; no differences were found in UF patients. 7 statistically significant differences were registered between EC and UF. Relative expression of the gene encoding the synthesis of IL10 was maximal in EC (2.8+0.2 vs. 1.8+0.3 in healthy women (p1= 0.006) and 1.8+0.2 in UF (p2= 0.002)). The IL10/IL18 ratio in EC statistically significantly exceeded the ratios in UF patients and in healthy women (61.4+21.7 (p1= 0.003), 46.3+32.2 (p2< 0.001) and 53.7+47.1 respectively). The TNFA/IL18 ratio in EC patients was also higher than in UF patients (1.1+0.7 vs. 0.5+0.2 (p2= 0.035)) due to higher TNFA levels (3.7+0.1 vs. 3.3+0.1 (p2= 0.006)), one of which effects includes stimulation of neoangiogenesis. The ratio of TLR4/GATA3, on the contrary, was lower in EC than in UF (0.7+0.3 and 1.5+0.9 respectively (p2= 0.001). Apparently, it characterized antimicrobial immunity because both of these genes are involved in the response to PAMP (TLR4) and in the genesis of intraepithelial lymphocytes related to innate immunity, as well as in the development of a humoral response via stimulation of Th2 (GATA3). The latter, in addition, is involved in the ontogenesis some organs, including the vagina and uterus. The highest TLR4/GATA3 ratio was found in UF, which, in our opinion, indicated the predominance of the inflammatory process in UF and local immunosuppression in EC. The inflammation index determined with the ImmunoQuantex test system did not differ between the studied groups of women. Conclusions: Some differences were observed in local reactions of immunity and inflammation in benign and malignant uterine tumors, involving the prevalence of immunosuppressive and angiogenic factors in EC and inflammatory factors in UF.

Enhanced antitumor activity of combined lipid bubble ultrasound and anticancer drugs in gynecological cervical cancers.

Chemotherapy plays an important role in the treatment of patients with gynecological cancers. Delivering anticancer drugs effectively to tumor cells with just few side effects is key in cancer treatment. Lipid bubbles (LB) are compounds that increase the vascular permeability of the tumor under diagnostic ultrasound (US) exposure and enable the effective transport of drugs to tumor cells. The aim of our study was to establish a novel drug delivery technique for chemotherapy and to identify the most effective anticancer drugs for the bubble US‐mediated drug delivery system (BUS‐DDS) in gynecological cancer treatments. We constructed xenograft models using cervical cancer (HeLa) and uterine endometrial cancer (HEC1B) cell lines. Lipid bubbles were injected i.v., combined with either cisplatin (CDDP), pegylated liposomal doxorubicin (PLD), or bevacizumab, and US was applied to the tumor. We compared the enhanced chemotherapeutic effects of these drugs and determined the optimal drugs for BUS‐DDS. Tumor volume reduction of HeLa and HEC1B xenografts following cisplatin treatment was significantly enhanced by BUS‐DDS. Both CDDP and PLD significantly enhanced the antitumor effects of BUS‐DDS in HeLa tumors; however, volume reduction by BUS‐DDS was insignificant when combined with bevacizumab, a humanized anti‐vascular endothelial growth factor mAb. The BUS‐DDS did not cause any severe adverse events and significantly enhanced the antitumor effects of cytotoxic drugs. The effects of bevacizumab, which were not as dose‐dependent as those of the two drugs used prior, were minimal. Our data suggest that BUS‐DDS technology might help achieve “reinforced targeting” in the treatment of gynecological cancers.

In search for biomarkers and potential drug targets for uterine serous endometrial cancer

ObjectiveSerous endometrial cancer (USC) is a challenging malignancy associated with metastasis, recurrence and poor outcome. To identify clinically relevant prognostic biomarkers, we focused on a panel of proteins selected after a comprehensive literature review, for tumour profiling of a homogeneous cohort of USC patients.MethodsProtein levels and localization were assessed by immunohistochemistry analysis in 36 hysterectomy samples. Tissue sections were stained with the following antibodies: Aurora A, phospho (T288) Aurora A, BRCA1, CHK1, CIP2A, Cyclin B1, Cyclin E, E2F-1, phospho (S364) E2F-1, FBXW7, FOXM1, phospho (S9) GSK3Beta, PLK1, phospho (T210) PLK1, PPP2R1B, p73, RAD51. Each marker was evaluated as a continuously-scaled variable for association with disease progression and death, using Cox proportional hazards models. The sample consisted of 36 patients with USC, half with stage III or IV disease.ResultsResults showed that higher CHK1 (Checkpoint kinase 1) expression was associated with a decreased risk of progression and death, after adjusting for stage. Interestingly, analysis of a TCGA data set of 109 USC patients corroborates our results showing a favourable prognostic role of CHEK1 after adjusting for stage. Higher FBXW7 (F-box and WD repeat domain containing 7) expression and higher cytoplasmic expression of PPP2R1B (Protein Phosphatase 2 A, Scaffold Subunit Abeta) were each associated with a decreased risk of progression, after adjusting for stage.ConclusionsIn conclusion, results from the present study identify new clinically relevant biomarkers and potential drug targets for uterine serous endometrial cancer.

Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers.

Proteomic signatures associated with clinical measures of more aggressive cancers could yield molecular clues as to disease drivers. Here, utilizing the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets, we defined differentially expressed proteins and mRNAs associated with higher grade or higher stage, for each of seven cancer types (breast, colon, lung adenocarcinoma, clear cell renal, ovarian, uterine, and pediatric glioma), representing 794 patients. Widespread differential patterns of total proteins and phosphoproteins involved some common patterns shared between different cancer types. More proteins were associated with higher grade than higher stage. Most proteomic signatures predicted patient survival in independent transcriptomic datasets. The proteomic grade signatures, in particular, involved DNA copy number alterations. Pathways of interest were enriched within the grade-associated proteins across multiple cancer types, including pathways of altered metabolism, Warburg-like effects, and translation factors. Proteomic grade correlations identified protein kinases having functional impact in vitro in uterine endometrial cancer cells, including MAP3K2, MASTL, and TTK. The protein-level grade and stage associations for all proteins profiled—along with corresponding information on phosphorylation, pathways, mRNA expression, and copy alterations—represent a resource for identifying new potential targets. Proteomic analyses are often concordant with corresponding transcriptomic analyses, but with notable exceptions.

Abstract PO068: Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling

Abstract Although immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite instability (MSI-HI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors. To dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery. Chemotherapy-resistant MSI-HI uterine cancer patients treated with nivolumab had a proliferative T cell response 2-4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells, especially expansion of T-bet+ subset, were enriched in responders, whereas early expansion of regulatory T cells (Treg) and enrichment of terminally differentiated effector/senescence-like T cells were observed in non-responders. Unlike patients with uterine endometrial cancer, patients with TMB-low ovarian cancer did not have a clear proliferative CD8 T cell response, but had an uncoupled proliferation of Treg, after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression in ovarian cancer patients. At baseline, ovarian cancer without recurrence had more terminally differentiated effector-like CD8 T cells, in contrast to TMB-high uterine cancer. Furthermore, in both cohorts, non-responders or patients with recurrence, had more naive-like cell population. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-HI uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration and clinical response. This suggests that therapeutic timing and optimized strategies for combining chemotherapy and immunotherapy are still needed. Collectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that high TMB (inflamed) versus low TMB (cold) tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells. Citation Format: Yuki Muroyama, Sasikanth Manne, Alexander C. Huang, Divij Mathew, Lakshmi Chilukuri, Allison R. Greenplate, Takuya Ohtani, Dmitriy Zamarin, Claire F. Friedman, E. John Wherry. Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO068.

Abstract PO008: ARID1A prevents H3K27-hyperacetylation at active super-enhancers

Abstract Mutations in the multi-subunit SWI/SNF (BAF) chromatin remodeling complex are observed in nearly all types of cancer. The most highly mutated subunit across cancer is ARID1A, which occurs in roughly half of uterine endometrial cancer cases. ARID1A mutations and loss of expression are also common in endometriosis. We have previously demonstrated that ARID1A loss drives transcriptional alterations leading to invasive phenotypes through multiple model systems. Yet, how ARID1A regulates transcription through chromatin regulation is poorly understood. We have generated genome-wide profiles of seven chromatin features associated with transcriptional regulation in human endometrial epithelial cells, in both the presence and absence of ARID1A, in order to identify a mechanism by which ARID1A regulates chromatin. Unbiased genome segmentation using these features revealed that ARID1A interacts with chromatin at highly active and accessible enhancers genome-wide. Out of all tested chromatin features, ARID1A most strongly co-localizes with H3K27ac, a mark of transcriptional activation at proximal and distal enhancers. ARID1A depletion also displayed the greatest effect on genomic H3K27ac as opposed to other histone modifications, H3K18ac, H3K4me1, H3K4me3, and H3K27me3. While the majority of typical enhancers had reduced H3K27ac with ARID1A loss, super-enhancers marked by high basal H3K27ac levels displayed hyperacetylation following ARID1A loss. Moreover, increasing H3K27ac was also associated with heightened eRNA transcription, indicating enhancer hyperactivation. Finally, RNA-seq revealed that genes associated with active super-enhancers were preferentially dysregulated following ARID1A loss. These results suggest that ARID1A-SWI/SNF differentially regulate typical enhancers vs. super-enhancers in the endometrial epithelium, and ARID1A may normally restrict super-enhancer hyperactivation to maintain epithelial identity and prevent endometrial invasion. Citation Format: Jake J. Reske, Mike R. Wilson, Ronald L. Chandler. ARID1A prevents H3K27-hyperacetylation at active super-enhancers [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO008.

A Case Report of Resected Liver Metastasis and Solitary Peritoneal Dissemination Developed 14 Years after Resection of Uterine Endometrial Cancer

症例は71歳，女性．術後14年経過後の子宮体癌，術後1年6カ月経過後の多発早期胃癌，術後1年経過後の肺癌の重複癌既往があり，外来経過観察中であった．CTにて胃癌の診断時より存在した腹膜結節の増大および新規の肝腫瘍が指摘され，治療方針相談目的に当科初診となった．MRIやFDG-PET検査などの画像検査が施行され，他病変は認められなかったが，腹膜結節と肝腫瘍が同一疾患か否か，転移性病変か否かなどの確定診断は困難であった．そのため，十分なインフォームドコンセントの後に診断的治療目的にて両病変ともに外科的切除を施行した．病理組織学的検査では両病変ともに子宮体癌の転移再発と診断された．術後10年以上経過後の子宮体癌の転移再発は非常にまれであり，既往症の術後経過年数にとらわれずに再発の可能性を念頭に置くべきと考えられ，文献的考察を加えて報告する．

A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese.

Causal inference is one of the challenges in epidemiologic studies. Gynecologic diseases have been reported to have association with obesity, however the causality remained controversial except for uterine endometrial cancer. We conducted two‐sample Mendelian randomization (MR) analysis using the large‐scale genome‐wide association study (GWAS) results of gynecologic diseases and body mass index (BMI) in the Japanese population to assess causal effect of BMI on gynecologic diseases. We first conducted GWAS of ovarian cancer, uterine endometrial cancer, uterine cervical cancer, endometriosis, and uterine fibroid (n = 647, 909, 538, 5236, and 645 cases, respectively, and 39 556 shared female controls), and BMI (81 610 males and non‐overlapping 23 924 females). We then applied two‐sample MR using 74 BMI‐associated variants as instrumental variables. We observed significant causal effect of increased BMI on uterine endometrial cancer (β = 0.735, P = .0010 in inverse variance‐weighted analysis), which is concordant with results of European studies. Causal effect of obesity was not apparent in the other gynecologic diseases tested. Our MR analyses provided strong evidence of the causal role of obesity in gynecologic diseases etiology, and suggested a possible preventive effect of intervention for obesity.

Abstract A27: Microsatellite instability and tumor mutation burden as factors in ovarian clear-cell carcinoma therapy selection

Abstract Background: Microsatellite instability (MSI) and tumor mutation burden (TMB) are being considered as predictive biomarkers for PD-1 and PD-L1 blockade immunotherapy. However, in ovarian clear-cell carcinoma (OCC), which demonstrates characteristic resistance to standard chemotherapy, the extent of MSI and TMB and their subsequent prognostic capability are unresolved. The aim of this study is to investigate TMB and MSI in OCC for improved therapy decision making. Methods: Tumor-normal paired whole-exome data of 55 OCC patients (Itamochi et al., Br J Cancer 2017) were analyzed. Sequence data preprocessing was performed in accordance with GATK best practice workflows using BWA, Picard, the GATK toolkit, and SAMtools. Somatic SNVs and indels were detected by using Mutect and VarScan. Resulting variants were annotated by ANNOVAR, and exonic or splicing variants were extracted. SNVs with allele frequency >= 2.0% were kept and further processed by the combination of the pathogenicity prediction values obtained from SIFT, PolyPhen-2, and PROVEAN; SNVs annotated as deleterious or damaging by at least one of the tools were retained. The TMB of each sample was evaluated by the total number of nonsynonymous SNVs called by the preannotation pipeline. A threshold defining high TMB was derived from the inflection point on the right tail of the TMB distribution; the resulting value was positioned at the 85th percentile of TMB values. MSI was calculated using MSIsensor, with the MSI-high classification threshold set as per the software’s documentation. Results: Among the 55 OCC cases, 11 (20%) had at least one or a combination of either MSI-high status, mismatch repair (MMR) mutations, or TMB-high status. Specifically, three had MSI-high status, five had MMR gene mutations, and eight had TMB-high status. MSI-high samples showed elevated TMB (p= 0.052 Fisher-T). TMB was also elevated in MMR-mutated samples (p=0.018 Fisher-T). Among the three samples with MSI-high status, only one contained a deleterious mutation in MMR gene MSH6. One TMB-high sample had a POLE1 mutation. Critically, discrete- and continuous-valued survival analyses using MSI and TMB as independent variables did not suggest correlation with patient prognosis. Conclusion: Within gynecologic oncology, MSI and TMB are correlated with prognosis in uterine endometrial cancer subtypes, though here they have demonstrated relatively reduced prognostic ability in OCC so far as examined by the samples available for this study. Thus, OCC patients are warranted the consideration of immune checkpoint inhibitor therapy at an earlier stage of treatment, and further studies to improve the resolution between MSI/TMB/MMR and phenotypical aspects should be encouraged. Citation Format: Shiro Takamatsu, Noriomi Matsumura, J.B. Brown, Hiroaki Itamochi, Junzo Hamanishi, Ken Yamaguchi, Toru Sugiyama, Tsukasa Baba, Masaki Mandai. Microsatellite instability and tumor mutation burden as factors in ovarian clear-cell carcinoma therapy selection [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A27.

Data on RT-qPCR assay of nuclear progesterone receptors (nPR), membrane progesterone receptors (mPR) and progesterone receptor membrane components (PGRMC) from human uterine endometrial tissue and cancer cells of the Uterine Cervix.

A previous investigation showed that the endometrium normalized in women with endometrial hyperplasia after three months treatment with high dose levonorgestrel IUS (intrauterine system) [1] . The effect was maintained even if immunohistochemical analyses of the endometrium showed that nuclear progesterone receptors (nPRs) were completely downregulated. These observations indicated that some type of non-genomic effect existed [2]. We conducted new investigations of endometrial hyperplasia, now with 6 months low dose levonorgestrel IUS treatment. Again, the growth disturbances were reversed with normalization of the endometrium [3,4]. In the context of these studies, RT-qPCR analyses of the endometrium were performed before and after treatment, to determine expression of nuclear progesterone receptors (nPRA+B and nPRB), membrane progesterone receptors (mPR, α-, β- and γ-subtypes) and progesterone receptor membrane components (PGRMC1and PGRMC2). The human cervical cell line (C-4 I) [5] with no detectable nPRs [6,7] , was included in the investigation as biological control .The gene expression of nPRs, mPRs and PGRMCs was determined in the logarithmic growth phase. Tissue and cellular mRNA was determined with RT-qPCR and used as a surrogate marker for receptor (protein) expression. The present data are connected to the related article entitled “Expression of nuclear progesterone receptors (nPRs), membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in the human endometrium after 6 months levonorgestrel low dose intrauterine therapy” [8].

Coincidental detection of diffuse large B-cell lymphoma in the inner inguinal lymph node of a woman undergoing laparoscopic pelvic lymph node dissection for uterine endometrial cancer

Coincidental detection of diffuse large B-cell lymphoma in the inner inguinal lymph node of a woman undergoing laparoscopic pelvic lymph node dissection for uterine endometrial cancer

An Investigation to Study the Role of Novel Rhenium Compounds on Endometrial Uterine Cancer Cell Lines

Endometrial cancer of the uterus is highly maslignant with an increase rate of morbidity and mortality in both childbearing age and postmenopausal women. Rhenium compounds have been shown to have therapeutic properties against various cancers both in vitro cell lines and in vivo animal models. In this in vitro study, we investigated the effects of a novel group of Rhenium ligands on a uterine cancer cell line. Our initial results showed that these compounds are cytotoxic, induces apoptosis and prevents tubulin polymerization in these uterine cancer cell lines, we also found these novel Rhenium compounds to be noncytocidal to healthy human blood lymphocyte cells, thus proving their safety and efficacy in future translational studies.

Melatonin alleviates progression of uterine endometrial cancer by suppressing estrogen/ubiquitin C/SDHB-mediated succinate accumulation.

Succinate is an important intermediate of the tricarboxylic acid cycle. Recently discovered roles of succinate demonstrate its involvement in immunity and cancer biology; however, the precise underlying mechanisms of its involvement in these additional roles remain to be determined. In the present study, succinate dehydrogenase (SDH) B was decreased in uterine endometrial cancer cells (UECC) under negative regulation of estrogen. This decrease was the result of lower expression levels of ubiquitin C (UBC), which was associated with the activation of peroxisome proliferator-activated receptor gamma and specificity protein 1. The decreased levels of SDHB resulted in the accumulation of succinate in UECC, and thus, a decrease in the production of fumaric acid. Succinate downregulated voltage-gated potassium channel subfamily Q member 1 (KCNQ1) levels by activating serum/glucocorticoid regulated kinase 1 and promoted the growth of UECC in vitro and in vivo. Treatment with melatonin restricted estrogen/UBC/SDHB-induced succinate accumulation and upregulated expression of KCNQ1 and reduced the succinate-mediated growth of UECC in vitro and in vivo. Furthermore, overexpression of melatonin receptor 1B amplified the inhibitory effects of melatonin on succinate-mediated UECC growth. Together, the data in the present study suggest that melatonin suppresses UECC progression by inhibiting estrogen/UBC/SDHB-induced succinate accumulation. The present study provides a scientific basis for potential therapeutic strategies and targets in UEC, particularly for patients with abnormally low levels of SDHB.

ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer.

SummaryUterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

GWAS of five gynecologic diseases and cross-trait analysis in Japanese

We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10−8 and rs567534295:C > T, BRCA1, P = 3.1 × 10−8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10−8 and rs140991990:A > G, SOX9, P = 3.3 × 10−8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10−8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10−8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10−8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10−8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = −0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology.

Automatic segmentation of the uterus on MRI using a convolutional neural network

BackgroundThis study was performed to evaluate the clinical feasibility of a U-net for fully automatic uterine segmentation on MRI by using images of major uterine disorders. MethodsThis study included 122 female patients (14 with uterine endometrial cancer, 15 with uterine cervical cancer, and 55 with uterine leiomyoma). U-net architecture optimized for our research was used for automatic segmentation. Three-fold cross-validation was performed for validation. The results of manual segmentation of the uterus by a radiologist on T2-weighted sagittal images were used as the gold standard. Dice similarity coefficient (DSC) and mean absolute distance (MAD) were used for quantitative evaluation of the automatic segmentation. Visual evaluation using a 4-point scale was performed by two radiologists. DSC, MAD, and the score of the visual evaluation were compared between uteruses with and without uterine disorders. ResultsThe mean DSC of our model for all patients was 0.82. The mean DSCs for patients with and without uterine disorders were 0.84 and 0.78, respectively (p = 0.19). The mean MADs for patients with and without uterine disorders were 18.5 and 21.4 [pixels], respectively (p = 0.39). The scores of the visual evaluation were not significantly different between uteruses with and without uterine disorders. ConclusionsFully automatic uterine segmentation with our modified U-net was clinically feasible. The performance of the segmentation of our model was not influenced by the presence of uterine disorders.

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism

BackgroundExcessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated.MethodsGlutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro.ResultsOur study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC’s growth and autophagy in vitro and / or in vivo.ConclusionsCB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

Brachytherapy: An overview for clinicians.

Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high-level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high-risk prostate cancer to perform dose escalation and improve progression-free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.