Survival Of Endometriotic Cells Research Articles

NK Cells as Potential Targets for Immunotherapy in Endometriosis

Endometriosis is a common gynecological disease defined by the presence of endometrial-like tissue outside the uterus, most frequently on the pelvic viscera and ovaries, which is associated with pelvic pains and infertility. It is an inflammatory disorder with some features of autoimmunity. It is accepted that ectopic endometriotic tissue originates from endometrial cells exfoliated during menstruation and disseminating into the peritoneum by retrograde menstrual blood flow. It is assumed that the survival of endometriotic cells in the peritoneal cavity may be partially due to their abrogated elimination by natural killer (NK) cells. The decrease of NK cell cytotoxic activity in endometriosis is associated with an increased expression of some inhibitory NK cell receptors. It may be also related to the expression of human leukocyte antigen G (HLA-G), a ligand for inhibitory leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) receptors. The downregulated cytotoxic activity of NK cells may be due to inhibitory cytokines present in the peritoneal milieu of patients with endometriosis. The role of NK cell receptors and their ligands in endometriosis is also confirmed by genetic association studies. Thus, endometriosis may be a subject of immunotherapy by blocking NK cell negative control checkpoints including inhibitory NK cell receptors. Immunotherapies with genetically modified NK cells also cannot be excluded.

Dual inhibition of ERK1/2 and AKT pathways is required to suppress the growth and survival of endometriotic cells and lesions

Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. Current hormonal therapies targeting estrogen can be prescribed only for a short time. It indicates a need for non-hormonal therapy. ERK1/2 and AKT pathways control several intracellular signaling molecules that control growth and survival of cells. Objectives of the present study are to determine the dual inhibitory effects of ERK1/2 and AKT pathways: (i) on proliferation, survival, and apoptosis of human endometrioitc epithelial cells and stromal cells in vitro; (ii) on growth and survival of endometrioitc lesions in vivo in xenograft mouse model of endometriosis of human origin; and (iii) establish the associated ERK1/2 and AKT downstream intracellular signaling modules in the pathogenesis of endometriosis. Our results indicated that combined inhibition of ERK1/2 and AKT pathways highly decreased the growth and survival of human endometriotic epithelial cells and stromal cells in vitro and suppressed the growth of endometriotic lesions in vivo compared to inhibition of either ERK1/2 or AKT pathway individually. This cause-effect is associated with dysregulated intracellular signaling modules associated with cell cycle, cell survival, and cell apoptosis pathways. Collectively, our results indicate that dual inhibition of ERK1/2 and AKT pathways could emerge as potential non-hormonal therapy for the treatment of endometriosis.

Molecular, Cellular, and Epigenetic Signatures of Prostaglandin E2 in Endometriosis

Background: Endometriosis is a debilitating and chronic inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic pelvic pain and infertility, which profoundly affect the quality of life in women. Current treatment strategies include surgical intervention, anti-estrogen hormonal therapy, or a combination of both. The existing treatment modalities fail to prevent recurrence of disease and affect reproductive health of women. This suggests a fundamental need to identify potential cell signaling pathways for nonestrogen or nonsteroidal targets for endometriosis. A growing body of evidence indicates that growth factors, cytokines, and prostaglandins promote the establishment and maintenance of endometriosis. Objective: Published literatures related with prostaglandin E2 (PGE2) signaling and pathophysiology and pathogenesis of endometriosis are comprehensively reviewed. This review specifically focused on the interaction between PGE2 receptors EP2 and EP4 signaling and adhesion, invasion, growth, survival, and epigenetics, fertility, and pain in endometriosis. Results: EP2 and EP4 receptor proteins are highly expressed in endometriotic lesions compared to endometrium from women with or without endometriosis. Inhibition of EP2 and EP4 signaling decreases adhesion, invasion, growth and survival of human endometriotic cells in vitro through multiple cell signaling pathways. Inhibition of EP2 and EP4 signaling modulates DNA methylation and H3 histone methylation machinery in human endometriotic cells in vitro. Inhibition of EP2 and EP4 signaling decreases innervation of the endometriotic lesions and decreases pelvic pain and decreases progesterone resistance and restores endometrial receptivity mechanisms in vivo in preclinical xenograft mice model of endometriosis. Conclusion: The advantages of selective inhibition of EP2 and EP4 are to: (i) inhibit of adhesion, invasion, growth and survival of endometriotic cells; (ii) decrease PGE2-inudced inflammation and pain; (iii) decrease estrogen-dominant and progesterone resistant states in endometriotic lesions and endometrium, and (iv) improve endometrial microenvironment to support implantation and pregnancy. These findings suggest that inhibition of EP2 and EP4 receptors could emerge as a potential nonsteroidal therapy for the treatment of endometriosis. Keywords: PGE2, EP2, EP4, endometriosis, epigenetic, fertility.

P38 Mitogen-Activated Protein Kinase is Involved in the Pathogenesis of Endometriosis by Modulating Inflammation, but not Cell Survival.

Local pro-inflammatory environment and enhanced cell survival contribute to the endometriosis development. A serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) mediates intracellular signaling of cytokine production, cell proliferation, and apoptosis in different cell types. The current study compares p38 MAPK activity in normal endometrium and endometriosis, and assesses role(s) of p38 MAPK on cytokine production and cell survival in endometriosis. Immunohistochemical levels of total and phosphorylated (active) p38 MAPK as well as its correlation with interleukin 8 (IL-8) expression, and cell proliferation and apoptosis were compared in normal human endometrium and endometriosis. The action of p38 MAPK on pro-inflammatory cytokine-induced IL-8 and monocyte chemotactic protein (MCP)-1 expression in endometriotic cells were assessed by enzyme-linked immunosorbent assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell survival, 5-bromo-2'-deoxyuridine incorporation, and Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assays were used to determine the function of p38 MAPK in cultured human endometriotic stromal cell proliferation and apoptosis. p38 MAPK activity was significantly higher in both eutopic and ectopic endometria compared to normal endometria during late proliferative and early secretory phases ( P < .05). Increased p38 MAPK activity in endometriotic cells correlated with IL-8 expression (Pearson correlation coefficient r = 0.83, P < .01), but not with apoptosis in vivo. The pro-inflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α induced activation of p38 MAPK. Inhibition of p38 MAPK activity blocked IL-1β and TNF-α-induced IL-8 and MCP-1 secretion in cultured endometriotic stromal cells ( P < .05), but did not impact on endometriotic cell survival. These results suggest that rather than modulating cell survival, increased p38 MAPK activity in endometriotic cells contributes to the pathogenesis of endometriosis by promoting the local inflammatory milieu.

Critical Factors Involved in Chronic Inflammation in the Pathophysiology of Endometriosis

Chronic inflammation is the cause and effect in the pathogenesis of endometriosis. Characterized as an imbalance of various kinds of cytokines and deficient immune-surveillance in the peritoneal cavity, endometriosis creates its own system to maintain the survival of endometriotic cells outside of the uterus. Characteristics of the cells present in the microenvironment including immune cells and endometriotic cells have been changed by cytokines and other protein molecules, which are the critical keys that determine the development of the disease. In this review, we will focus on the effects from the inflammation-related factors on the phenotypic changes in cells in the pathogenesis of endometriosis to discuss.

Regulation of apoptotic pathways during endometriosis: from the molecular basis to the future perspectives

Endometriosis is defined as the presence of endometrial-like endometrial cells, glands and stroma outside the uterus, causing a strong inflammatory-like microenvironment in the affected tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease. Considering the pivotal role of interaction between immune and endometriotic cells, in this paper, we aim to shed light about the role of apoptosis pathways in modulating the fine-regulated peritoneal microenvironment during endometriosis. Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. In normal conditions, endometriotic cells, refluxed through the fallopian tubes into the peritoneal cavity, should be attacked and removed by phagocytes and NK cells. During endometriosis, the breakdown of peritoneal homeostasis causes the failure of scavenging mechanisms, allowing the survival of endometriotic cells. The consequent so-called "immunoescaping" of endometriotic cells could be due, at least in part, to the reduction of apoptotic-mediated pathways previously described. Considering the large amount of evidence retrieved from in vitro as well as in vivo models, the reduced apoptosis of endometriotic cells together with the increased apoptosis of peritoneal fluid mononuclear cells may address the peritoneal homeostasis to a permissive environment for the progression of the disease.

Cordycepin (3′-Deoxyadenosine), an Inhibitor of mRNA Polyadenylation, Suppresses Proliferation and Activates Apoptosis in Human Epithelial Endometriotic Cells in vitro

Background/Aims: Endometriosis is a benign but chronic disorder associated with pelvic pain and infertility. Enhanced proliferation and reduced apoptosis susceptibility are characteristics of endometriosis. Cordycepin is a poly(A) polymerase inhibitor. It induces shortening of poly(A) tails, leading to destabilization of mRNAs and finally to proliferation inhibition and cell death in normal and tumor cells. The potential of cordycepin to block proliferation and survival of 11z human immortalized epithelial endometriotic cells was determined. Methods: 11z cell cultures were treated with cordycepin. Cordycepin-induced inhibition of proliferation and alterations in protein expression and protein phosphorylation were determined by the methyl thiazolyl tetrazolium assay and immunoblot analysis, respectively. Results: Cordycepin induced the rapid and significant upregulation of the cell cycle progression inhibitor p21 and the downregulation of the cell cycle progression promoter cyclin D₁, finally leading to the inhibition of the proliferation of 11z human epithelial endometriotic cells. Cordycepin reduced the phosphorylation of the p38 mitogen-activated protein kinase and the retinoblastoma protein. It also activated caspase-dependent, intrinsic apoptosis, as documented by the proteolytic cleavage of the caspase-9, caspase-3 and the poly(ADP ribose) polymerase 1 precursor. Conclusion: The mRNA polyadenylation inhibitor cordycepin inhibits proliferation and survival of endometriotic cells.

Cyclooxygenase-2 Regulates Survival, Migration, and Invasion of Human Endometriotic Cells through Multiple Mechanisms

Endometriosis is a debilitating disease characterized by the presence of functional endometrial glandular epithelium and stroma outside the uterine cavity that affects up to 20% of women of child-bearing age. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandin E(2) (PGE(2)), is highly expressed in endometriotic tissues and results in increased concentrations of peritoneal PGE(2) in women. In this study, we determined the expression of COX-2 protein in ectopic and eutopic endometria in humans and the role of COX-2 in endometriotic cell survival, migration, and invasion in humans. Our results indicate that COX-2 protein is abundantly expressed in ectopic endometria compared with eutopic endometria. Comparatively, expression of COX-2 protein is higher in eutopic endometria from women with endometriosis compared with women without endometriosis. Inhibition of COX-2 decreases survival, migration, and invasion of endometriotic cells that are associated with decreased production of PGE(2). Cell growth inhibitory effects of COX-2 inhibition/silencing are mediated through nuclear poly (ADP-ribose) polymerase-mediated apoptosis. Cell motility and invasion inhibitory effects of COX-2 inhibition/silencing are mediated through matrix metalloproteinase-2 and -9 activities. Interestingly, effects of COX-2 inhibition is more profound in endometriotic epithelial than in stromal cells. Furthermore, inhibition of COX-2 affects invasion rather than migration of endometriotic epithelial and stromal cells. It is the first evidence showing that inhibition of COX-2 decreases endometriotic epithelial and stromal cell survival, migration, and invasion in humans. Our results support the emerging concept that COX-2/PGE(2) promotes the pathophysiology and pathogenesis of endometriosis in humans.

Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium

To use DNA microarrays to identify differentially expressed genes in eutopic endometrium compared with ectopic endometrium. Prospective, cross-sectional, observational study. University Medical Center and Research Laboratory. Eleven women with endometriosis. None. Differential gene expression. Seven hundred seventeen of the 53,000 probes on the whole human DNA microarrays were changed by twofold or greater in ectopic versus eutopic endometrium. Families of genes that were expressed differentially include genes that code for proteins associated with the immune system and inflammatory pathways, cell adhesion, cell-cell junctions, the extracellular matrix and its remodeling, cytoskeletal proteins, and signal transduction pathway components, among others. The altered immune environment may allow survival of endometriotic cells that enter the abdominal cavity. Alterations of cell adhesion-associated genes may contribute to the adhesive and invasive properties of ectopic endometrium, and changes in signal transduction pathways support a change in the communication among cells of the endometrial explant compared with eutopic endometrium. These families of differentially expressed genes provide multiple opportunities for the development and testing of new hypotheses regarding endometriosis.