1 1891 149 ENDOMETRIOSIS. PELVIC ENDOMETRIOSIS IS A COMPLEX SYNDROME CHARACTERIZED BY AN ESTROGEN-DEPENDENT CHRONIC INFLAMMATORY PROCESS THAT AFFECTS PRIMARILY PELVIC TISSUES, INCLUDING THE OVARIES. IT IS CAUSED WHEN SHED ENDOMETRIAL TISSUE TRAVELS RETROGRADE INTO THE LOWER ABDOMINAL CAVITY. ENDOMETRIOSIS IS THE MOST COMMON CAUSE OF CHRONIC PELVIC PAIN IN WOMEN AND IS ASSOCIATED WITH INFERTILITY. THE UNDERLYING PATHOLOGIC MECHANISMS IN THE INTRACAVITARY ENDOMETRIUM AND EXTRAUTERINE ENDOMETRIOTIC TISSUE INVOLVE DEFECTIVELY PROGRAMMED ENDOMETRIAL MESENCHYMAL PROGENITOR/STEM CELLS. ALTHOUGH ENDOMETRIOTIC STROMAL CELLS, WHICH COMPOSE THE BULK OF ENDOMETRIOTIC LESIONS, DO NOT CARRY SOMATIC MUTATIONS, THEY DEMONSTRATE SPECIFIC EPIGENETIC ABNORMALITIES THAT ALTER EXPRESSION OF KEY TRANSCRIPTION FACTORS. FOR EXAMPLE, GATA-BINDING FACTOR-6 OVEREXPRESSION TRANSFORMS AN ENDOMETRIAL STROMAL CELL TO AN ENDOMETRIOTIC PHENOTYPE, AND STEROIDOGENIC FACTOR-1 OVEREXPRESSION CAUSES EXCESSIVE PRODUCTION OF ESTROGEN, WHICH DRIVES INFLAMMATION VIA PATHOLOGICALLY HIGH LEVELS OF ESTROGEN RECEPTOR-BETA. PROGESTERONE RECEPTOR DEFICIENCY CAUSES PROGESTERONE RESISTANCE. POPULATIONS OF ENDOMETRIAL AND ENDOMETRIOTIC EPITHELIAL CELLS ALSO HARBOR MULTIPLE CANCER DRIVER MUTATIONS, SUCH AS KRAS, WHICH MAY BE ASSOCIATED WITH THE ESTABLISHMENT OF PELVIC ENDOMETRIOSIS OR OVARIAN CANCER. IT IS NOT KNOWN HOW INTERACTIONS BETWEEN EPIGENOMICALLY DEFECTIVE STROMAL CELLS AND THE MUTATED GENES IN EPITHELIAL CELLS CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS-ASSOCIATED PELVIC PAIN IS MANAGED BY SUPPRESSION OF OVULATORY MENSES AND ESTROGEN PRODUCTION, CYCLOOXYGENASE INHIBITORS, AND SURGICAL REMOVAL OF PELVIC LESIONS, AND IN VITRO FERTILIZATION IS FREQUENTLY USED TO OVERCOME INFERTILITY. ALTHOUGH NOVEL TARGETED TREATMENTS ARE BECOMING AVAILABLE, AS ENDOMETRIOSIS PATHOPHYSIOLOGY IS BETTER UNDERSTOOD, PREVENTIVE APPROACHES SUCH AS LONG-TERM OVULATION SUPPRESSION MAY PLAY A CRITICAL ROLE IN THE FUTURE. 2019 2 6272 32 THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS. RECENT MOLECULAR GENETIC FINDINGS ON ENDOMETRIOSIS AND NORMAL ENDOMETRIUM SUGGEST A MODIFIED MODEL IN WHICH CIRCULATING EPITHELIAL PROGENITOR OR STEM CELLS INTENDED TO REGENERATE UTERINE ENDOMETRIUM AFTER MENSTRUATION MAY BECOME OVERREACTIVE AND TRAPPED OUTSIDE THE UTERUS. THESE TRAPPED EPITHELIUM-COMMITTED PROGENITOR CELLS FORM NASCENT GLANDS THROUGH CLONAL EXPANSION AND RECRUIT POLYCLONAL STROMAL CELLS, LEADING TO THE ESTABLISHMENT OF DEEP INFILTRATING ENDOMETRIOSIS. ONCE FORMED, THE ECTOPIC TISSUE BECOMES SUBJECT TO IMMUNE SURVEILLANCE, RESULTING IN CHRONIC INFLAMMATION. THE INFLAMMATORY RESPONSE ORCHESTRATED BY NUCLEAR FACTOR-KAPPAB SIGNALING IS EXACERBATED BY ABERRATIONS IN THE ESTROGEN RECEPTOR-BETA AND PROGESTERONE RECEPTOR PATHWAYS, WHICH ARE ALSO AFFECTED BY LOCAL INFLAMMATION, FORMING A DYSREGULATED INFLAMMATION-HORMONAL LOOP. GLANDULAR EPITHELIUM WITHIN ENDOMETRIOTIC TISSUE HARBORS CANCER-ASSOCIATED MUTATIONS THAT ARE FREQUENTLY DETECTED IN ENDOMETRIOSIS-RELATED OVARIAN CANCERS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES THAT HAVE ILLUMINATED THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS AND HAVE PROVIDED NEW AVENUES FOR RESEARCH THAT PROMISE TO IMPROVE THE EARLY DIAGNOSIS AND MANAGEMENT OF ENDOMETRIOSIS. 2020 3 236 36 ADENOMYOSIS: MECHANISMS AND PATHOGENESIS. ADENOMYOSIS IS A COMMON DISORDER OF THE UTERUS, AND IS ASSOCIATED WITH AN ENLARGED UTERUS, HEAVY MENSTRUAL BLEEDING (HMB), PELVIC PAIN, AND INFERTILITY. IT IS CHARACTERIZED BY ENDOMETRIAL EPITHELIAL CELLS AND STROMAL FIBROBLASTS ABNORMALLY FOUND IN THE MYOMETRIUM WHERE THEY ELICIT HYPERPLASIA AND HYPERTROPHY OF SURROUNDING SMOOTH MUSCLE CELLS. WHILE BOTH THE MECHANISTIC PROCESSES AND THE PATHOGENESIS OF ADENOMYOSIS ARE UNCERTAIN, SEVERAL THEORIES HAVE BEEN PUT FORWARD ADDRESSING HOW THIS DISEASE DEVELOPS. THESE INCLUDE INTRINSIC OR INDUCED (1) MICROTRAUMA OF THE ENDOMETRIAL-MYOMETRIAL INTERFACE; (2) ENHANCED INVASION OF ENDOMETRIUM INTO MYOMETRIUM; (3) METAPLASIA OF STEM CELLS IN MYOMETRIUM; (4) INFILTRATION OF ENDOMETRIAL CELLS IN RETROGRADE MENSTRUAL EFFLUENT INTO THE UTERINE WALL FROM THE SEROSAL SIDE; (5) INDUCTION OF ADENOMYOTIC LESIONS BY ABERRANT LOCAL STEROID AND PITUITARY HORMONES; AND (6) ABNORMAL UTERINE DEVELOPMENT IN RESPONSE TO GENETIC AND EPIGENETIC MODIFICATIONS. DYSMENORRHEA, HMB, AND INFERTILITY ARE LIKELY RESULTS OF INFLAMMATION, NEUROGENESIS, ANGIOGENESIS, AND CONTRACTILE ABNORMALITIES IN THE ENDOMETRIAL AND MYOMETRIAL COMPONENTS. ELUCIDATING MECHANISMS UNDERLYING THE PATHOGENESIS OF ADENOMYOSIS RAISE POSSIBILITIES TO DEVELOP TARGETED THERAPIES TO AMELIORATE SYMPTOMS BEYOND THE CURRENT AGENTS THAT ARE LARGELY INEFFECTIVE. HEREIN, WE ADDRESS THESE POSSIBLE ETIOLOGIES AND DATA THAT SUPPORT UNDERLYING MECHANISMS. 2020 4 4310 44 MICRORNAS AND PROGESTERONE RECEPTOR SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY. ENDOMETRIOSIS IS A SIGNIFICANT DISEASE CHARACTERIZED BY INFERTILITY AND PELVIC PAIN IN WHICH ENDOMETRIAL STROMAL AND GLANDULAR TISSUE GROW IN ECTOPIC LOCATIONS. ALTERED RESPONSIVENESS TO PROGESTERONE IS A CONTRIBUTING FACTOR TO ENDOMETRIOSIS PATHOPHYSIOLOGY, BUT THE PRECISE MECHANISMS ARE POORLY UNDERSTOOD. PROGESTERONE RESISTANCE INFLUENCES BOTH THE EUTOPIC AND ECTOPIC (ENDOMETRIOTIC LESION) ENDOMETRIUM. AN INABILITY OF THE EUTOPIC ENDOMETRIUM TO PROPERLY RESPOND TO PROGESTERONE IS BELIEVED TO CONTRIBUTE TO THE INFERTILITY ASSOCIATED WITH THE DISEASE, WHILE AN ALTERED RESPONSIVENESS OF ENDOMETRIOTIC LESION TISSUE MAY CONTRIBUTE TO THE SURVIVAL OF THE ECTOPIC TISSUE AND ASSOCIATED SYMPTOMS. WOMEN WITH ENDOMETRIOSIS EXPRESS ALTERED LEVELS OF SEVERAL ENDOMETRIAL PROGESTERONE TARGET GENES WHICH MAY BE DUE TO THE ABNORMAL EXPRESSION AND/OR FUNCTION OF PROGESTERONE RECEPTORS AND/OR CHAPERONE PROTEINS, AS WELL AS INFLAMMATION, GENETICS, AND EPIGENETICS. MIRNAS ARE A CLASS OF EPIGENETIC MODULATORS PROPOSED TO PLAY A ROLE IN ENDOMETRIOSIS PATHOPHYSIOLOGY, INCLUDING THE MODULATION OF PROGESTERONE SIGNALING. IN THIS PAPER, WE SUMMARIZE THE ROLE OF PROGESTERONE RECEPTORS AND PROGESTERONE SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY, REVIEW MIRNAS, WHICH ARE OVER-EXPRESSED IN ENDOMETRIOSIS TISSUES AND FLUIDS, AND FOLLOW THIS WITH A DISCUSSION ON THE POTENTIAL REGULATION OF KEY PROGESTERONE SIGNALING COMPONENTS BY THESE MIRNAS, CONCLUDING WITH SUGGESTIONS FOR FUTURE RESEARCH ENDEAVORS IN THIS AREA. 2022 5 2668 35 ESTROGEN RECEPTORS AND ENDOMETRIOSIS. ENDOMETRIOSIS IS A FREQUENT AND CHRONIC INFLAMMATORY DISEASE WITH IMPACTS ON REPRODUCTION, HEALTH AND QUALITY OF LIFE. THIS DISORDER IS HIGHLY ESTROGEN-DEPENDENT AND THE PURPOSE OF HORMONAL TREATMENTS IS TO DECREASE THE ENDOGENOUS OVARIAN PRODUCTION OF ESTROGENS. HIGH ESTROGEN PRODUCTION IS A CONSISTENTLY OBSERVED ENDOCRINE FEATURE OF ENDOMETRIOSIS. MRNA AND PROTEIN LEVELS OF ESTROGEN RECEPTORS (ER) ARE DIFFERENT BETWEEN A NORMAL HEALTHY ENDOMETRIUM AND ECTOPIC/EUTOPIC ENDOMETRIAL LESIONS: ENDOMETRIOTIC STROMAL CELLS EXPRESS EXTRAORDINARILY HIGHER ERBETA AND SIGNIFICANTLY LOWER ERALPHA LEVELS COMPARED WITH ENDOMETRIAL STROMAL CELLS. ABERRANT EPIGENETIC REGULATION SUCH AS DNA METHYLATION IN ENDOMETRIOTIC CELLS IS ASSOCIATED WITH THE PATHOGENESIS AND DEVELOPMENT OF ENDOMETRIOSIS. ALTHOUGH THERE IS A LARGE BODY OF DATA REGARDING ERS IN ENDOMETRIOSIS, OUR UNDERSTANDING OF THE ROLES OF ERALPHA AND ERBETA IN THE PATHOGENESIS OF ENDOMETRIOSIS REMAINS INCOMPLETE. THE GOAL OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE LINKS BETWEEN ENDOMETRIOSIS, ERS AND THE RECENT ADVANCES OF TREATMENT STRATEGIES BASED ON ERS MODULATION. WE WILL ALSO ATTEMPT TO SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS OF ACTION OF ERS AND HOW THIS COULD PAVE THE WAY TO NEW THERAPEUTIC STRATEGIES. 2020 6 5239 40 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 7 1114 39 COMMONALITIES AND DISPARITIES BETWEEN ENDOMETRIOSIS AND CHRONIC ENDOMETRITIS: THERAPEUTIC POTENTIAL OF NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ECTOPIC ENDOMETRIUM. CHRONIC ENDOMETRITIS (CE) IS A LOCAL MUCOSAL INFLAMMATORY DISORDER OF THE UTERINE LINING, WHICH IS HISTOPATHOLOGICALLY RECOGNIZED AS THE UNUSUAL INFILTRATION OF CD138(+) PLASMACYTES INTO THE ENDOMETRIAL STROMAL COMPARTMENT. ACCUMULATING BODY OF RESEARCH DOCUMENTED THAT CE IS ASSOCIATED WITH FEMALE INFERTILITY AND SEVERAL OBSTETRIC/NEONATAL COMPLICATIONS. THE MAJOR CAUSE OF CE IS THOUGHT TO BE INTRAUTERINE INFECTION REPRESENTED BY COMMON BACTERIA (ESCHERICHIA COLI, ENTEROCOCCUS FAECALIS, STREPTOCOCCUS, AND STAPHYLOCOCCUS), MYCOPLASMA/UREAPLASMA, AND MYCOBACTERIUM. ADDITIONALLY, LOCAL DYSBIOSIS IN THE FEMALE REPRODUCTIVE TRACT MAY BE INVOLVED IN THE ONSET AND DEVELOPMENT OF CE. ANTIBIOTIC TREATMENTS AGAINST THESE MICROORGANISMS ARE EFFECTIVE IN THE ELIMINATION OF ENDOMETRIAL STROMAL PLASMACYTES IN THE AFFECTED PATIENTS. MEANWHILE, ENDOMETRIOSIS IS A COMMON FEMALE REPRODUCTIVE TRACT DISEASE CHARACTERIZED BY ENDOMETRIOTIC TISSUES (ECTOPIC ENDOMETRIUM) GROWING OUTSIDE THE UTERUS AND POTENTIALLY CAUSES CHRONIC PELVIC SYMPTOMS (DYSMENORRHEA, DYSPAREUNIA, DYSCHEZIA, AND DYSURIA), INFERTILITY, AND OVARIAN CANCERS. ENDOMETRIOSIS INVOLVES ENDOCRINOLOGICAL, GENETIC, AND EPIGENETIC FACTORS IN ITS ETIOLOGY AND PATHOGENESIS. RECENT STUDIES FOCUS ON IMMUNOLOGICAL, INFLAMMATORY, AND INFECTIOUS ASPECTS OF ENDOMETRIOSIS AND DEMONSTRATE SEVERAL COMMON CHARACTERISTICS BETWEEN ENDOMETRIOSIS AND CE. THIS REVIEW AIMED TO BETTER UNDERSTAND THE IMMUNOLOGICAL AND MICROBIAL BACKGROUNDS UNDERLYING ENDOMETRIOSIS AND CE AND LOOK INTO THE THERAPEUTIC POTENTIAL OF THE NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ENDOMETRIOSIS IN LIGHT OF ENDOMETRIAL INFECTIOUS DISEASE. 2023 8 2669 46 ESTROGEN- AND PROGESTERONE (P4)-MEDIATED EPIGENETIC MODIFICATIONS OF ENDOMETRIAL STROMAL CELLS (ENSCS) AND/OR MESENCHYMAL STEM/STROMAL CELLS (MSCS) IN THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A COMMON CHRONIC INFLAMMATORY CONDITION IN WHICH ENDOMETRIAL TISSUE APPEARS OUTSIDE THE UTERINE CAVITY. BECAUSE ECTOPIC ENDOMETRIOSIS CELLS EXPRESS BOTH ESTROGEN AND PROGESTERONE (P4) RECEPTORS, THEY GROW AND UNDERGO CYCLIC PROLIFERATION AND BREAKDOWN SIMILAR TO THE ENDOMETRIUM. THIS DEBILITATING GYNECOLOGICAL DISEASE AFFECTS UP TO 15% OF REPRODUCTIVE AGED WOMEN. DESPITE MANY YEARS OF RESEARCH, THE ETIOPATHOGENESIS OF ENDOMETRIAL LESIONS REMAINS UNCLEAR. RETROGRADE TRANSPORT OF THE VIABLE MENSTRUAL ENDOMETRIAL CELLS WITH RETAINED ABILITY FOR ATTACHMENT WITHIN THE PELVIC CAVITY, PROLIFERATION, DIFFERENTIATION AND SUBSEQUENT INVASION INTO THE SURROUNDING TISSUE CONSTITUTES THE RATIONALE FOR WIDELY ACCEPTED IMPLANTATION THEORY. ACCORDINGLY, THE MOST ABUNDANT CELLS IN THE ENDOMETRIUM ARE ENDOMETRIAL STROMAL CELLS (ENSCS). THESE CELLS CONSTITUTE A PARTICULAR POPULATION WITH CLONOGENIC ACTIVITY THAT RESEMBLES PROPERTIES OF MESENCHYMAL STEM/STROMAL CELLS (MSCS). THUS, A SIGNIFICANT ROLE OF STEM CELL-BASED DYSFUNCTION IN FORMATION OF THE INITIAL ENDOMETRIAL LESIONS IS SUSPECTED. THERE IS INCREASING EVIDENCE THAT THE ROLE OF EPIGENETIC MECHANISMS AND PROCESSES IN ENDOMETRIOSIS HAVE BEEN UNDERESTIMATED. THE IMPORTANCE OF EXCESS ESTROGEN EXPOSURE AND P4 RESISTANCE IN EPIGENETIC HOMEOSTASIS FAILURE IN THE ENDOMETRIAL/ENDOMETRIOTIC TISSUE ARE CRUCIAL. EPIGENETIC ALTERATIONS REGARDING TRANSCRIPTION FACTORS OF ESTROGEN AND P4 SIGNALING PATHWAYS IN MSCS ARE ROBUST IN ENDOMETRIOTIC TISSUE. THUS, PERSPECTIVES FOR THE FUTURE MAY INCLUDE MSCS AND ENSCS AS THE TARGETS OF EPIGENETIC THERAPIES IN THE PREVENTION AND TREATMENT OF ENDOMETRIOSIS. HERE, WE REVIEWED THE CURRENT KNOWN CHANGES IN THE EPIGENETIC BACKGROUND OF ENSCS AND MSCS DUE TO ESTROGEN/P4 IMBALANCES IN THE CONTEXT OF ETIOPATHOGENESIS OF ENDOMETRIOSIS. GRAPHICAL ABSTRACT. 2021 9 1889 32 ENDOMETRIOSIS MALIGNANT TRANSFORMATION: EPIGENETICS AS A PROBABLE MECHANISM IN OVARIAN TUMORIGENESIS. ENDOMETRIOSIS, DEFINED AS THE PRESENCE OF ECTOPIC ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY, IS A CHRONIC, HORMONE-DEPENDENT GYNECOLOGIC DISEASE AFFECTING MILLIONS OF WOMEN ACROSS THE WORLD, WITH SYMPTOMS INCLUDING CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, DYSURIA, AND SUBFERTILITY. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION, WITH THE INVOLVEMENT OF VARIOUS MECHANISMS OF DEVELOPMENT. MORE AND MORE EVIDENCE REVEALS AN IMPORTANT CONTRIBUTION OF EPIGENETIC MODIFICATION NOT ONLY IN ENDOMETRIOSIS BUT ALSO IN MECHANISMS OF ENDOMETRIOSIS MALIGNANT TRANSFORMATION, INCLUDING DNA METHYLATION AND DEMETHYLATION, HISTONE MODIFICATIONS, AND MIRNA ABERRANT EXPRESSIONS. IN THIS PRESENT REVIEW, WE MAINLY SUMMARIZE THE RESEARCH PROGRESS ABOUT THE CURRENT KNOWLEDGE REGARDING THE EPIGENETIC MODIFICATIONS OF THE RELATIONS BETWEEN ENDOMETRIOSIS MALIGNANT TRANSFORMATION AND OVARIAN CANCER IN AN EFFORT TO IDENTIFY SOME RISK FACTORS PROBABLY ASSOCIATED WITH ECTOPIC ENDOMETRIUM TRANSFORMATION. 2018 10 4129 32 MECHANISMS OF ENDOMETRIAL PROGESTERONE RESISTANCE. THROUGHOUT THE REPRODUCTIVE YEARS, THE RISE AND FALL IN OVARIAN HORMONES ELICIT IN THE ENDOMETRIUM WAVES OF CELL PROLIFERATION, DIFFERENTIATION, RECRUITMENT OF INFLAMMATORY CELLS, APOPTOSIS, TISSUE BREAKDOWN AND REGENERATION. THE ACTIVATED PROGESTERONE RECEPTOR, A MEMBER OF THE SUPERFAMILY OF LIGAND-DEPENDENT TRANSCRIPTION FACTORS, IS THE MASTER REGULATOR OF THIS INTENSE TISSUE REMODELLING PROCESS IN THE UTERUS. ITS ACTIVITY IS TIGHTLY REGULATED BY INTERACTION WITH CELL-SPECIFIC TRANSCRIPTION FACTORS AND COREGULATORS AS WELL AS BY SPECIFIC POSTTRANSLATIONAL MODIFICATIONS THAT RESPOND DYNAMICALLY TO A VARIETY OF ENVIRONMENTAL AND INFLAMMATORY SIGNALS. ENDOMETRIOSIS, A CHRONIC INFLAMMATORY DISORDER, DISRUPTS COORDINATED PROGESTERONE RESPONSES THROUGHOUT THE REPRODUCTIVE TRACT, INCLUDING IN THE ENDOMETRIUM. THIS PHENOMENON IS INCREASINGLY REFERRED TO AS 'PROGESTERONE RESISTANCE'. EMERGING EVIDENCE SUGGESTS THAT PROGESTERONE RESISTANCE IN ENDOMETRIOSIS IS NOT JUST A CONSEQUENCE OF PERTURBED PROGESTERONE SIGNAL TRANSDUCTION CAUSED BY CHRONIC INFLAMMATION BUT ASSOCIATED WITH EPIGENETIC CHROMATIN CHANGES THAT DETERMINE THE INTRINSIC RESPONSIVENESS OF ENDOMETRIAL CELLS TO DIFFERENTIATION CUES. 2012 11 603 39 BETULINIC ACID INHIBITS ENDOMETRIOSIS THROUGH SUPPRESSION OF ESTROGEN RECEPTOR BETA SIGNALING PATHWAY. ENDOMETRIOSIS IS AN INFLAMMATORY GYNECOLOGICAL DISORDER CHARACTERIZED BY ENDOMETRIAL TISSUE GROWTH LOCATED OUTSIDE OF THE UTERINE CAVITY IN ADDITION TO CHRONIC PELVIC PAIN AND INFERTILITY. IN THIS STUDY, WE AIM TO DEVELOP A POTENTIAL THERAPEUTIC TREATMENT BASED ON THE PATHOGENESIS AND MECHANISM OF ENDOMETRIOSIS. OUR PRELIMINARY DATA SHOWED THAT THE EXPRESSION OF ESTROGEN RECEPTOR BETA (ERBETA) WAS SIGNIFICANTLY INCREASED, WHILE ERALPHA WAS SIGNIFICANTLY DECREASED, IN ENDOMETRIOTIC CELLS COMPARED TO NORMAL ENDOMETRIAL CELLS. FURTHER INVESTIGATION SHOWED THAT BETULINIC ACID (BA) TREATMENT SUPPRESSED ERBETA EXPRESSION THROUGH EPIGENETIC MODIFICATION ON THE ERBETA PROMOTER, WHILE HAD NO EFFECT ON ERALPHA EXPRESSION. IN ADDITION, BA TREATMENT SUPPRESSES ERBETA TARGET GENES, INCLUDING SUPEROXIDE DISMUTASE 2 (SOD2), NUCLEAR RESPIRATORY FACTOR-1 (NRF1), CYCLOOXYGENASE 2 (COX2), AND MATRIX METALLOPROTEINASE-1 (MMP1), SUBSEQUENTLY INCREASING OXIDATIVE STRESS, TRIGGERING MITOCHONDRIAL DYSFUNCTION, DECREASING ELEVATED PROINFLAMMATORY CYTOKINES, AND EVENTUALLY SUPPRESSING ENDOMETRIOTIC CELL PROLIFERATION, MIMICKING THE EFFECT OF ERBETA KNOCKDOWN. ON THE OTHER HAND, GAIN OF ERBETA BY LENTIVIRUS INFECTION IN NORMAL ENDOMETRIAL CELLS RESULTED IN INCREASED CELL PROLIFERATION AND PROINFLAMMATORY CYTOKINE RELEASE, WHILE BA TREATMENT DIMINISHED THIS EFFECT THROUGH ERBETA SUPPRESSION WITH SUBSEQUENT OXIDATIVE STRESS AND APOPTOSIS. OUR RESULTS INDICATE THAT ERBETA MAY BE A MAJOR DRIVING FORCE FOR THE DEVELOPMENT OF ENDOMETRIOSIS, WHILE BA INHIBITS ENDOMETRIOSIS THROUGH SPECIFIC SUPPRESSION OF THE ERBETA SIGNALING PATHWAY. THIS STUDY PROVIDES A NOVEL THERAPEUTIC STRATEGY FOR ENDOMETRIOSIS TREATMENT THROUGH BA-MEDIATED ERBETA SUPPRESSION. 2020 12 3688 38 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 13 5241 36 PROGESTERONE RESISTANCE IN ENDOMETRIOSIS: CURRENT EVIDENCE AND PUTATIVE MECHANISMS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE THE UTERUS. PROGESTINS ARE CURRENTLY THE MOST COMMONLY USED TREATMENT FOR ENDOMETRIOSIS BECAUSE OF THEIR EXCELLENT THERAPEUTIC EFFECTS AND LIMITED SIDE EFFECTS. HOWEVER, PROGESTINS HAVE BEEN UNSUCCESSFUL IN SOME SYMPTOMATIC PATIENTS. THE INABILITY OF THE ENDOMETRIUM TO RESPOND PROPERLY TO PROGESTERONE IS KNOWN AS PROGESTERONE RESISTANCE. AN INCREASING BODY OF EVIDENCE SUGGESTS THE LOSS OF PROGESTERONE SIGNALING AND THE EXISTENCE OF PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. THE MECHANISMS OF PROGESTERONE RESISTANCE HAVE RECEIVED CONSIDERABLE SCHOLARLY ATTENTION IN RECENT YEARS. ABNORMAL PGR SIGNALING, CHRONIC INFLAMMATION, ABERRANT GENE EXPRESSION, EPIGENETIC ALTERATIONS, AND ENVIRONMENTAL TOXINS ARE CONSIDERED POTENTIAL MOLECULAR CAUSES OF PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. THE GENERAL OBJECTIVE OF THIS REVIEW WAS TO SUMMARIZE THE EVIDENCE AND MECHANISMS OF PROGESTERONE RESISTANCE. A DEEPER UNDERSTANDING OF HOW THESE MECHANISMS CONTRIBUTE TO PROGESTERONE RESISTANCE MAY HELP DEVELOP A NOVEL THERAPEUTIC REGIMEN FOR WOMEN WITH ENDOMETRIOSIS BY REVERSING PROGESTERONE RESISTANCE. 2023 14 791 27 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017 15 2575 34 EPIGENETICS OF ESTROGEN AND PROGESTERONE RECEPTORS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT INFLAMMATORY GYNECOLOGICAL DISEASE. INCREASED ESTROGEN ACTIVITY AND PROGESTERONE RESISTANCE ARE THE MAIN HORMONAL SUBSTRATE OF THIS DISEASE AND ARE ASSOCIATED WITH INFLAMMATORY RESPONSE AND DEBILITATING SYMPTOMS, INCLUDING PAIN AND INFERTILITY. ESTROGENS AND PROGESTERONE ACT VIA THEIR SPECIFIC NUCLEAR RECEPTORS. THE REGULATION OF RECEPTOR EXPRESSION BY EPIGENETICS MAYBE A CRITICAL FACTOR FOR ENDOMETRIOSIS. THE PRESENT REVIEW AIMS TO DISCUSS THE EPIGENETIC MECHANISMS RELATED TO THE EXPRESSION OF ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS, INCLUDING TWO CLASSIC EPIGENETIC MECHANISMS: DNA METHYLATION AND HISTONE MODIFICATION, AND, OTHER NON-CLASSIC MECHANISMS: MIRNAS AND LNCRNA. SEVERAL IN VITRO AND IN VIVO STUDIES SUPPORT THE KEY ROLE OF EPIGENETICS IN THE REGULATION OF THE EXPRESSION OF ERS AND PRS, WHICH MAY PROVIDE NEW MOLECULES AND TARGETS FOR THE DIAGNOSIS AND TREATMENT OF ENDOMETRIOSIS. 2020 16 6076 43 THE DYNAMICS OF NUCLEAR RECEPTORS AND NUCLEAR RECEPTOR COREGULATORS IN THE PATHOGENESIS OF ENDOMETRIOSIS. BACKGROUND: ENDOMETRIOSIS IS DEFINED AS THE COLONIZATION AND GROWTH OF ENDOMETRIAL TISSUE AT ANATOMIC SITES OUTSIDE THE UTERINE CAVITY. UP TO 15% OF REPRODUCTIVE-AGED WOMEN IN THE USA SUFFER FROM PAINFUL SYMPTOMS OF ENDOMETRIOSIS, SUCH AS INFERTILITY, PELVIC PAIN, MENSTRUAL CYCLE ABNORMALITIES AND INCREASED RISK OF CERTAIN CANCERS. HOWEVER, MANY OF THE CURRENT CLINICAL TREATMENTS FOR ENDOMETRIOSIS ARE NOT SUFFICIENTLY EFFECTIVE AND YIELD UNACCEPTABLE SIDE EFFECTS. THERE IS CLEARLY AN URGENT NEED TO IDENTIFY NEW MOLECULAR MECHANISMS THAT CRITICALLY UNDERPIN THE INITIATION AND PROGRESSION OF ENDOMETRIOSIS IN ORDER TO DEVELOP MORE SPECIFIC AND EFFECTIVE THERAPEUTICS WHICH LACK THE SIDE EFFECTS OF CURRENT THERAPIES. THE AIM OF THIS REVIEW IS TO DISCUSS HOW NUCLEAR RECEPTORS (NRS) AND THEIR COREGULATORS PROMOTE THE PROGRESSION OF ENDOMETRIOSIS. UNDERSTANDING THE PATHOGENIC MOLECULAR MECHANISMS FOR THE GENESIS AND MAINTENANCE OF ENDOMETRIOSIS AS MODULATED BY NRS AND COREGULATORS CAN REVEAL NEW THERAPEUTIC TARGETS FOR ALTERNATIVE ENDOMETRIOSIS TREATMENTS. METHODS: THIS REVIEW WAS PREPARED USING PUBLISHED GENE EXPRESSION MICROARRAY DATA SETS OBTAINED FROM PATIENTS WITH ENDOMETRIOSIS AND PUBLISHED LITERATURE ON NRS AND THEIR COREGULATORS THAT DEAL WITH ENDOMETRIOSIS PROGRESSION. USING THE ABOVE OBSERVATIONS, OUR CURRENT UNDERSTANDING OF HOW NRS AND NR COREGULATORS ARE INVOLVED IN THE PROGRESSION OF ENDOMETRIOSIS IS SUMMARIZED. RESULTS: ABERRANT LEVELS OF NRS AND NR COREGULATORS IN ECTOPIC ENDOMETRIOSIS LESIONS ARE ASSOCIATED WITH THE PROGRESSION OF ENDOMETRIOSIS. AS AN EXAMPLE, ENDOMETRIOTIC CELL-SPECIFIC ALTERATIONS IN GENE EXPRESSION ARE CORRELATED WITH A DIFFERENTIAL METHYLATION STATUS OF THE GENOME COMPARED WITH THE NORMAL ENDOMETRIUM. THESE DIFFERENTIAL EPIGENETIC REGULATIONS CAN GENERATE FAVORABLE CELL-SPECIFIC NR AND COREGULATOR MILIEUS FOR ENDOMETRIOSIS PROGRESSION. GENETIC ALTERATIONS, SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS AND INSERTION/DELETION POLYMORPHISMS OF NR AND COREGULATOR GENES, ARE FREQUENTLY DETECTED IN ECTOPIC LESIONS COMPARED WITH THE NORMAL ENDOMETRIUM. THESE GENETIC VARIATIONS IMPART NEW MOLECULAR PROPERTIES TO NRS AND COREGULATORS TO INCREASE THEIR CAPACITY TO STIMULATE PROGRESSION OF ENDOMETRIOSIS. FINALLY, POST-TRANSLATIONAL MODIFICATIONS OF NR COREGULATORS, SUCH AS PROTEOLYTIC PROCESSING, GENERATE ENDOMETRIOSIS-SPECIFIC ISOFORMS. COMPARED WITH THE UNMODIFIED COREGULATORS, THESE COREGULATOR ISOFORMS HAVE UNIQUE FUNCTIONS THAT ENHANCE THE PATHOGENESIS OF ENDOMETRIOSIS. CONCLUSIONS: EPIGENETIC/GENETIC VARIATIONS AND POSTTRANSLATIONAL MODIFICATIONS OF NRS AND COREGULATORS ALTER THEIR ORIGINAL FUNCTION SO THAT THEY BECOME POTENT 'DRIVERS' OF ENDOMETRIOSIS PROGRESSION. 2014 17 3694 52 INFLAMMATORY COMPONENTS OF THE THYROID CANCER MICROENVIRONMENT: AN AVENUE FOR IDENTIFICATION OF NOVEL BIOMARKERS. THE INCIDENCE OF THYROID CANCER IN THE UNITED STATES IS ON THE RISE WITH AN APPRECIABLY HIGH DISEASE RECURRENCE RATE OF 20-30%. ANAPLASTIC THYROID CANCER (ATC), ALTHOUGH RARE IN OCCURRENCE, IS AN AGGRESSIVE FORM OF CANCER WITH LIMITED TREATMENT OPTIONS AND BLEAK CURE RATES. THIS CHAPTER USES DISCUSSIONS OF IN VITRO MODELS THAT ARE REPRESENTATIVE OF PAPILLARY, ANAPLASTIC, AND FOLLICULAR THYROID CANCER TO EVALUATE THE CROSSTALK BETWEEN SPECIFIC CELLS OF THE TUMOR MICROENVIRONMENT (TME), WHICH SERVES AS A HIGHLY HETEROGENEOUS REALM OF SIGNALING CASCADES AND METABOLISM THAT ARE ASSOCIATED WITH TUMORIGENESIS. THE CELLULAR CONSTITUENTS OF THE TME CARRY OUT VARYING CHARACTERISTIC IMMUNOMODULATORY FUNCTIONS THAT ARE DISCUSSED THROUGHOUT THIS CHAPTER. THE AFOREMENTIONED CELL TYPES INCLUDE CANCER-ASSOCIATED FIBROBLASTS (CAFS), ENDOTHELIAL CELLS (ECS), AND CANCER STEM CELLS (CSCS), AS WELL AS SPECIFIC IMMUNE CELLS, INCLUDING NATURAL KILLER (NK) CELLS, DENDRITIC CELLS (DCS), MAST CELLS, T REGULATORY (TREG) CELLS, CD8+ T CELLS, AND TUMOR-ASSOCIATED MACROPHAGES (TAMS). TAM-MEDIATED INFLAMMATION IS ASSOCIATED WITH A POOR PROGNOSIS OF THYROID CANCER, AND THE MOLECULAR BASIS OF THE CELLULAR CROSSTALK BETWEEN MACROPHAGES AND THYROID CANCER CELLS WITH RESPECT TO INDUCING A METASTATIC PHENOTYPE IS NOT YET KNOWN. THE DYNAMIC NATURE OF THE PHYSIOLOGICAL TRANSITION TO PATHOLOGICAL METASTATIC PHENOTYPES WHEN ESTABLISHING THE TME ENCOMPASSES A WIDE RANGE OF CHARACTERISTICS THAT ARE FURTHER EXPLORED WITHIN THIS CHAPTER, INCLUDING THE ROLES OF SOMATIC MUTATIONS AND EPIGENETIC ALTERATIONS THAT DRIVE THE GENETIC HETEROGENEITY OF CANCER CELLS, ALLOWING FOR SELECTIVE ADVANTAGES THAT AID IN THEIR PROLIFERATION. INDUCTION OF THESE PROLIFERATING CELLS IS TYPICALLY ACCOMPLISHED THROUGH INFLAMMATORY INDUCTION, WHEREBY CHRONIC INFLAMMATION SETS UP A CONSTANT PHYSIOLOGICAL STATE OF INFLAMMATORY CELL RECRUITMENT. THE SECRETIONS OF THESE INFLAMMATORY CELLS CAN ALTER THE GENETIC MAKEUP OF PROLIFERATING CELLS, WHICH CAN IN TURN, PROMOTE TUMOR GROWTH.THIS CHAPTER ALSO PRESENTS AN IN-DEPTH ANALYSIS OF MOLECULAR INTERACTIONS WITHIN THE TME, INCLUDING SECRETORY CYTOKINES AND EXOSOMES. SINCE THE EXOSOMAL CARGO OF A CELL IS A REFLECTION AND FINGERPRINT OF THE ORIGINATING PARENTAL CELLS, THE PROFILING OF EXOSOMAL MIRNA DERIVED FROM THYROID CANCER CELLS AND MACROPHAGES IN THE TME MAY SERVE AS AN IMPORTANT STEP IN BIOMARKER DISCOVERY. IDENTIFICATION OF A DISTINCT SET OF TUMOR SUPPRESSIVE MIRNAS DOWNREGULATED IN ATC-SECRETED EXOSOMES INDICATES THEIR ROLE IN THE REGULATION OF TUMOR SUPPRESSIVE GENES THAT MAY INCREASE THE METASTATIC PROPENSITY OF ATC. ADDITIONALLY, THE HIGH EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN STUDIES LOOKING AT THYROID CANCER AND ACTIVATED MACROPHAGE CONDITIONED MEDIA SUGGESTS THE EXISTENCE OF AN INFLAMMATORY TME IN THYROID CANCER. NEW FINDINGS ARE SUGGESTIVE OF THE PRESENCE OF A METASTATIC NICHE IN ATC TISSUES THAT IS INFLUENCED BY THYROID TUMOR MICROENVIRONMENT SECRETOME-INDUCED EPITHELIAL TO MESENCHYMAL TRANSITION (EMT), MEDIATED BY A RECIPROCAL INTERACTION BETWEEN THE PRO-INFLAMMATORY M1 MACROPHAGES AND THE THYROID CANCER CELLS. THUS, TARGETING THE METASTATIC THYROID CARCINOMA MICROENVIRONMENT COULD OFFER POTENTIAL THERAPEUTIC BENEFITS AND SHOULD BE EXPLORED FURTHER IN PRECLINICAL AND TRANSLATIONAL MODELS OF HUMAN METASTATIC THYROID CANCER. 2021 18 1028 42 CIRCULATING MIRNAS RELATED TO EPITHELIAL-MESENCHYMAL TRANSITIONS (EMT) AS THE NEW MOLECULAR MARKERS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC GYNECOLOGICAL DISEASE DEFINED BY THE PRESENCE OF ENDOMETRIAL-LIKE TISSUE FOUND OUTSIDE THE UTERUS, MOST COMMONLY IN THE PERITONEAL CAVITY. ENDOMETRIOSIS LESIONS ARE HETEROGENOUS BUT USUALLY CONTAIN ENDOMETRIAL STROMAL CELLS AND EPITHELIAL GLANDS, IMMUNE CELL INFILTRATES AND ARE VASCULARIZED AND INNERVATED BY NERVES. THE COMPLEX ETIOPATHOGENESIS AND HETEROGENITY OF THE CLINICAL SYMPTOMS, AS WELL AS THE LACK OF A SPECIFIC NON-INVASIVE DIAGNOSTIC BIOMARKERS, UNDERLINE THE NEED FOR MORE ADVANCED DIAGNOSTIC TOOLS. UNFORTUNATELY, THE CONTRIBUTION OF ENVIRONMENTAL, HORMONAL AND IMMUNOLOGICAL FACTORS IN THE DISEASE ETIOLOGY IS INSUFFICIENT, AND THE CONTRIBUTION OF GENETIC/EPIGENETIC FACTORS IS STILL FRAGMENTARY. THEREFORE, THERE IS A NEED FOR MORE FOCUSED STUDY ON THE MOLECULAR MECHANISMS OF ENDOMETRIOSIS AND NON-INVASIVE DIAGNOSTIC MONITORING SYSTEMS. MICRORNAS (MIRNAS) DEMONSTRATE HIGH STABILITY AND TISSUE SPECIFICITY AND PLAY A SIGNIFICANT ROLE IN MODULATING A RANGE OF MOLECULAR PATHWAYS, AND HENCE MAY BE SUITABLE DIAGNOSTIC BIOMARKERS FOR THE ORIGIN AND DEVELOPMENT OF ENDOMETRIOSIS. OF THESE, THE MOST FREQUENTLY STUDIED ARE THOSE RELATED TO ENDOMETRIOSIS, INCLUDING THOSE INVOLVED IN EPITHELIAL-MESENCHYMAL TRANSITION (EMT), WHOSE EXPRESSION IS ALTERED IN PLASMA OR ENDOMETRIOTIC LESION BIOPSIES; HOWEVER, THE RESULTS ARE AMBIGUOUS. SPECIFIC MIRNAS EXPRESSED IN ENDOMETRIOSIS MAY SERVE AS DIAGNOSTICS MARKERS WITH PROGNOSTIC VALUE, AND THEY HAVE BEEN PROPOSED AS MOLECULAR TARGETS FOR TREATMENT. THE AIM OF THIS REVIEW IS TO PRESENT SELECTED MIRNAS ASSOCIATED WITH EMT KNOWN TO HAVE EXPERIMENTALLY CONFIRMED SIGNIFICANCE, AND DISCUSS THEIR UTILITY AS BIOMARKERS IN ENDOMETRIOSIS. 2021 19 5892 37 SYSTEMS GENETICS VIEW OF ENDOMETRIOSIS: A COMMON COMPLEX DISORDER. ENDOMETRIOSIS IS A CONDITION IN WHICH CELLS DERIVED FROM THE ENDOMETRIUM GROW OUTSIDE THE UTERUS, E.G. IN THE PERITONEUM (EXTERNAL GENITAL ENDOMETRIOSIS). AS THESE CELLS ARE UNDER THE INFLUENCE OF FEMALE HORMONES, MAJOR SYMPTOMS OF ENDOMETRIOSIS ARE PAIN, ESPECIALLY DURING THE CYCLE, AND INFERTILITY. NUMEROUS HYPOTHESES FOR THE FORMATION OF ENDOMETRIOSIS CAN BE FOUND IN THE LITERATURE, BUT THERE IS GROWING EVIDENCE OF SERIOUS GENETIC CONTRIBUTIONS TO ENDOMETRIOSIS SUSCEPTIBILITY. THE INVOLVEMENT OF GENES, STEROID HORMONE METABOLISM, IMMUNOLOGICAL REACTIONS, RECEPTOR FORMATION, INFLAMMATION, PROLIFERATION, APOPTOSIS, INTERCELLULAR ADHESION, CELL INVASION AND ANGIOGENESIS AS WELL AS GENES REGULATING THE ACTIVITY OF AFOREMENTIONED ENZYMES HAVE BEEN SUGGESTED. SOME MORE RECENTLY SUGGESTED CANDIDATE GENES PICKED UP IN GENOME-WIDE ASSOCIATION STUDIES ARE INVOLVED IN ONCOGENESIS, METAPLASIA OF ENDOMETRIUM CELLS AND PATHWAYS OF EMBRYONIC DEVELOPMENT OF THE FEMALE REPRODUCTIVE SYSTEM. HOWEVER, GENE MUTATIONS PROVEN TO BE CAUSATIVE FOR ENDOMETRIOSIS HAVE NOT BEEN IDENTIFIED SO FAR, EVEN THOUGH THE ABNORMAL EXPRESSION OF CANDIDATE GENES FOR ENDOMETRIOSIS COULD BE PROVOKED BY DIFFERENT EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION, HETEROCHROMATIZATION OR INTRODUCTION OF REGULATORY MIRNA. WE HYPOTHESIZE THAT ENDOMETRIOSIS IS INDUCED BY A COMBINATION OF ABNORMAL GENETIC AND/OR EPIGENETIC MUTATIONS: THE LATTER PAVE THE WAY FOR PATHOLOGICAL CHANGES WHICH BECOME IRREVERSIBLE, AND ACCORDING TO THE "EPIGENETIC LANDSCAPE" THEORY, THIS PROCEEDS TO THE TYPICAL CLINICAL MANIFESTATIONS. TWO STAGES IN THE ENDOMETRIOSIS PATHWAY ARE SUGGESTED: (1) INDUCTION OF PRIMARY ENDOMETRIAL CELLS TOWARD ENDOMETRIOSIS, AND (2) IMPLANTATION AND PROGRESSION OF THESE CELLS INTO ENDOMETRIOSIS LESIONS. THE MODEL FAVORS ENDOMETRIOSIS AS AN OUTGROWTH OF PRIMARY CELLS DIFFERENT IN THEIR ORIGIN, CANALIZATION OF PATHOLOGICAL PROCESSES, MANIFESTATION DIVERSITY PROVOKED BY UNIQUE GENETIC BACKGROUND AND EPIGENETIC INFLUENCES, WHICH RESULT IN MANY DIFFERENT CLINICAL FORMS OF THE DISEASE. 2015 20 111 42 A ROLE FOR G-PROTEIN COUPLED ESTROGEN RECEPTOR (GPER) IN ESTROGEN-INDUCED CARCINOGENESIS: DYSREGULATED GLANDULAR HOMEOSTASIS, SURVIVAL AND METASTASIS. MECHANISMS OF CARCINOGENESIS BY ESTROGEN CENTER ON ITS MITOGENIC AND GENOTOXIC POTENTIAL ON TUMOR TARGET CELLS. THESE MODELS SUGGEST THAT ESTROGEN RECEPTOR (ER) SIGNALING PROMOTES EXPANSION OF THE TRANSFORMED POPULATION AND THAT SUBSEQUENT ACCUMULATION OF SOMATIC MUTATIONS THAT DRIVE CANCER PROGRESSION OCCUR VIA METABOLIC ACTIVATION OF CATHECOL ESTROGENS OR BY EPIGENETIC MECHANISMS. RECENT FINDINGS THAT GPER IS LINKED TO OBESITY, VASCULAR PATHOLOGY AND IMMUNOSUPPRESSION, KEY EVENTS IN THE DEVELOPMENT OF METABOLIC SYNDROME AND INTRA-TISSULAR ESTROGEN SYNTHESIS, PROVIDES AN ALTERNATE VIEW OF ESTROGEN-INDUCED CARCINOGENESIS. CONSISTENT WITH THIS CONCEPT, GPER IS DIRECTLY ASSOCIATED WITH CLINICOPATHOLOGICAL INDICES THAT PREDICT CANCER PROGRESSION AND POOR SURVIVAL IN BREAST AND GYNECOLOGICAL CANCERS. MOREOVER, GPER MANIFESTS CELL BIOLOGICAL RESPONSES AND A MICROENVIRONMENT CONDUCIVE FOR TUMOR DEVELOPMENT AND CANCER PROGRESSION, REGULATING CELLULAR RESPONSES ASSOCIATED WITH GLANDULAR HOMEOSTASIS AND SURVIVAL, INVADING SURROUNDING TISSUE AND ATTRACTING A VASCULAR SUPPLY. THUS, THE CELLULAR ACTIONS ATTRIBUTED TO GPER FIT WELL WITH THE KNOWN MOLECULAR MECHANISMS OF G-PROTEIN COUPLED RECEPTORS, GPCRS, NAMELY, THEIR ABILITY TO TRANSACTIVATE INTEGRINS AND EGF RECEPTORS AND ALTER THE INTERACTION BETWEEN GLANDULAR EPITHELIA AND THEIR EXTRACELLULAR ENVIRONMENT, AFFECTING EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND ALLOWING FOR TUMOR CELL SURVIVAL AND DISSEMINATION. THIS PERSPECTIVE REVIEWS THE MOLECULAR AND CELLULAR RESPONSES MANIFESTED BY GPER AND EVALUATES ITS CONTRIBUTION TO FEMALE REPRODUCTIVE CANCERS AS DISEASES THAT PROGRESS AS A RESULT OF DYSREGULATED GLANDULAR HOMEOSTASIS RESULTING IN CHRONIC INFLAMMATION AND METASTASIS. THIS REVIEW IS ORGANIZED IN SECTIONS AS FOLLOWS: I) A BRIEF SYNOPSIS OF THE CURRENT STATE OF KNOWLEDGE REGARDING ESTROGEN-INDUCED CARCINOGENESIS, II) A REVIEW OF EVIDENCE FROM CLINICAL AND ANIMAL-BASED STUDIES THAT SUPPORT A ROLE FOR GPER IN CANCER PROGRESSION, AND III) A MECHANISTIC FRAMEWORK DESCRIBING HOW GPER-MEDIATED ESTROGEN ACTION MAY INFLUENCE THE TUMOR AND ITS MICROENVIRONMENT. 2018