Proteogenomic insights suggest druggable pathways in endometrial carcinoma.

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of ß-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

The Alterations of Serum IgG Fucosylation as a Potential Additional New Diagnostic Marker in Advanced Endometriosis.

BACKGROUND: Endometriosis is an inflammatory disease leading to the growth of endometrial-like tissue outside of the uterus, which affects approximately 10% of young women of reproductive potential. The diagnosis of this disease is difficult, often invasive and time-consuming, therefore non-invasive diagnostic methods are strongly desirable in endometriosis detection. The aim of our project was to investigate whether any associations exist between the expression of serum IgG fucosylation and advanced stages of endometriosis. We were also interested in whether native serum IgG (s-IgG) fucosylation analysis, without prior IgG isolation, could provide a panel of parameters helpful in non-invasive diagnostics of advanced endometriosis. METHODS: IgG fucosylation was examined using a lectin-ELISA test with fucose-specific lectins: AAL and LCA, specific for core fucose α1,6-linked, as well as LTA and UEA which recognize α1,3- and α1,2-linked fucose, respectively. RESULTS: ROC curve and cluster analysis showed s-IgG reactivities with the panel of fucose-specific lectins AAL, LCA and LTA. CONCLUSION: s-IgG reactivity with the panel of fucose-specific lectins AAL, LCA and LTA can be taken into account as a useful diagnostic and clinical tool to differentiate women with advanced endometriosis. Moreover, it has been shown that the analysis of native IgG fucosylation directly in serum, without prior time-consuming, expensive IgG isolation, is sufficient to distinguish advanced stages of endometriosis from a control group of healthy women.

Proteogenomic Characterization of Endometrial Carcinoma.

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/ß-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

Correlation Between Disease Stage and the Presence of Viable Circulating Tumor Cells in Endometrial Cancer.

BACKGROUND/AIM: The presence of circulating tumor cells (CTCs) in the peripheral blood of patients with solid tumors is associated with a poor prognosis. However, there are limited data concerning the detection of CTCs in endometrial cancer (EC). The aim of this study was to evaluate the presence of CTCs in the peripheral blood of patients with EC. MATERIALS AND METHODS: Peripheral blood samples from 92 patients who underwent a surgical procedure were evaluated using MetaCell® separation technology for CTCs. RESULTS: CTCs were detected in 69 (75%) patients with EC. CONCLUSION: CTCs were detected in a higher percentage of patients than in other studies. The results showed that the technology applied in this study can efficiently capture viable tumor cells in the blood that can be cultured while maintaining their original phenotype. This paper discusses the first successful culturing of human circulating endometrial cancer cells for further downstream functional and molecular characterization.

Increased Endothelial Progenitor Cell Number in Early Stage of Endometrial Cancer.

OBJECTIVES: It is generally believed that circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) reflect the state of the endothelium, its injury and/or repair possibilities. In different types of cancers, increased numbers of CECs and EPCs were found, suggesting their participation in cancer angiogenesis. The objective of this study was to determine whether, in the blood circulation of women with early endometrial cancer, CEC and EPC levels differ from those of healthy women of similar age. METHODS: For CEC number evaluation, samples of peripheral blood cells of women with endometrial carcinoma and control subjects were labeled with anti-CD31 and anti-CD45 antibodies; for EPCs, with anti-VEGFR2 (vascular-endothelium growth factor receptor 2)/KDR and anti-CD34 antibodies. The CEC and EPC cells were then quantified by flow cytometry. RESULTS: Endothelial progenitor cell numbers (CD34, VEGFR2/KDR) in the peripheral blood of women with endometrial carcinoma were significantly augmented as compared with those of control healthy women and CEC numbers (CD31, CD45) were similar in both groups. Cancer patients were divided according to the grading into G1 and G2 groups and according to the stage into International Federation of Gynecology and Obstetrics (FIGO) stage IA and FIGO IB groups. Statistically significant augmented EPC numbers were demonstrated only in G1 and FIGO IA patients. CONCLUSIONS: These results strongly suggest new vessel formation from recruited endothelial precursors as being involved mainly at the early stages of tumor progression.

Pregnancy-induced hypertension is accompanied by decreased number of circulating endothelial cells and circulating endothelial progenitor cells.

Maternal endothelial dysfunction is one of the main features of pregnancy-induced hypertension (PIH). It is generally accepted that circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) reflect the state of the endothelium, its injury and/or repair possibilities. The objective of this study was to determine whether the CECs and EPCs numbers in the circulation of women with PIH reflect the presence of this pathology. Peripheral blood cells of PIH and normotensive pregnant women were labeled with specific monoclonal antibodies. For CECs evaluation, samples were labeled with anti-CD31 and anti-CD45 antibodies; for EPCs with anti-VEGFR2/KDR and anti-CD34 antibodies. Cells were quantified by flow cytometry. The levels of both CECs (CD31(+), CD45(-)) and EPCs (CD34(+), VEGFR2/KDR(+)) in the peripheral blood of women with PIH were significantly lower compared with those of control pregnant women with normal blood pressure level. Lowered accessibility of maternal CECs and EPCs may diminish general regenerative potential of the patient endothelia, contributing to PIH symptoms and to the risk of subsequent coronary and arterial disease.

[The role of endothelium in the pathogenesis of pregnancy-induced hypertension]. / Rola sródblonków w patogenezie nadcisnienia indukowanego ciaza.

Pregnancy-induced hypertension (PIH) is the major cause of maternal and perinatal morbidity. However, the mechanisms responsible for PIH pathogenesis have not yet been fully elucidated. The known risk factors of PIH development are: multiple pregnancy, masculine sex of fetus, very young age of women (below 18 years), advanced age (above 40 years), and obesity of the pregnant woman. In this article an attempt is made to summarize recent knowledge of the pathogenesis of PIH and, particularly, the postulated link between placental ischemia and microvascular dysfunction. The initiating event in PIH has been implicated to be reduced uteroplacental perfusion as a result of abnormal extravillous cytotrophoblast invasion. Focal ischemia and hypoxia, deportation of hypoxemic trophoblast cells, and abnormal expression of various placental biological molecules, particularly the cytokines, are thought to lead to widespread activation/dysfunction of the maternal vascular endothelium. The increased expression of adhesion molecules on activated endothelium intensifies the inflammation process and causes further endothelial injury. The quantitative importance of the various endothelial and humoral factors in mediating PIH symptoms is still unclear. Some of the factors that activate and damage endothelial cells may be of prognostic significance; however, more intensive research should be performed for a precise description of their predictive value.