{"paper_id":"af4c2d2d-2646-4d88-b3cb-6c58c94459a9","body_text":"© 2016 Kralickova Milena and Vetvicka Vaclav. This open access article is distributed under a Creative Commons \nAttribution (CC-BY) 3.0 license. \nAmerican Journal of Immunology \n \n \n \nReview \nEndometriosis-Search for Biomarkers \n \n1,2,3 Kralickova Milena and 4Vetvicka Vaclav \n \n1Department of Histology and Embryology, Faculty of Medicine, Charles University, \n Karlovarska 48, Plzen, Czech Republic, CZ-301 00, Czech Republic \n2Department of Obstetrics and Gynecology, Faculty of Medicine, \nUniversity Hospital, Charles University, Alej Svobody 80, Plzen, Czech Republic, CZ-301 66, Czech Republic \n3Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Plzen, Czech Republic \n4Department of Pathology, University of Louisville, 511 S, Floyd, Louisville, KY 40202, USA \n \nArticle history \nReceived: 06-07-2016 \nRevised: 11-07-2016 \nAccepted: 27-07-2016 \n \nCorresponding Author: \nVetvicka Vaclav \nDepartment of Pathology, \nUniversity of Louisville, 511 S, \nFloyd, Louisville, KY 40202, \nUSA \nEmail: \n vaclav.vetvicka@louisville.edu \nAbstract: Numerous studies are seeking noninvasive methods to  \ndiagnose endometriosis, but a clinically applicable  test is still missing. \nCurrent paper compares the current results in our s earch for the best \ndiagnostic marker. We summarize that despite the ex tensive research on \nendometriosis biomarkers, timely diagnosis using sp ecific biomarkers \nremains an unfilled dream. \n \nKeywords: Biomarkers, Endometriosis, CA125, microRNA \n \nIntroduction \nEndometriosis is manifested by the presence of both \nendometrial glandular and stromal cells outside the uterine \ncavity, mainly in the pelvis. Endometriosis, occurring  in \n10-20% of females of reproductive age, is characteriz ed \nby ectopic implantation of endometrial cells with elevated \nproliferation and migration and represents the leading \ncause of morbidity among premenopausal women. It is a \ncommon, benign and chronic disease affecting 2-18% of \nwomen in reproductive age and over 40% of patients with \ninfertility (Missmer and Cramer, 2003). The complex \npathogenesis of this enigmatic disorder remains \ncontroversial despite extensive research (Baldi et al ., \n2008). Among existing theories on the cell origin of  \nendometriosis, one should mention retrograde \nmenstruation and implantation, coelomic metaplasia \n(Burney et al ., 2007), embryonic cell rest theory or stem \ncell theory (Kralickova and Vetvicka, 2015). \nResearch in the field of endometriosis is limited due \nto the absence of a low-cost and reliable method for \ndiagnosing endometriosis, especially in the early stages.  \nThe validation of numerous markers suggested to be \nimportant in endometriosis could represent significant \nimprovement leading to early and non-invasive diagnosis \nof this disease. So far, the diagnosis is generally \nachieved by invasive procedures including laparoscopy \nfollowed by histology. \nEndometrium represents a highly dynamic tissue, \nwith a significant number of molecules relevant to \nadhesion, attachment, proliferation, invasion and \nmigration (Sundqvist et al ., 2012). Numerous studies are \nseeking noninvasive methods to diagnose endometriosis, \nbut a clinically applicable test is still missing. Most of \nthese studies are focused on finding a single marker \nwhich would be up-or down-regulated in patients with \nendometriosis. \nEndometriosis is an estrogen-dependent disease; \ntherefore the presence of estrogen androgen and \nprogesterone receptors is not surprising. However, \ndespite the fact that these steroid receptors play an \nimportant role in development of endometriosis, their \nexpression is not specific for diagnostic purposes. A \nsimple, preferably blood, test for endometriosis-specific \nbiomarker/s would offer fast and accurate diagnosis, \nallowing faster and earlier medical intervention. \nTumor Markers CA125 and CA19-9 \nTumor marker CA125 is one of the most studied \nbiomarkers, with more than a 40 year history and over \n2,000 published papers (Bast et al ., 1998). It is a high \nMW glycoprotein originally used as a tumor marker for \novarian tumors (Bast et al ., 1981). Its use in \nendometriosis is based on a well-established \nconnection between endometriosis and ovarian cancer  \n(Kralickova et al ., 2014). However, it is important to \nremember that it cannot be used for differential diagnosis  \nbetween endometriosis and cancer, as the level is \nincreased in patients with both endometriosis and cancer \n(Lenhard et al ., 2009). \n\nKralickova Milena and Vetvicka Vaclav / American Journal of Immunol ogy 2016, 12 (2): 43.48 \nDOI: 10.3844/ajisp.2016.43.48  \n \n44 \nIt was shown that its level is suppressed during \ntreatment, but elevated again after treatment even in \nwomen in whom the disease had not recurred (Vard et al ., \n1991). In addition to levels in serum, CA125 is also \nproduced in vitro  by endometrial tissue in explant \ncultures (Bersinger et al ., 1993). \nThe degree to which the level of serum CA125 is \nraised in endometriosis correlates with the disease \nseverity (Pittaway and Fayez, 1986), however, the \nbiological significance is still not fully established. \nStudies comparing levels of CA135, CA19-9 and Ki-67 \nin late stages of endometriosis found no correlation \nbetween serum levels of CA125 and CA19-9 and no \nstrong correlation between serum levels and \nhistochemical staining. With the strong positive \ncorrelation between serum CA125 levels and KI-67 \nlabeling index, the authors concluded that serum CA125 \nmight correlate with proliferative activity of \nendometriotic epithelial cells (Toki et al ., 2000).  \nSimilarly, the usefulness of CA125 can be increased by \nsimultaneous evaluation of the level of CA72-4 antigen \n(Anastasi et al ., 2013a). Additional findings not only \nsupported this conclusion, but added human epididymis \nprotein 4 as the best approach to confirm the benign \nnature of endometrioma in women with high level of \nCA125 (Anastasi et al ., 2013b). \nThe importance of the CA125 biomarker was further \nsupported in a study using 164 women, indicating both \nCA125 and CA19-9 markers were significantly increased. \nFurther analysis revealed correlation with hsCRP and \nwith the severity of endometriosis (Komur et al ., 2015). \nAll these markers were thus suggested to be used in the \ndiagnosis of endometriosis. In addition, both markers are  \nuseful in differentiating between endometriosis and \novarian tumors (Nakagawa et al ., 2015). \nA meta-analysis of the diagnostic value of serum \nCA125, CA19-9 and CA15-3 used papers published \nbetween 2000 and 2014 and concluded that both CA125 \nand CA19-9 are useful markers for the noninvasive \ndiagnosis of endometriosis, CA1503 is not worth further  \nstudies (Shen et al ., 2015). Similarly, the known \nusefulness of the combination of CA-125 and CA19-9 \nwas further improved by testing of IL-6 and hsCRP, \nparticularly during the secretory phase (Sutcu et al ., \n2015). Many researchers are, however, still convinced \nthat sensitivity and specificity of such markers is \ninsufficiently low (Mol et al ., 1998). \nMicroRNA \nCurrently, microRNAs represent novel biomarkers \nfor both endometriosis and endometriosis-related ovarian \ncancers. MicroRNAs (miRNAs) are a class of short, \nsingle-stranded non coding RNA molecules. Latest \nstudies suggested that mRNAs might play an important \nrole in both the development and prognosis of \nendometriosis. This hypothesis is further strengthened by \nthe fact that mRNAs are exceptionally stable and can be \nreliably detected in serum. \nUsing a reverse transcriptase quantitative PCR, \nSuryawanshi’s group identified 23 microRNAs which \nare differentially expressed in healthy people and \npatients with endometriosis. These microRNAs were \nsubsequently further evaluated in a larger cohort. The \nresults showed that plasma microRNA expressing \npatterns might serve as specific and reliable diagnostic \nbiomarkers (Suryawanshi et al ., 2013)  resulting in some \nauthors suggesting than microRNA studies will lead to \nchanges in current treatment of both endometriosis and \novarian cancer (Neto et al ., 2014). \nA meta-analysis of 194 studies showed that mRNAs \nappear to be potent regulators of gene expression in \nendometriosis (Wei et al ., 2015). Based on these studies, \nthe authors proposed the use of mRNAs as both \nbiomarkers and therapeutic agents. The problem with \nmRNA originated from the fact that there are simply too \nmany of those, the studies found 134 different mRNAs \nwith only 28 of them reported in at least two studies. \nAnother review painted a similarly pessimistic picture \n(Nothnick et al ., 2015). \nGenetic Studies \nSeveral genes have been found to be upregulated or \nchanged in endometriosis (Fassbender et al ., 2015). \nThe major genes include hypermethylated HOXA10 \n(Wu et al ., 2005) and PR-B (Wu et al ., 2006), aromatase \n(Izawa et al ., 2008) and E-cadherin (Wu et al ., 2007). \nHowever, it is not known if these aberrations are cause \nor consequence of endometriosis and it seems that the \nlevels are not sensitive for diagnostic purposes. \nOverexpression of p53 in atypical endometriosis is \nquite common, but these findings are probably more \nsuited for identification of endometriosis with \npremalignant potential than for diagnosis of \nendometriosis “only” (de la Cuesta et al ., 2004). Recent \nwhole genome microarray data involving 144 samples \nfrom women with endometriosis was performed, but the \nresults are still unclear (Tamaresis et al ., 2014). \nImmunological Markers \nImmunity is one of the proposed factors in \npathogenesis of endometriosis, so it is not surprising  that \ninflammatory cytokines and other immunological \nmarkers have been suggested (May et al ., 2010). \nAdditional potential biomarkers being elevated in \nendometriosis are TGF- β1, COX-2, VEGF, ER-1 α and \naromatase (Meng et al ., 2011), but their elevated levels \nare unfortunately not fully endometriosis-specific to be \nutilized in clinical practice. Despite extensive research, \n\nKralickova Milena and Vetvicka Vaclav / American Journal of Immunol ogy 2016, 12 (2): 43.48 \nDOI: 10.3844/ajisp.2016.43.48  \n \n45 \nco consensus exists on the use of cytokines in diagnosis \n(Fassbender et al ., 2015). \nHuman Epididymis Protein 4 \nAnother possible marker is a Human Epididymis \nprotein 4 (HE4), found elevated in endometriosis, \nparticularly in premenopausal women (Ortiz-Munoz et al ., \n2014). Serum concentration can help to differentiate \nmalignant ovarian cancer from ovarian endometriotic \ncysts (Huhtinen et al ., 2009). Comparison of both HE4 \nand CA125 markers favors HE4 over CA125, mainly \nbecause even when both markers are increased in non-\ntreated patients, hormone treatment returns concentrat ion \nof CA125 to normal levels, but concentration of HE4 is  \nsignificantly below the control levels (McKinnon et al ., \n2015). A multicentric study in four European centers \nshowed that HE4 is a useful biomarker for excluding \nmalignant disease in patients with endometriosis \n(Zapardiel et al ., 2016). On the other hand, some studies \nshowed no elevation of HE4 levels in endometriosis \n(Jacob et al ., 2010), making the use of this biomarker \ndoubtful.  Like with many other markers such as CA125 , \nkallikrein 6 or osteopontin, this marker is probabl y better \nsuited for diagnostic role in epithelial ovarian cancer  \n(Bandiera et al ., 2013). \nOther Markers \nVitamin E-binding protein afamin is altered in the \nperitoneal fluid of endometriosis patients. The levels of \nvitamin E are depressed in these patients, probably due \nto the lower level of antioxidants. Subsequent study \nshowed correlation between levels of vitamin E and \nafamin, which was ascribed to increased oxidative stress \n(Seeber et al ., 2010a). These findings were, however, \nless pronounced in patients with stage III and IV disease, \nmaking the use of afamin as a biomarker questionable. \nProteomic analysis of serum found six proteins with \ndifferential expression between control and \nendometriotic patients, however, these proteins were \nable to confirm the diagnosis in only 55% of patients. \nCombination with other serum markers increased the \ndiagnostic ability to 73% (Seeber et al ., 2010b). \nAn interesting study used proteomic fingerprint \ntechnology combining nanosized magnetic beads with \nMALDI-TOF-MS for screening for potential biomarkers \nin serum. Using 126 patients and 100 healthy volunteers, \nthe study identified three peaks with high separation \nbetween endometriosis and control values (Zheng et al ., \n2011). However, this is rather time consuming effort and \ndirect description of peaks found in this study will be \nnecessary for clinical use. \nHistochemical analysis showed that epithelial \nantigen CD10 and Ber-Ep4 expression was positive in  \nmost cases of endometrium, in the case of \nhyperplastic epithelium or cytological atypia, Ber- Ep4 \nexpression was negative (Capobianco et al ., 2013). As \nnumerous studies suggested the important role of \nperitoneal fluid, scientists also checked it for po ssible \nmarkers. Levels of galectin-3 positively correlated  \nwith the stage of endometriosis and duration of the  \nsyndromes, but levels of Stimulation Expressed Gene  \n2 (ST2) did not (Caserta et al ., 2014). A more recent \nstudy, however, found elevated levels of ST2 in \npatients with endometriosis and suggested its possi ble \nuse in correlation with levels of IL-33 (Mbarik et al ., \n2015). However, this study used only Tunisian \npopulation, which might influence the outcome. \nA promoter of neovasculatization glycodelin A as a \nbiomarker for endometriosis is still questionable. \nWhereas some studies showed high sensitivity, over \n82%, (Kocbek et al ., 2013), some found no specificity at \nall (Dropsdzol-Cop and Skrzypulec-Plinta, 2012). \nA histochemical analysis focused on expression of \nmatrix metalloproteinases MMP-2 and MMP-9. Using \nsamples from invasive colorectal endometriosis, \nsuperficial peritoneal endometriosis and endometrial \ncancer, the study showed significant differences in \nexpression patterns of these two markers allowing them \nto be used in evaluation of aggressiveness and \ninvasiveness of endometriosis in different locations \n(Weigel et al ., 2012). \nOne of the currently accepted hypotheses on causes \nof endometriosis is based on the role of stem cells. Some \nof the new studies evaluated the expression of stem \ncells-related markers CD133 and ABCG2. The results \nsuggested that aberrant expression of both these markers \nin eutopic and ectopic endometrial tissue is associated \nwith the pathogenesis of endometriosis (Liu et al ., 2015), \nsuggesting that these markers might be utilized in \ndiagnosis. However, more research is clearly needed. \nConclusion \nEndometriosis represents a significant medical \nproblem for women in reproductive age. Despite the \nextensive research on endometriosis biomarkers, \ntimely diagnosis using specific biomarkers remains an \nunfilled dream. The traditional markers such as \nCA125 look promising, but never really got into \npractice. More modern approaches such as use of \nmicro-RNAs suffer from the problem that no \nendometriotic lesions-specific mRNAs have been \nidentified. So far, biomarker research in this area  is \nstill lacking reproducible data. So, the search for  the \never-elusive diagnostic biomarker continues. \nAcknowledgement \nExcellent editorial help of Ms. Tassie Deppert is \nacknowledged. \n\nKralickova Milena and Vetvicka Vaclav / American Journal of Immunol ogy 2016, 12 (2): 43.48 \nDOI: 10.3844/ajisp.2016.43.48  \n \n46 \nFunding Information \nThis study was supported by internal financial \nsupport from the Department of Pathology. \nAuthor’s Contribution \nBoth authors equally contributed in this work. \nEthics \nThe article is original and contains unpublished \nmaterial. The corresponding author confirms that all of \nthe other authors have read and approved the manuscript \nand no ethical issues are involved. \nReferences \nAnastasi, E., L. Manganaro, S.T. Granato, P.B. Panici \nand L. Frati et al ., 2013a. Is CA-72-4 a useful \nbiomarker in differential diagnosis between ovarian \nendometrioma and epithelial ovarian cancer. Disease \nMarkers, 35: 331-335. DOI:  10.1155/2013/984641 \nAnastasi, E., T. 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