Apostolos Kaponis1 , Georgia Kollia1, Fuminori Taniguchi2, Tasuku Harada2 and George Decavalas1
Department of Obstetrics and Gynecology, Patra University School of Medicine, Rio, 26441 Peloponnisos, Patra, Greece
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Japan
Endometriosis is an inflammatory, estrogen-dependent disease characterized by the growth of endometrial tissues outside the uterus. The eutopic endometrium from women with endometriosis has some fundamental differences compared with the normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that gained a lot of interests is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. A common characteristic of endometriotic cells is their ability to evade the apoptotic machinery. Endometriosis could result from increased cellular proliferation or decreased apoptosis in response to appropriate stimuli. This chapter focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Finally, the role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.
Endometriosis is a common and enigmatic disease characterized by the presence of endometrium-like glandular tissue and stroma outside the uterus. The pathophysiology of the disease remains a mystery. Nearly all women of reproductive age exhibit some degree of reflux of endometrial debris . Menstrual effluents, retrogradely shed into the peritoneal cavity, were observed to contain viable endometrial cells . These mechanisms are necessary but insufficient to explain why only some patients develop the disease. The fact that the eutopic endometrium of women with endometriosis shares changes with ectopic tissue and that these changes are not found in the eutopic endometrium of disease-free women has advanced the view that the primary defect in endometriosis is to be found in the eutopic endometrium . Cells and tissue elements, derived from such an altered eutopic endometrium and shed into the peritoneal cavity, have been proposed to have a higher potential for implantation and growth on peritoneal surfaces and development into endometriosis . Many differences are observed between eutopic endometrium of disease-free women and ectopic tissue of a patient with endometriosis. These differences can be explained as the direct influence of the different environment of peritoneal fluid (PF) . One of the endometrial alterations appearing in eutopic and ectopic endometrium from women with endometriosis refers to the regulation of apoptosis. In particular, decreased susceptibility of endometrial tissue to apoptosis may contribute to the pathogenesis of endometriosis.
12.2 Apoptosis in Pathophysiology of Endometriosis
Endometrial cells from women with and without endometriosis have fundamental differences. Endometrial cells from women with endometriosis has enhanced proliferation and increased ability to implant and survive in ectopic locations. Impaired sensitivity of endometrial tissue to apoptosis contributes to abnormal implantation and growth of endometrium at ectopic sites. The inability of endometrial cells to transmit a “death” signal or their ability to avoid cell death is associated with increased expression of antiapoptotic factors (e.g., Bcl-2) and decreased expression of proapoptotic factors (e.g., BAX) . It is unclear whether the abnormal apoptosis in the eutopic endometrium from patients with endometriosis is primary in origin or secondary after establishment of pelvic endometriosis process. This could be attributed to the fact that at the time of clinical presentation and diagnosis most women have already established disease and therefore, it is very difficult to investigate the early developmental stages of the endometriosis.
Reflux of endometrial fragments during menstruation into the peritoneal cavity is a common phenomenon. Under normal conditions, cells that do not adhere to their extracellular matrix enter apoptosis as they receive different signals from their adhesion receptors . In endometriosis, these cells have the ability to adhere to mesothelial cells of peritoneum, to proliferate, and to produce neoangiogenesis resulting in the development of active endometriosis. The effect of MMPs on apoptotic factors and their regulation by steroid hormones may provide a link between endometrial turnover and the invasive process necessary for the development of endometriosis. Immunoglobulin-like cell adhesion molecules (nectins and Necls) involved in apoptosis and cell proliferation have also stronger expression in eutopic and ectopic endometrium of women with endometriosis . High levels of VEGF and IL-1β have been found in the PF of patients with endometriosis. VEGF and IL-1β reduce apoptosis and decrease Bax expression in endometrial epithelial cells from patients with endometriosis. VEGF and IL-1β may protect endometriotic cells from undergoing apoptosis favoring the establishment and progression of endometriotic lesions by promoting the formation of new blood vessels and by protecting endometriotic cells from undergoing cell death .
Intrinsic abnormalities in transplanted eutopic endometrium are contributed to the pathogenesis of endometriosis. Abnormal signaling pathways in the eutopic endometrium of women with endometriosis have been recently reported. Two different groups demonstrated increased activity of the protein kinase A and B pathways regulating the function of many cellular proteins involved in apoptosis and proliferation [10, 11]. It was suggested that increased Akt phosphorylation may be related to the altered apoptosis/proliferation harmony in endometriosis. Another pathway whose activation confers a resistant to apoptosis phenotype in endometriotic cell is the NF-κΒ . In vivo, NF-κB inhibition in early-stage endometriotic lesions induced in nude mice was found to decrease the proliferation of endometriotic cells and stimulate their apoptosis .
cDNA microarray analysis has provided an interesting insight for altered gene expression profiles in patients with endometriosis. Arimoto et al. found 97 upregulated and 337 downregulated genes in women with endometriosis . Genes related to apoptosis (GADD34, GADD45A, GADD45B, PIG11) and the tumor suppressor TP53 gene were downregulated in endometriotic tissues. These findings are inconsistent with the decreased spontaneous apoptosis observed in eutopic endometrium from women with endometriosis.
Survivin is a member of the inhibitors of apoptosis family (IAP). IAP proteins directly inhibit the terminal effector caspases 3 and 7 and thus protect cells from apoptosis. Endometriotic cells express more survivin genes than normal endometrial cells without endometriosis . Survivin plays a critical role in susceptibility of endometriotic stromal cells to apoptosis and survivin inhibitors may be effective as treatment for endometriosis . Increased survivin expression was present in eutopic and ectopic epithelial cells, but only ectopic epithelial cells lost the cyclic variation of survivin expression during menstrual cycles.
Recently, aberrant miRNA expression has been shown to play an important role in the pathogenesis of endometriosis as a part of epigenetic mechanisms. A global miRNA microarray technique used to evaluate the expression of miRNAs in endometriotic cyst stromal cells . In normal endometrial stromal cells miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation, and induces apoptosis. In contrast, in endometriotic cells, the expression of miR-196b was repressed by DNA hypermethylation of the miR-196b gene and this repression may be involved in the development of proliferative and antiapoptotic characteristics of endometriosis .
Steroid hormones are able to modulate the apoptotic machinery in endometriotic cells. Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to exacerbate in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2 . On the other hand, the main effect of progesterone is to inhibit interleukin-8 (IL-8) and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is effective to induce apoptosis through the inhibition of Bcl-2 and NF-κΒ .
12.3 Apoptosis in the Normal Endometrium
Apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium . In normal endometrium, apoptotic cells were identified in the glandular epithelium of late secretory and menstruating endometrium due to progesterone withdrawal, while very little apoptosis was detected during the proliferative phase or at the beginning of the secretory phase . The pattern of apoptosis negatively correlates to serum estradiol concentrations in the proliferative phase . Considering the cyclical nature of apoptosis in normal endometrium, it seems likely that estrogen and progesterone can regulate the signals that result in apoptosis in this tissue.
Bcl-2 has been considered to inhibit apoptosis in the endometrium during the proliferative phase. Bcl-2 cyclically expressed in endometrial glandular and stromal cells peaks during the late proliferative phase, while it decreases dramatically in the early and mid-secretory phase to reappear in the late secretory phase. In contrast, myometrial smooth muscle cells showed consistent Bcl-2 immunoreactivity throughout the menstrual cycle . Higher expression of Bcl-2 was observed in the basal layer, whereas death receptor Fas and caspase-3 were higher in the functional layer of the endometrium . These results fit well with the functional biology of endometrium. Since the basal layer remains relatively constant throughout the menstrual cycle, apoptosis is less common in this layer. The functional layer that undergoes cyclical growth, differentiation, and shedding appears with increased level of apoptosis.
Susceptibility of any given cells to a potential apoptotic stimulus may be determined by the ratio of pro- and antiapoptotic Bcl-2 family members presented in the cell at that time . Bax and Bak are Bcl-2 family members promoting cell death susceptibility, possibly by countering the effect of Bcl-2 on cellular survival through heterodimer interaction. BAX and BAK were upregulated in the glandular epithelial cells during the secretory phase of the normal menstrual cycle [24, 25]. These data imply the existence of a dynamic interplay among many members of the Bcl-2 family in triggering apoptosis.
The Fas ligand (FasL) belongs to the tumor necrosis factor superfamily. The Fas/FasL interaction is essential in inducing apoptosis. Fas expression seems to be unchanged in the different phases of the menstrual cycle . FasL exhibits peak expression during the secretory and menstrual phases . Taken together, Bcl-2 is expressed in human endometrial glandular cells during the proliferative phase but not during the late secretory phase. In contrast, both Fas and FasL are expressed throughout the cycle in weak or moderate amount, except relatively higher expression of FasL in the late secretory phase. It is generally accepted that Bcl-2 blocks apoptosis via the mitochondrial pathway and not the death receptor pathway induced by the Fas/FasL system. Therefore, in the normal human endometrium, caspase-8 is initially activated by the Fas/FasL signal, resulting in the caspase cascade. Activated caspase-8 can switch on both the death receptor pathway and the mitochondrial pathwayvia Bid degradation . It is possible that both the mitochondrial and the death receptor pathways are involved in apoptosis of human endometrial cells.
12.4 Apoptosis in Endometriosis
The percentage of apoptosis in sloughed endometrial cells is greatly reduced among women with endometriosis implying that the number of surviving cells that enter the peritoneal cavity is greater in women who develop endometriosis. The apoptosis indices in the eutopic endometrium of women with endometriosis were lower compared to women without endometriosis . This difference caused primarily by a significant decrease in apoptosis during the late secretory/menstrual and early proliferative phases in women with endometriosis. The cyclic variability of apoptosis may be lost in these women.
12.4.1 Bcl-2 Family in Endometriosis
The expression of Bcl-2 in endometrial glandular cells has a cyclic pattern in eutopic endometrium in patients with endometriosis, but that cyclic changes were not apparent in peritoneal and ovarian endometriotic tissues . Jones et al. did not detect apoptosis in stromal cells from peritoneal endometriotic tissues . In accordance with these findings, Bcl-2 is expressed to a greater extent in stromal cells from ectopic tissues. This overexpression may be directly correlated to the increase in the number of estrogen receptors expressed by ectopic stroma . ncreased expression of Bcl-2 protein was found in proliferative eutopic endometrium from women with endometriosis when compared with normal endometrium from healthy women . BAX expression was absent in proliferative endometrium, whereas there was an increase in its expression in secretory endometrium from women with endometriosis and healthy women. The Bcl-xL/Bcl-xS ratio (antiapoptotic/proapoptotic) was substantially higher in eutopic endometrium from women with endometriosis compared to endometria from women without endometriosis . Altered expression of Bcl-2 family members in eutopic endometrium of women with endometriosis resulted to a decreased number of apoptotic cells and consequently to their abnormal survival in the ectopic locations.
Increased prostaglandin E2 (PGE2) signaling was observed in ectopic endometriotic tissues compared with eutopic endometrium tissues during the menstrual cycle . The ability of endometriotic cells to circumvent apoptotic signals can be the result of increased PGE2 signaling, which is associated with abundant expression of the antiapoptotic Bcl-2 and Bcl-XL proteins, low expression of proapoptotic Bax protein, phosphorylation/inactivation of proapoptotic Bad protein, and activation of multiple cell survival signaling pathways (ERK1/2, Akt, nuclear factor-κΒ, β-catenin) .
12.4.2 Fas/FasL System in Endometriosis
Few studies have been published on the expression of Fas in endometriotic tissues. Harada et al. found that Fas is expressed randomly in both eutopic and ectopic glandular endometrial cells . Fas expression was constant in both tissues throughout the menstrual cycle. Abundant expression of Fas antigen was found in NKcells of PF of women with early stages of endometriosis . The activated PF NK-cells can be intensively eliminated via the Fas/FasL apoptosis, thus providing conditions for the survival of ectopic endometrium cells and the development of the disease at the initial stages of endometriosis.
In contrast with Fas, many studies indicated that higher expression of FasL by endometriotic cells contributes to their survival and the development of endometriosis. The levels of soluble/active FasL are higher in serum and PF in women with moderate to severe endometriosis than in women with early-stage disease or in disease-free women . Higher levels of soluble FasL in the PF of women with endometriosis may contribute to increased apoptosis of Fas-bearing immune cells in the peritoneal cavity, leading to their decreased scavenger activity . This may result in prolonged survival of endometrial cells into the peritoneal cavity.
The sources of the elevated levels of soluble FasL in the peritoneal cavity were endometriotic lesions and PF leukocytes. Endometrial glandular and stromal cells presented with increased FasL expression. Peritoneal macrophages in endometriosis might stimulate a Fas-mediated apoptosis of immune cells . FasL expression in the endometriotic cells may protect them from attack by T lymphocytes. Consequently, ectopic endometrium cells escaping from immune surveillance in the peritoneal cavity may contribute to the maintenance of the disease. It is, therefore, possible that many endometriotic cells not only become resistant to Fas-mediated apoptosis, but additionally they have acquired the ability to utilize this pathway to their advantage by launching a “Fas counterattack” against the host’s immune system.
Upregulation of FasL expression by endometriotic cells could be induced after the adhesion of these cells to the extracellular matrix proteins laminin, fibronectin, and collagen IV . MMPs have been implicated in the conversion of FasL to active/soluble forms, suggesting that these molecules can activate or release factors involved in the apoptotic process . FasL expression that occurs when endometrial stromal cells attach to the extracellular matrix may be one of the critical events in the development of endometriosis.
Interleukin-8 (IL-8), a chemokine for neutrophils and a potent angiogenic agent, is elevated in the PF of women with endometriosis . IL-8 promotes proliferation of stromal cells derived from endometriotic tissues , suggesting that it may facilitate growth of endometriotic implants. Selam et al. demonstrated a concentration-dependent increase in IL-8-induced FasL expression in endometrial stromal cells. Elevated IL-8 levels in PF, via stimulation of FasL, induce apoptosis in activated T lymphocytes and contribute to an immune-privileged environment around the endometriosis implants supporting their survival . On the other hand, IL-8 exerts a chemotactic activity primarily on neutrophils and inhibits their apoptosis even in the presence of Fas engagement. IL-8 is one of the neutrophil survival factors in the PF of endometriosis patients. IL-8 exerts the antiapoptotic effects by activating the PTEN/Akt pathway and mediating the expression of survivin and Bcl-2 . IL-2 also enhanced survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway . The impaired clearance of cells responsible for innate immunity in the PF of patients with endometriosis may be associated with the development of the disease.
12.4.3 Apoptosis and Treatment of Endometriosis
Endometriosis is an estrogen-dependent disease. Current therapeutic alternatives consist of various hormone treatments aimed at decreasing circulating estrogen to postmenopausal levels. Incubation with GnRH agonists increased the apoptotic rate in eutopic and ectopic endometrium cells from women with endometriosis . Treatment with GnRH-a affects the expression of a diverse range of genes, including those that encode apoptotic factors. GnRH-a significantly induced apoptosis, as was shown from the increased expression of activated caspase-3, in eutopic endometrium cells and lesions from women with endometriosis . GnRH-a inhibit cell proliferation and increase the apoptotic rate in eutopic endometrium cell cultures, an effect that appears to be mediated by an increase in the expression of the proapoptotic proteins Bax and FasL and a decrease in the expression of the antiapoptotic protein Bcl-2. GnRH-a treatment attenuated IL-8 expression by reducing TNF-α-induced NF-κB activation . Inhibitors of NF-κB activity (BAY 11-7085, apigenin, pyrrolidine dithiocarbamate) were used to examine the potential application for the treatment of endometriosis. It has been shown that NF-κΒ inhibitors significantly inhibited the cell proliferation and induced apoptosis [50–52].
Mutants of estrogen receptor genes delivered to endometriotic cells via an adenovirus vector decreased cell proliferation, induced apoptosis, and decreased cytokine production, suggesting that adenovirus-mediated gene therapy may represent a potential therapy for endometriosis in the future . Aromatase overexpression is observed in endometriotic tissues. Aromatase inhibitors, letrozole and anastrozole, produced significant and positive effects on apoptosis of epithelial endometrial cells from patients with endometriosis . Combined oral contraceptives (OC) can be administered to women with endometriosis in order to reduce pain symptoms and to prevent progression or recurrence of the disease . OC can enhance programmed cell death (decreased Bcl-2/BAX expression ratio) in the eutopic endometrium of women with endometriosis . Progestogens exert inhibitory effects on endometrial proliferation and enhance apoptosis in the endometrium . Levonorgestrel increased Fas expression and enhanced apoptotic index in eutopic and ectopic endometrium of patients with endometriosis .
Several new compounds have been investigated as new treatment modalities for endometriosis in in vitro or in animal models (bufalin, beta-hydroxyisovalerylshikonin, raloxifene, fasudil). These compounds act as apoptosis-induced agents in endometriotic cells [58–61]. Histone deacetylase inhibitors have been shown also to induce apoptosis in endometriotic cells . Selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased PGE2 production . Modulation of apoptotic factors may result in the effective treatment of endometriosis.
Apoptosis has an important role in the development of endometriosis. Manipulation of cell death processes could be used to treat endometriosis. However, it is important to remember that no biochemical pathway stands on its own. Apoptosis represents the final execution step that defines the fate of a cell. However, the decision for the survival or the death of a cell has been taken earlier through various and complicated gene regulations. Advances in molecular biology and genetics will help us to understand these issues and may yield prevention and treatment modalities for endometriosis in the near future.
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