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

Purpose 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. Similar content being viewed by others

Giudice LC, Kao LC (2004) Endometriosis. Lancet 364:1789–1799. doi:10.1016/S0140-6736(04)17403-5 Bulun SE (2009) Endometriosis. N Engl J Med 360:268–279. doi:10.1056/NEJMra0804690 Meuleman C, Vandenabeele B, Fieuws S et al (2009) High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 92:68–74. doi:10.1016/j.fertnstert.2008.04.056 Missmer SA, Cramer DW (2003) The epidemiology of endometriosis. Obstet Gynecol Clin North Am 30:1–19. doi:10.1016/S0889-8545(02)00050-5 Viganò P, Parazzini F, Somigliana E, Vercellini P (2004) Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol 18:177–200. doi:10.1016/j.bpobgyn.2004.01.007 Triolo O, Laganà AS, Sturlese E (2013) Chronic pelvic pain in endometriosis: an overview. J Clin Med Res 5:153–163 Butticè S, Laganà AS, Barresi V et al (2013) Lumbar ureteral stenosis due to endometriosis: our experience and review of the literature. Case Rep Urol 2013:812475. doi:10.1155/2013/812475 Laganà AS, Condemi I, Retto G et al (2015) Analysis of psychopathological comorbidity behind the common symptoms and signs of endometriosis. Eur J Obstet Gynecol Reprod Biol 194:30–33. doi:10.1016/j.ejogrb.2015.08.015 Sampson JA (1927) Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3(93–110):43 Bellelis P, Dias JA Jr, Podgaec S et al (2010) Aspectos epidemiológicos e clínicos da endometriose pélvica: uma série de casos. Rev Assoc Med Bras 56:467–471. doi:10.1590/S0104-42302010000400022 Anger DL, Foster WG (2008) The link between environmental toxicant exposure and endometriosis. Front Biosci 13:1578–1593. doi:10.2741/2782 Laganà AS, Sturlese E, Retto G et al (2013) Interplay between misplaced müllerian-derived stem cells and peritoneal immune dysregulation in the pathogenesis of endometriosis. Obstet Gynecol Int 2013:527041. doi:10.1155/2013/527041 Maniglio P, Ricciardi E, Laganà AS et al (2016) Epigenetic modifications of primordial reproductive tract: a common etiologic pathway for Mayer-Rokitansky-Kuster-Hauser Syndrome and endometriosis? Med Hypotheses 90:4–5. doi:10.1016/j.mehy.2016.02.015 Pizzo A, Salmeri FM, Ardita FV et al (2002) Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obs Invest 54:82–87. doi:10.1159/000067717 Borrelli GM, Abrão MS, Mechsner S (2014) Can chemokines be used as biomarkers for endometriosis? A systematic review. Hum Reprod 29:253–266. doi:10.1093/humrep/det401 May KE, Villar J, Kirtley S et al (2011) Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update 17:637–653. doi:10.1093/humupd/dmr013 Andreoli CG, Genro VK, Souza CA et al (2011) T helper (Th)1, Th2, and Th17 interleukin pathways in infertile patients with minimal/mild endometriosis. Fertil Steril 95:2477–2480. doi:10.1016/j.fertnstert.2011.02.019 Králíčková M, Vetvicka V (2015) Immunological aspects of endometriosis: a review. Ann Transl Med 3:153. doi:10.3978/j.issn.2305-5839.2015.06.08 Laganà AS, Triolo O, Salmeri FM et al (2016) Natural Killer T cell subsets in eutopic and ectopic endometrium: a fresh look to a busy corner. Arch Gynecol Obstet 293:941–949. doi:10.1007/s00404-015-4004-7 Hirata T, Osuga Y, Hamasaki K et al (2008) Interleukin (IL)-17A stimulates IL-8 secretion, cyclooxygensase-2 expression, and cell proliferation of endometriotic stromal cells. Endocrinology 149:1260–1267. doi:10.1210/en.2007-0749 Hirata T, Osuga Y, Takamura M et al (2010) Recruitment of CCR6-expressing Th17 cells by CCL 20 secreted from IL-1 beta-, TNF-alpha-, and IL-17A-stimulated endometriotic stromal cells. Endocrinology 151:5468–5476. doi:10.1210/en.2010-0398 Basta P, Majka M, Jozwicki W et al (2010) The frequency of CD25+ CD4+ and FOXP3+ regulatory T cells in ectopic endometrium and ectopic decidua. Reprod Biol Endocrinol 8:116. doi:10.1186/1477-7827-8-116 Berbic M, Fraser IS (2011) Regulatory T cells and other leukocytes in the pathogenesis of endometriosis. J Reprod Immunol 88:149–155. doi:10.1016/j.jri.2010.11.004 Polanczyk MJ, Hopke C, Huan J et al (2005) Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 170:85–92. doi:10.1016/j.jneuroim.2005.08.023 Polanczyk MJ, Hopke C, Vandenbark Aa, Offner H (2007) Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol 19:337–343. doi:10.1093/intimm/dxl151 Sofo V, Götte M, Laganà AS et al (2015) Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease. Arch Gynecol Obstet. doi:10.1007/s00404-015-3739-5 Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430. doi:10.1016/S0002-9440(10)64779-7 Nuñez G, Benedict MA, Hu Y, Inohara N (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17:3237–3245. doi:10.1038/sj.onc.1202581 Bonora M, Wieckowsk MR, Chinopoulos C et al (2015) Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34:1608. doi:10.1038/onc.2014.462 Shi Y (2006) Mechanical aspects of apoptosome assembly. Curr Opin Cell Biol 18:677–684. doi:10.1016/j.ceb.2006.09.006 Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219 Sturlese E, Salmeri FM, Retto G et al (2011) Dysregulation of the Fas/FasL system in mononuclear cells recovered from peritoneal fluid of women with endometriosis. J Reprod Immunol 92:74–81 Salmeri FM, Laganà AS, Sofo V et al (2015) Behavior of tumor necrosis factor-α and tumor necrosis factor receptor 1/tumor necrosis factor receptor 2 system in mononuclear cells recovered from peritoneal fluid of women with endometriosis at different stages. Reprod Sci 22:165–172. doi:10.1177/1933719114536472 Bredesen DE, Mehlen P, Rabizadeh S (2004) Apoptosis and dependence receptors: a molecular basis for cellular addiction. Physiol Rev 84:411–430. doi:10.1152/physrev.00027.2003 Tago K, Funakoshi-Tago M, Itoh H et al (2015) Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5. Oncogene 34:314–322. doi:10.1038/onc.2013.561 Song J, Lee B, Kang S et al (2016) Agmatine ameliorates high glucose-induced neuronal cell senescence by regulating the p21 and p53 signaling. Exp Neurobiol 25:24–32. doi:10.5607/en.2016.25.1.24 Chtourou Y, Aouey B, Kebieche M, Fetoui H (2015) Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-κB and P53 signaling pathways. Chem Biol Interact 239:76–86. doi:10.1016/j.cbi.2015.06.036 Pan Q, Luo X, Toloubeydokhti T, Chegini N (2007) The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression. Mol Hum Reprod 13:797–806. doi:10.1093/molehr/gam063 Shi XY, Gu L, Chen J et al (2014) Downregulation of miR-183 inhibits apoptosis and enhances the invasive potential of endometrial stromal cells in endometriosis. Int J Mol Med 33:59–67. doi:10.3892/ijmm.2013.1536 Tian X, Xu L, Wang P (2015) MiR-191 inhibits TNF-α induced apoptosis of ovarian endometriosis and endometrioid carcinoma cells by targeting DAPK1. Int J Clin Exp Pathol 8:4933–4942 Long M, Wan X, La X et al (2015) miR-29c is downregulated in the ectopic endometrium and exerts its effects on endometrial cell proliferation, apoptosis and invasion by targeting c-Jun. Int J Mol Med 35:1119–1125. doi:10.3892/ijmm.2015.2082 Wang C, Jin A, Huang W et al (2015) Up-regulation of Bcl-2 by CD147 through ERK activation results in abnormal cell survival in human endometriosis. J Clin Endocrinol Metab 100:E955–E963. doi:10.1210/jc.2015-1431 Zubor P, Hatok J, Galo S et al (2009) Anti-apoptotic and pro-apoptotic gene expression evaluated from eutopic endometrium in the proliferative phase of the menstrual cycle among women with endometriosis and healthy controls. Eur J Obstet Gynecol Reprod Biol 145:172–176. doi:10.1016/j.ejogrb.2009.04.024 Korkmaz D, Bastu E, Dural O et al (2013) Apoptosis through regulation of Bcl-2, Bax and Mcl-1 expressions in endometriotic cyst lesions and the endometrium of women with moderate to severe endometriosis. J Obstet Gynaecol 33:725–728. doi:10.3109/01443615.2013.824416 Garcia-Velasco JA, Arici A (2003) Apoptosis and the pathogenesis of endometriosis. Semin Reprod Med 21:165–172. doi:10.1055/s-2003-41323 Harada T, Taniguchi F, Izawa M et al (2007) Apoptosis and endometriosis. Front Biosci 12:3140–3151 Agic A, Djalali S, Diedrich K, Hornung D (2009) Apoptosis in endometriosis. Gynecol Obstet Invest 68:217–223. doi:10.1159/000235871 Choi J, Jo M, Lee E et al (2014) Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts. Mol Hum Reprod 20:309–317. doi:10.1093/molehr/gat091 Chen X, Wang W, Zhang L et al (2010) Effects of Ad-p27mt gene transfer on the expression of Bax, Bcl-2, VEGF, and MMP-9 in the transplanted liver tumors in nude mice. J Huazhong Univ Sci Technolog Med Sci 30:611–614. doi:10.1007/s11596-010-0551-0 Gonçalves GA, Camargo-Kosugi CM, Bonetti TCS et al (2015) p27kip1 overexpression regulates VEGF expression, cell proliferation and apoptosis in cell culture from eutopic endometrium of women with endometriosis. Apoptosis 20:327–335. doi:10.1007/s10495-014-1079-8 Jin A, Chen H, Wang C et al (2014) Elevated expression of CD147 in patients with endometriosis and its role in regulating apoptosis and migration of human endometrial cells. Fertil Steril 101(1681–7):e1. doi:10.1016/j.fertnstert.2014.02.007 Chen Y, Cai S, Wang J, Xu M (2015) Valproic acid-induced histone acetylation suppresses CYP19 gene expression and inhibits the growth and survival of endometrial stromal cells. Int J Mol Med 36:725–732. doi:10.3892/ijmm.2015.2263 Minami T, Kosugi K, Suganuma I et al (2013) Antiproliferative and apoptotic effects of norethisterone on endometriotic stromal cells in vitro. Eur J Obstet Gynecol Reprod Biol 166:76–80. doi:10.1016/j.ejogrb.2012.08.023 Tandrasasmita OM, Sutanto AM, Arifin PF, Tjandrawinata RR (2015) Anti-inflammatory, antiangiogenic, and apoptosis-inducing activity of DLBS1442, a bioactive fraction of Phaleria macrocarpa, in a RL95-2 cell line as a molecular model of endometriosis. Int J Womens Health 7:161–169. doi:10.2147/IJWH.S74552 Izawa M, Harada T, Deura I et al (2006) Drug-induced apoptosis was markedly attenuated in endometriotic stromal cells. Hum Reprod 21:600–604. doi:10.1093/humrep/dei372 Roshangar L, Abdollahifard S, Majdi A et al (2013) Study of ultrastructure and apoptosis in the endometrium of women with or without endometriosis. Iran J Reprod Med 11:399–404 Depalo R, Cavallini A, Lorusso F et al (2009) Apoptosis in normal ovaries of women with and without endometriosis. Reprod Biomed Online 19:808–815 Agostinis C, Zorzet S, De Leo R et al (2015) The combination of N-acetyl cysteine, alpha-lipoic acid, and bromelain shows high anti-inflammatory properties in novel in vivo and in vitro models of endometriosis. Mediators Inflamm 2015:918089. doi:10.1155/2015/918089 Jana S, Paul S, Swarnakar S (2012) Curcumin as anti-endometriotic agent: implication of MMP-3 and intrinsic apoptotic pathway. Biochem Pharmacol 83:797–804. doi:10.1016/j.bcp.2011.12.030 García-Pascual CM, Martínez J, Calvo P et al (2015) Evaluation of the potential therapeutic effects of a double-stranded RNA mimic complexed with polycations in an experimental mouse model of endometriosis. Fertil Steril 104:1310–1318. doi:10.1016/j.fertnstert.2015.07.1147 Uegaki T, Taniguchi F, Nakamura K et al (2015) Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis. Hum Reprod 30:149–158. doi:10.1093/humrep/deu288 Leconte M, Santulli P, Chouzenoux S et al (2015) Inhibition of MAPK and VEGFR by sorafenib controls the progression of endometriosis. Reprod Sci 22:1171–1180. doi:10.1177/1933719115592708 Wang Y, Lin M, Weng H et al (2014) ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model. Am J Obstet Gynecol 210(531):e1–e8. doi:10.1016/j.ajog.2014.01.040 Szymanowski K, Mikołajczyk M, Skrzypczak J (2003) Apoptosis expression in rats’ endometrium after surgical induction of endometriosis. Ginekol Pol 74:262–266 Sugihara K, Kobayashi Y, Suzuki A et al (2014) Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis. Nat Commun 5:4478. doi:10.1038/ncomms5478 Borroni R, Di Blasio AM, Gaffuri B et al (2000) Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate. Mol Cell Endocrinol 159:37–43 Khan KN, Kitajima M, Hiraki K et al (2010) Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod 25:642–653. doi:10.1093/humrep/dep437 Selam B, Kayisli UA, Mulayim N, Arici A (2001) Regulation of Fas ligand expression by estradiol and progesterone in human endometrium. Biol Reprod 65:979–985 Otsuki Y (2001) Apoptosis in human endometrium: apoptotic detection methods and signaling. Med Electron Microsc 34:166–173. doi:10.1007/s007950100011 Sbracia M, Valeri C, Antonini G et al (2016) Fas and Fas-ligand in eutopic and ectopic endometrium of women with endometriosis: the possible immune privilege of ectopic endometrium. Reprod Sci 23:81–86. doi:10.1177/1933719115594019 Maeda N, Izumiya C, Taniguchi K et al (2012) Role of NK cells and HLA-G in endometriosis. Front Biosci (Schol Ed) 4:1568–1581 Barrier BF, Kendall BS, Ryan CE, Sharpe-Timms KL (2006) HLA-G is expressed by the glandular epithelium of peritoneal endometriosis but not in eutopic endometrium. Hum Reprod 21:864–869. doi:10.1093/humrep/dei408 Wicherek L (2008) Alterations in RCAS1 serum concentration levels during the normal menstrual cycle and the lack of analogical changes in ovarian endometriosis. Am J Reprod Immunol 59:535–544. doi:10.1111/j.1600-0897.2008.00584.x Popiela TJ, Klimek M, Wicherek L et al (2006) The characterization of the exposure to immune mediated apoptosis and the regulation of immune cytotoxic activity in the environment of a neoplasm and in decidua. Neuro Endocrinol Lett 27:779–785 Author information Authors and Affiliations Corresponding author Ethics declarations Funding This article was not supported by any fund/grant. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Rights and permissions About this article Cite this article Vetvicka, V., Laganà, A.S., Salmeri, F.M. et al. Regulation of apoptotic pathways during endometriosis: from the molecular basis to the future perspectives. Arch Gynecol Obstet 294, 897–904 (2016). https://doi.org/10.1007/s00404-016-4195-6 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00404-016-4195-6