{"paper_id":"72eebae9-ee7f-4cc0-9a11-90c65f0a43a8","body_text":"Accepted Article\nThe peritoneum: healing, immunity and diseases \n \nAnnalisa Capobianco1, Lucia Cottone1,2, Antonella Monno1, Angelo A. \nManfredi1,3, Patrizia Rovere-Querini1,3 \n1San Raffaele Scientific Institute, Division of Immunology, Transplantation, \nand Infectious Diseases, Milan, Italy; 2University College London, Genetics \nand Cell Biology of Sarcoma Group, London, UK; 3Vita-Salute San Raffaele \nUniversity, Milan, Italy \n \nKey words: \nendometriosis, peritoneal carcinomatosis, peritoneal adhesions, autoimmune \nserositis, sterile inflammation, fibrosis, macrophages, angiogenesis \n \nRunning title: \nPersisting repair fosters inflammatory peritoneal diseases  \nCorrespondence to:  \nAnnalisa Capobianco, PhD  \nDibit1 2A1 San Raffaele Institute  \nvia Olgettina 58, 20132, Milano \ntel +39 0226434694 \ne-mail capobianco.annalisa@hsr.it \n \nThe authors declare that no conflict of interest exists. \nAbstract \nThe peritoneum defines a confined microenvironment, which is stable under \nnormal conditions, but is exposed to the damaging effect of infections, \nThis article is protected by copyright. All rights reserved. \n \nThis article has been accepted for publication and undergone full peer review but has not \nbeen through the copyediting, typesetting, pagination and proofreading process, which \nmay lead to differences between this version and the Version of Record. Please cite this \narticle as doi: 10.1002/path.4942\n  \n\nAccepted Article\nsurgical injuries, and other neoplastic and non-neoplastic events. Its response \nto damage includes the recruitment, proliferation and activation of a variety of \nhaematopoietic and stromal cells. In physiologic conditions, effective \nresponses to injuries are organized, inflammatory triggers are eliminated, \ninflammation quickly abates, and the normal tissue architecture is restored. \nHowever, if inflammatory triggers are not cleared, fibrosis or scarring occur \nand impaired tissue function ultimately leads to organ failure. Autoimmune \nserositis is characterized by the persistence of self-antigens and a relapsing \nclinical pattern. Peritoneal carcinomatosis and endometriosis are \ncharacterized by the persistence of cancer cells or ectopic endometrial cells in \nthe peritoneal cavity. Some of the molecular signals orchestrating the \nrecruitment of inflammatory cells in the peritoneum have been identified in the \nlast few years. Alternative activation of peritoneal macrophages was shown to \nguide angiogenesis and fibrosis, and could represent a novel target for \nmolecular intervention. This review summarizes current knowledge of the \nalterations to the immune response in the peritoneal environment, highlighting \nthe ambiguous role played by persistently activated reparative macrophages \nin the pathogenesis of common human diseases. \n \n \n \n \n \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n The peritoneum: a peculiar (and crowded) microenvironment \nThe mesothelial membrane that lines the abdominal cavity is situated directly \nbeneath the abdominal musculature (rectus abdominis and transversus \nabdominis) and comprises a thin layer of loose connective tissue covered by a \nsingle layer of mesothelial cells [1]. The latter is referred to as the peritoneum \nand collectively, the connective tissue and peritoneum are referred to as the \nserosa (Figure 1). Mesothelial cells are squamous cells of mesodermal origin, \ncharacterized by apical microvilli, fragility and high turnover [1,2]. The \nperitoneal membrane contributes to the protection of the abdominal cavity, \nproviding an environment that facilitates response to mechanical stresses and \nin which organs are kept separate and slide on one another. Two layers of \nperitoneum line the abdomen: the parietal layer lines the abdominal wall, \nwhile the visceral layer lines the abdominal viscera. The narrow space within \nthese two layers is referred to as the peritoneal cavity [2]. The peritoneum \nprovides a route for entry of nerves, blood and lymphatic vessels. Pathogens \nand bacterial toxins are also readily absorbed and cause inflammation [3]. \nThe peritoneum contains the peritoneal fluid (PF), continuously produced by \nmesothelial cells as a plasma transudate, and reabsorbed through the large \nsurface area of the peritoneum. The PF facilitates frictionless movement of \nabdominal organs (e.g. during peristalsis), permits the exchange of nutrients, \nremoves pathogens and cells ascending from the female genital tract, and \nallows reparative events [4]. The PF is in equilibrium with the plasma, even if \nit does not contain large molecules. The PF is highly fibrinolytic, an activity \nthat may restrict the formation of adhesions in response to injury (see below).  \nGrowth factors, nutrients, cytokines and chemokines, as well as leukocytes, \nare continuously exchanged between the PF and the blood. Monocytes and \nmacrophages account for 50-90% of the leukocytes, and in normal conditions \ndispose of debris and pathogens [5]. Regulation of the composition of the \nperitoneal extracellular matrix (ECM) and of the receptors involved in matrix \nsensing (integrins and the α5β1 receptor in particular) shapes the mobilization \nof leukocytes from the bone marrow to the blood. Actively generated signals \npromote their active recruitment to the peritoneal cavity, in normal resting \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nconditions and upon induction of local acute inflammation [6, 7]. Matrix \nremodelling and clearance of apoptotic cells and other particulate substrates \nmodulate the function of peritoneal macrophages, committing them to an \nalternatively activated state with the upregulation of chemokine receptors \nsuch as CXCR4 [8]. \nThe second most represented cells are B1 lymphocytes. These are a source \nof natural antibodies (IgM and IgA, in particular) with broad specificity and low \nantigen affinity [9]. Although initial reports suggested a constitutive \nspontaneous production of antibodies by B1 lymphocytes, further evidence \npoints towards a requirement for an activation signal for IgM production [10], \nfollowed by the relocation of these cells in secondary lymphoid organs [11]. \nB1 cells contribute to the removal of microbes early after infection and \nfacilitate the switch from innate to adaptive immunity. Their survival in \nphysiological conditions is tightly regulated, via a mechanism dependent on \nthe inhibitory FcγRIIb receptor and modulated by B-cell activating factor \n(BAFF) and its receptor [12, 13]. T lymphocytes, dendritic cells, neutrophils, \nnatural killer cells and mast cells are also represented [14]. \nThe peritoneum is exposed to a variety of stressing events, including surgical \nor accidental injuries as well as viral and bacterial infection. Advanced liver or \nkidney failure cause the accumulation of PF, that upon infection leads to \nmicrobial peritonitis [15]. Damage-associated and pathogen-associated \nmolecular patterns (DAMPs and PAMPs, released by dying cells and by \ninvading microorganisms respectively) induce the recruitment, the proliferation \nand the activation of haematopoietic and non-haematopoietic cells, which \ntogether contribute to repair the tissue [16, 17]. The response leads to the \nelimination of the stimuli from the peritoneal cavity. In this case, inflammation \nabates and the tissue heals (Figure 2A). However, if the triggers persist, \npathological fibrosis or scarring develop, impairing normal tissue function and \nleading to organ failure [18, 19] (Figure 2B).\n \nConditions in which inflammatory triggers are eliminated: healing vs. \nfibrosis \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nThe recognition of microbes in the peritoneal cavity induces an inflammatory \nresponse, either localized or widespread. Archetypal inflammation is followed \nby oedema and production of fibrogenic exudates, with the formation of \nfibrotic tissue in the form of adhesions between serosal surfaces [20-22]. \nPeritoneal repair involves the proliferation of the normally quiescent \nmesothelial cells in response to inflammatory signals released by bystander \ninjured cells and by inflammatory leukocytes in the early phases. Later on, \nangiogenesis, cell migration and regulated turnover of the ECM predominate \n[23, 24]. Repair occurs diffusely through the injured mesothelial membrane \nand not from the wound edges, as in the case of epithelial organs and tissues. \nThe integrity of the peritoneum is usually soon restored, possibly because of \nthe combined action of mesothelial cells migrating from the wound edges and \ndetaching from the opposing surfaces and from distant sites [24]. Other \nprecursors from the bone marrow may also float in the peritoneal fluid and \nadhere to the denuded surface of the serosa [25]. In all cases, the PF, now a \nhigh-protein exudate containing fibrin, histamines, monocytes, granulocytes, \nmacrophages and mesothelial cells, guides the reparative process [5]. The \nfluid coagulates within few hours, yielding fibrinous bands between \ncorresponding surfaces maintaining their contact. Later, neutrophils entangle \nin fibrin strands and macrophages cover the wound.  \nIn response to injury, macrophages increase their phagocytic activity, \ngenerate reactive oxygen species, an recruit and activate additional \nmesothelial cells and fibroblasts to prompt repair [26-28]. Adhesions are \nformed within 72 hours. Fibrinolysis counteracts this phenomenon and allows \nhealing of the tissue. The plasticity of mesothelial cells is reflected by the \n“mesothelial-mesenchymal transition” phenomenon [29]. This results in a \nTGF-β-dependent formation of motile fibroblastoid cells that up-regulate alpha \nsmooth muscle actin (α-SMA) and express type I collagen [24]. Mesothelial-\nderived myofibroblasts may play a role in the accumulation of ECM proteins \nand in the contraction of the repairing tissue, thus ensuring effective wound \nhealing or prompting fibrosis [23, 30-34] (serosal adhesions in particular). The \nperitoneal microenvironments contain many components essential for healing, \nincluding collagens I and III, fibronectin, glycoproteins, fibroblasts, \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nmacrophages, and blood and lymphatic vessels [30, 35]. The essential role of \nlocally generated pentraxins, such as the prototypical long pentraxin PTX3, in \nstabilizing the provisional matrix and prompting effective healing has been \nrecently demonstrated in various tissues [36-38]. \nDisruption of matrix assembly jeopardizes healing and/or favours adhesion \nformation [39-41]. It is known that hepatic fibrosis and even cirrhosis are \npotentially reversible if the underlying cause is removed [42]. Thus, at least in \nthe liver, fibrosis is not the final outcome of a process leading to scar \nformation, but an actively maintained condition reflecting a maladaptive and \nsustained inflammatory response. This concept is relevant for the biology of \nperitoneal diseases.  \nConditions in which inflammatory triggers are not eliminated: \nautoimmune serositis, cancer and endometriosis \nWhen the inflammatory triggers are not eliminated, peritoneal inflammation \ndoes not abate, and leads to scar formation, impaired tissue function and \neventually to organ failure. Examples comprise the response to self-antigens \nthat induce autoimmune serositis in a transient-recurrent manner, or the \nresponse to neoplastic or ectopic cells, the main players of peritoneal \ncarcinomatosis and endometriosis respectively. \nAutoimmune serositis \nHealthy individuals do not usually mount sustained adaptive responses to \ntheir own antigens; transient responses to damaged self-tissues do occur, but \nrarely cause tissue damage. Although self-tolerance is the rule, autoimmunity \noccurs in predisposed individuals. Consequently, tissue repair takes place \nand fibroplasia and granulation tissue are formed. Activated myofibroblasts \nproduce a provisional ECM by excreting collagens and fibronectin. Because \nautoantigens cannot be eliminated, they elicit cycles of injury and repair and \neventually overcome the ability of fibrinolysis to prevent fibrosis within the \nperitoneum. \nSerositis refers to an inflammation of the lining of the lung, heart, or abdomen \nand peritoneum. Recurrent serositis is associated with autoimmune diseases \nsuch as Crohn’s disease, familial mediterranean fever (FMF) and systemic \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nlupus erythematosus (SLE). Crohn’s disease is a characteristically segmental \ninflammatory bowel disease with extra-intestinal manifestations and immune-\nmediated features. The peritoneal serosa is usually spared, while the \nabdominal serosa is frequently involved. Rarely, inflammation of the lining of \nthe lung or of the lung sacs occurs [43]. \nFMF is an auto-inflammatory disease associated with mutations in the MEFV \ngene that encodes the pyrin innate immunity regulator. In FMF, unrestrained \nproduction of IL-1β causes fever and polyserositis. Emotional factors, trauma \nand infection trigger both serositis and musculoskeletal pain. Menstruation \nplays an important role [44]; the pathophysiology underlying this relationship, \nand the role of blood accumulating in the peritoneal cavity as an inflammatory \ntrigger (see below) are still unclear [45]. \nSLE is the prototypic autoimmune systemic disease, with antibodies specific \nfor ubiquitous and abundant antigens, such as chromatin and proteins of the \npre-mRNA splicing machinery. Inflammation of the peritoneum and the \npericardium or pleuritis are frequent. Inflammatory fluid contains high levels of \nDNA and low levels of complement, suggesting that SLE serositis depends on \ndeposition of immunocomplexes [46]. Inflammation abates with scar formation \nevery time autoantigens are transiently targeted, and consequently the \ndisease is exacerbated. Early appearance of serositis can be used to predict \nthe risk of SLE development [47]. \nPeritoneal cancers and endometriosis \nTumours have been described as ‘wounds that do not heal’. The signals \npromoting cell survival, proliferation and movement, as well as those \nfavouring neo-angiogenesis, are useful for tissue repair. Conversely, they \nmight be essential for the survival, growth and spreading of neoplastic cells. \nMost peritoneal tumors derive from extraperitoneal lesions. Primary peritoneal \nneoplasms of serosal origin are rare and usually of mesenchymal origin, \nderiving either from mesothelial cells (mesothelioma) or from adipose \nprecursor cells in the stroma [48]. Mesothelioma is correlated to asbestos \nexposure, and affects all serosas [49]. Calcification and ascites formation are \nfrequent [48]. Peritoneal carcinomatosis depends on the diffusion of cells from \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\ncarcinomas of the stomach, colon, ovaries, bladder, Fallopian tubes or \npancreas [50]. Growing tumours eventually infiltrate structures contacting the \nvisceral layer of the peritoneum and neoplastic cells detach and diffuse in the \nperitoneal cavity. Their fate within the peritoneal cavity has not been so far \nthoroughly investigated. Most cells die, but at least a fraction survive, attach to \nthe mesothelium and – if the environment is permissive – yield metastatic \nlesions. \nIslands of vascularized endometrial tissue at ectopic sites define \nendometriosis. During menstruation, the menstrual effluent is partially \nregurgitated through the Fallopian tubes into the peritoneal cavity. This is \nsupposed to be necessary for endometriosis establishment [51]. It is not \nsufficient, though, since retrograde menstruation is common in healthy women \n[52]. The events that influence the ability of shed endometrium to survive, to \nattach and infiltrate the peritoneum and to recruit vessels have been only \npartially elucidated. \nPeritoneal inflammation in endometriosis and carcinomatosis \nChronic inflammation, with persistent repair and eventual remodelling of the \nperitoneum, is a common feature of autoimmune serositis, cancer and \nendometriosis. Remodelling refers to the reorganization or renovation of the \nexisting tissue, and sustains tissue alteration, diffusion, survival, spreading, \nand organization of ectopic and inflammatory tissue. It is achieved through the \ndegradation and resynthesis of ECM components, orchestrated and guided by \nextracellular proteolysis and fibroblast activation [53]. Matrix \nmetalloproteinases degrade ECM components and produce biologically active \npeptides, create space for cell migration and modify intercellular junctions, \nregulating the overall tissue architecture [54]. \nECM dynamics result in altered synthesis or degradation of ECM \ncomponents, influencing its architecture. ECM components are laid down, \ncross-linked and organized together via covalent and non-covalent \nmodifications, determining the outcome of the interaction with \nstromal/inflammatory cells [55-58]. Thus the expression and function of ECM-\nmodifying enzymes and stromal/inflammatory cells influence the \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\ndissemination of ectopic or transformed cells, their diffusion in the peritoneal \ncavity and attachment to the serosa, specifically sustaining lesion \nvascularization. Each of these steps is discussed below. \nTissue remodelling by immune cells \nEpidemiological studies and experimental findings support a role for chronic \ninflammation in fostering cancer [59, 60] and endometriosis [61, 62]. \nRecruited leukocytes possibly remodel the tissue, favouring tumour \nprogression by supplying growth factors to sustain cell proliferation, survival \nfactors to overcome cell death, and angiogenic factors and extracellular \nmatrix-remodeling enzymes to foster angiogenesis [63]. Tumour-associated \nmacrophages (TAMs) release proteases, cytokines and chemokines such as \nCCL2 and CXCL8, that promote tissue remodelling [64-68], as well as growth \nfactors such as TGFβ, VEGFA, VEGFC, EGF and thymidine phosphorylase \n(TP), that promote angiogenesis and lymphangiogenesis under hypoxic \nconditions [69, 70]. Immune cells are crucial in the growth and vascularization \nof endometriotic lesions [71]. The presence of ectopic tissue in the peritoneal \ncavity is associated with overproduction of prostaglandins, cytokines and \nchemokines by infiltrating leukocytes [51]. Macrophages are a major source of \ninflammatory molecules that modify the peritoneal environment. They \nconsistently infiltrate ectopic endometrial lesions, which in the absence of \nmacrophages fail to establish and to grow in animal models [72, 73]. Thus the \nfailure of endometriotic lesion establishment in these systems underscores \nthe importance of leukocyte infiltration in the lesions. \nDiffusion and spreading \nPeritoneal colorectal cancer dissemination was originally thought to follow a \nrandom pattern. However, it is now clear that lesions develop at preferential \nsites following the PF hydrodynamics and gravity. In contrast, in the absence \nof ascites, cancer cells are restricted in motion and implant nearer to the \nprimary site [74, 75]. The neoplastic spreading in the peritoneum often \ndepends on passive intraperitoneal seeding of cells exfoliated from exposed \nprimary intraperitoneal tumors. Neoplastic cells detach spontaneously from \nthe abdominal masses because of high interstitial fluid pressure, contraction \nof the interstitial matrix, increased osmotic pressure and down-regulation of \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nthe molecules that ensure cell-to-cell adhesion within the primary neoplastic \nlesion [76]. Shed neoplastic cells are transported in the PF along mesentery \nand ligaments towards contiguous or non-contiguous organs. Malignant \nlesions accumulate preferentially where the fluid is deposited, including the \nliver surface (because of the negative pressure under the diaphragm) or \novaries (located in the cul-de-sac of the peritoneum). Antineoplastic \ntreatments can also paradoxically favor the access of cancer cells to the \nperitoneal cavity. Surgery in particular facilitates the dissemination of tumors \ninto the peritoneal cavity, with neoplastic cells being released from transected \nlymphatic vessels and from tumour-contaminated blood from the neoplastic \nspecimen [77, 78]. \nCancer cells also diffuse from primary lesions via lymphatic and blood \nvessels, which allow direct access to the sub-mesothelial space. \nDissemination via lymphatic vessels occurs from regional to central nodes, \nand haematogenous spread occurs via the mesenteric arteries. Accordingly, \nregions of the peritoneum enriched in lymphatics are early sites of metastasis. \nPeritoneal lesions derived from various distant cancers, including mammary \nand lung carcinoma and malignant melanoma, have been described [79]. \nDuring menstruation, erythrocytes and leucocytes accumulate in the \nperitoneal fluid of most women [80-82]. Haemolysis and/or defective \nclearance of dying red blood cells results in iron release, with production of a \nwide variety of damaging free radical species by the Fenton reaction, with lipid \nperoxidation, protein and DNA damage. These signals favour adherence to \nthe peritoneal wall of the endometrial fragments [71, 83-87]. Peritoneal \nmacrophages are professional phagocytes, whose primary role is the \nclearance of particulate debris, including apoptotic leukocytes and senescent \nred blood cells. When their clearance ability is overwhelmed, and in the \npresence of an excess of free radicals, peripheral macrophages generate, \nthrough NF-ߢB, multiple inflammatory signals supporting recruitment of further \nphagocytes at the site. These events might be specifically involved in the \npersisting inflammatory status of endometriotic lesions, in which the \nendometrial tissue still responds to normal hormonal signals, but menstrual \nblood cannot be eliminated by the normal process of physiological shedding \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n[84, 88-93] . Generally, oxidative injury occurs when continued delivery of iron \nto the peritoneal macrophages is associated with inhibition of iron storage in \nferritin [62, 84, 94-97] Macrophages also serve as a source of nitric oxide \n(NO) [84]. NO produced in abundance by the inducible form of NO synthase, \ninduced by oxidant-sensitive transcription factors like NF-ߢB [98], exacerbates \nendometriosis [99, 100]. The exfoliated cancer or ectopic cells must then: i) \nsurvive in the peritoneal environment; ii) adhere to the surface of the serosa; \niii) migrate into the sub-mesothelial space and iv) attach firmly via integrins to \nthe mesothelial basement membrane. At later stages, cancer cells express \nmatrix proteinases that disrupt the peritoneal blood barrier and invade the \nsub-peritoneal tissue. Angiogenesis is crucial for the further growth of \nestablished lesions [73]. \nAttachment/Dissemination.  \nPeritoneal cancer dissemination has been considered a random process for \nmany years. However, lesions develop at preferential sites, possibly because \nof the pattern of PF flow and sites of stasis, which in turn are influenced by \nphysical forces such as fluid hydrodynamics and gravity [74, 75]. In contrast, \nin the absence of ascites, cancer cells are restricted in motion and so implant \nnear to the primary site. Peritoneal dissemination of cancer cells involves \nseveral steps: detachment of cells from the primary tumour, survival in the \nabdominal cavity, attachment to the peritoneum, invasion of the subperitoneal \nspace and proliferation with angiogenesis. Various molecular events must \nthus cooperate for cancer cells to efficiently attach and adhere to the \nperitoneal lining, but limited information is available [101]. \nThis is probably also the case for endometriotic lesions, even if endometrial \nfragments and not isolated endometrial cells adhere to the serosa. In vitro \nmodels have shown that the process is short and that the active participation \nof mesothelial cells is necessary [102, 103]. After adhesion, the endometrial \ntissue invades the underlying mesothelial basement membrane without the \nneed for its physical disruption, as initially thought. It is a prerequisite for the \norganization of the ectopic endometrial cells in three-dimensional cysts [102]. \nInvasion per se is not sufficient: angiogenesis is necessary for the \nestablishment of endometriotic lesions.  \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nAscites reflects the accumulation of protein-rich exudate in the abdominal \ncavity, and represents a presenting feature of advanced-stage ovarian cancer \nor a relatively late event in carcinomatosis associated with other neoplasm. \nAccumulation of PF depends on enhanced filtration and/or decreased \ndrainage or clearance, because of:  i) hindrance of lymphatic vessels by \nmetastatic cells ii) VEGF-dependent increased permeability of the \nperitoneum-associated vasculature iii)  hypoproteinaemia facilitating fluid \nmovement to the peritoneal cavity iv) hepatic involvement with portal \nhypertension. Most PF accumulating in the peritoneal cavity depends on that \npart of peritoneal serosa which is not directly infiltrated by neoplastic cells [78] \nAngiogenesis \nThe formation of new blood vessels in adult tissues (neoangiogenesis) is \ncritical for the establishment of benign or malignant lesions in the peritoneal \ncavity. As the lesion burden grows, endothelial cells are recruited to form new \nblood vessels to meet the increased metabolic demands. This process \ndepends on inflammatory cells and specifically on the ability to attract \n“reparative” macrophages that release growth factors and matrix-remodelling \nenzymes, promote neoangiogenesis, and might play a role in the ability of \nendometriotic and neoplastic cells to yield peritoneal lesions. This general \nparadigm well agrees with data obtained in humans and in experimental \nmodels of peritoneal disease, including ovarian cancer [50, 104] and \nendometriosis [72, 73].  \nCarcinoma cells release a prototypic DAMP/alarmin, HMGB1, which guides \ntissue regeneration and supports neo-angiogenesis. Exogenous HMGB1 \naccelerates leukocyte recruitment, macrophage infiltration, tumour growth and \nneoangiogenesis in experimental models [105-107]. Chemotherapeutic \nagents in animal models induce HMGB1 in the peritoneal cavity. This \nobservation could underlie some paradoxical results of chemotherapeutic \ntreatments in patients with peritoneal carcinomatosis [108]. HMGB1 is also \nreleased by mesothelial cells challenged with asbestos, an event implicated in \nthe natural history of malignant mesothelioma [109-113]. Abdominal surgery \nresults per se in the release of HMGB1 in the peritoneal cavity. In turn, \nHMGB1 might create a negative loop via the recruitment of inflammatory \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nleukocytes, in particular myeloid derived suppressor cells (MDSC), to promote \nthe metastatization of colon cancer cells after surgery [114]. MDSC comprise \ncells phenotypically or morphologically similar to monocytes and cells closer \nto neutrophils [115]. The ability of HMGB1 to influence the metabolism, \nfunction and interaction of neutrophils with other innate immune cells [116-\n118] might be involved in the tumour-supporting action of MSDC. \nIn endometriosis, macrophages deliver signals that attract vessels, facilitating \nthe survival of ectopic endometrial cells in the relatively hypoxic peritoneal \ncavity [62]. Subpopulations of macrophages are preferentially involved in \nangiogenesis [119, 120]. The best characterized are possibly those that \nexpress the Tie-2 receptor (TEM or Tie-2-expressing \nmonocytes/macrophages), which sustain neo-angiogenesis in a variety of \nexperimental tumour models. Circulating monocytes express limited amounts \nof Tie-2 in normal conditions. They up-regulate it after homing to hypoxic \ntissue, where they yield a subset of perivascular macrophages [121-123]. \nThe VEGF family and associated receptors and the angiopoietin/Tie-2 \nsystems connect hormonal levels to vessel remodelling [124-127]. Peritoneal \nmacrophages are a source of VEGF and ovarian steroids regulate the \nproduction of this growth factor [128]. Estrogens act on various macrophage \nsignalling pathways, influencing in particular those related to the ability to \nsustain the recruitment of inflammatory cells and the remodelling of inflamed \ntissues, such as mitogen-activated protein kinase, phosphatidylinositide-3-\nkinase/protein kinase B and NF-κB. As a consequence, a deregulated \nresponse to steroids might influence the survival of ectopic endometrial cells \nand promote the neoangiogenesis of the lesions [129, 130]. \nEndometriotic lesions do not contain neoplastic cells. However they share \nwith neoplasm features such as unrestrained growth, invasion of adjacent \ntissues, defective apoptosis and sustained inflammatory responses. \nEndometriosis increases the risk of ovarian cancer, in particular invasive low-\ngrade serous, clear-cell and endometrioid subtypes [131, 132]. As discussed \nabove, macrophages are physiologically recruited to injured tissues, where \nthey activate the neo-angiogenic switch, sustain resistance to apoptotic stimuli \nand stimulate the proliferation and invasion of precursor cells, in order to \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nprompt tissue regeneration. Macrophages recruited in the endometriotic \nlesions indeed activate neo-angiogenesis, sustain survival and prompt \nproliferation, possibly contributing to the evolution toward atypical \nendometriosis, metaplasia and then borderline or fully malignant ovarian \ncancer [133]. Interference with the recruitment or the function of angiogenic \nmacrophages might prove valuable for targeted molecular intervention. \nInflammation in the peritoneum as a druggable target \nThe innate immune response plays a critical role in peritoneal cancers and \nendometriosis [14, 134], as summarized in Figure 3. Phagocyte depletion via \nclodronate treatment reduces neoplastic growth by limiting neoangiogenesis \nin mouse models of carcinomatosis [50, 108], reduces tumour burden, \ninvasion and metastasis in a mouse model of mesothelioma [135], and delays \ntumour progression while leaving unaltered ascites formation in an orthotopic \nmodel of ovarian cancer [104]. Genetic ablation of macrophages in models of \nexperimental colorectal cancer results in decreased infiltration by regulatory T \ncells, CCL20 production and tumour growth [136]. \nEndometriotic lesions fail to grow in the absence of macrophages, and \ndevelop a glandular and stromal architecture, due to impaired vascularization, \nwhile retaining the ability to adhere to and to infiltrate the serosal membrane \nin a mouse model [72]. Macrophages are critical for the continued growth of \nlesions, which in their absence fail to develop a glandular and stromal \narchitecture due to impaired vascularization [72]. When TEMs are depleted, \nvessels and overall lesions are disrupted. TEMs preferentially localize in \nperivascular areas [137], where they provide survival and growth signals to \nendothelial cells and progenitors [138]. In experimental peritoneal \ncarcinomatosis, pharmacological HMGB1 targeting resulted in substantial \nanti-neoplastic effects [105].  \nThe interaction between neoplastic or ectopic cells and immune cells in the \nperitoneal environment is a critical area for drug development. The \nidentification of new molecular targets is essential for progress in the \ntreatment of these diseases, a largely unmet medical need. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \nAcknowledgements \nThe work of the authors has been supported by the AIRC (Associazione \nItaiana Ricerca sul Cancro). \n \nAuthor’s contributions \nA.C. and L.C. wrote the manuscript, A.M. performed immunohistochemistry \nanalysis; A.A.M and P.R.Q supervised the work. \n \n \nReferences \n1. Di Paolo N, Nicolai GA, Garosi G. The peritoneum: from histological \nstudies to mesothelial transplant through animal experimentation. Perit \nDial Int 2008; 28 Suppl 5: S5-9. \n \n2. Di Paolo N, Sacchi G. Atlas of peritoneal histology. Perit Dial Int 2000; \n20 Suppl 3: S5-96. \n \n3. Mais D. Quick Compendium of Clinical Pathology. QuickQuick \nCompendium of Clinical Pathology 2nd Ed ASCP Press 2009 2009. \n \n4. Blackburn SC, Stanton MP. Anatomy and physiology of the \nperitoneum. Semin Pediatr Surg 2014; 23: 326-330. \n \n5. Heel KA, Hall JC. Peritoneal defences and peritoneum-associated \nlymphoid tissue. Br J Surg 1996; 83: 1031-1036. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n6. Sampaio AL, Zahn G, Leoni G , et al. Inflammation-dependent alpha 5 \nbeta 1 (very late antigen-5) expression on leukocytes reveals a \nfunctional role for this integrin in acute peritonitis. J Leukoc Biol 2010; \n87: 877-884. \n \n7. Brown RJ, Mallory C, McDougal OM , et al. Proteomic analysis of \nCol11a1-associated protein complexes. Proteomics 2011; 11: 4660-\n4676. \n \n8. Ariel A, Ravichandran KS. 'This way please': Apoptotic cells regulate \nphagocyte migration before and after engulfment. Eur J Immunol 2016; \n46: 1583-1586. \n9. Stoermann B, Kretschmer K, Duber S , et al. B-1a cells are imprinted by \nthe microenvironment in spleen and peritoneum. Eur J Immunol 2007; \n37: 1613-1620. \n \n10. Choi YS, Dieter JA, Rothaeusler K , et al. B-1 cells in the bone marrow \nare a significant source of natural IgM. Eur J Immunol 2012; 42: 120-\n129. \n \n11. Baumgarth N. Innate-like B cells and their rules of engagement. Adv \nExp Med Biol 2013; 785: 57-66. \n \n12. Amezcua Vesely MC, Schwartz M, Bermejo DA , et al. FcgammaRIIb \nand BAFF differentially regulate peritoneal B1 cell survival. J Immunol \n2012; 188: 4792-4800. \n \n13. Sindhava VJ, Scholz JL, Cancro MP. Roles for BLyS family members \nin meeting the distinct homeostatic demands of innate and adaptive B \ncells. Front Immunol 2013; 4: 37. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n14. Mier-Cabrera J, Jimenez-Zamudio L, Garcia-Latorre E , et al. \nQuantitative and qualitative peritoneal immune profiles, T-cell \napoptosis and oxidative stress-associated characteristics in women \nwith minimal and mild endometriosis. Bjog 2011; 118: 6-16 \n. \n15. Merrell RC. The abdomen as a source of sepsis  in critically ill patient. \nSurgical Treatment Evidence-Based and Problem-Oriented 2001. \n \n16. Zhang Q, Raoof M, Chen Y , et al. Circulating mitochondrial DAMPs \ncause inflammatory responses to injury. Nature 2010; 464: 104-107. \n \n17. Bertheloot D, Latz E. HMGB1, IL-1alpha, IL-33 and S100 proteins: \ndual-function alarmins. Cell Mol Immunol 2017; 14: 43-64. \n \n18. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic \ntranslation for fibrotic disease. Nat Med 2012; 18: 1028-1040. \n \n19. Ramalingam TR, Gieseck RL, Acciani TH , et al. Enhanced protection \nfrom fibrosis and inflammation in the combined absence of IL-13 and \nIFN-gamma. J Pathol 2016; 239: 344-354. \n \n20. Healy JC, Reznek RH. The peritoneum, mesenteries and omenta: \nnormal anatomy and pathological processes. Eur Radiol 1998; 8: 886-\n900. \n \n21. Padwal M, Siddique I, Wu L , et al. Matrix metalloproteinase 9 is \nassociated with peritoneal membrane solute transport and induces \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nangiogenesis through beta-catenin signaling. Nephrol Dial Transplant \n2017; 32: 50-61. \n22. van Baal JO, Van de Vijver KK, Nieuwland R , et al. The \nhistophysiology and pathophysiology of the peritoneum. Tissue Cell \n2017; 49: 95-105. \n \n23. Rout UK, Saed GM, Diamond MP. Transforming growth factor-beta1 \nmodulates expression of adhesion and cytoskeletal proteins in human \nperitoneal fibroblasts. Fertil Steril 2002; 78: 154-161. \n \n24. Mutsaers SE, Prele CM, Pengelly S , et al. Mesothelial cells and \nperitoneal homeostasis. Fertil Steril 2016; 106: 1018-1024. \n \n25. Bajpai R, Chen DA, Rada-Iglesias A , et al. CHD7 cooperates with \nPBAF to control multipotent neural crest formation. Nature 2010; 463: \n958-962. \n \n26. Fotev Z, Whitaker D, Papadimitriou JM. Role of macrophages in \nmesothelial healing. J Pathol 1987; 151: 209-219. \n \n27. Riese J, Niedobitek G, Lisner R , et al. Expression of interleukin-6 and \nmonocyte chemoattractant protein-1 by peritoneal sub-mesothelial cells \nduring abdominal operations. J Pathol 2004; 202: 34-40. \n \n28. Koninckx PR, Gomel V, Ussia A , et al. Role of the peritoneal cavity in \nthe prevention of postoperative adhesions, pain, and fatigue. Fertil \nSteril 2016; 106: 998-1010. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n29. Abelardo E, Roebuck D, McLaren C , et al. Right pulmonary artery sling \nin a single lung with bronchial isomerism. J Card Surg 2014; 29: 256-\n258. \n \n30. Buhimschi IA, Dussably L, Buhimschi CS , et al. Physical and \nbiomechanical characteristics of rat cervical ripening are not consistent \nwith increased collagenase activity. Am J Obstet Gynecol 2004; 191: \n1695-1704. \n \n31. Gerarduzzi C, Di Battista JA. Myofibroblast repair mechanisms post-\ninflammatory response: a fibrotic perspective. Inflamm Res 2017; 66: \n451-465. \n \n32. Witowski J, Kawka E, Rudolf A , et al. New developments in peritoneal \nfibroblast biology: implications for inflammation and fibrosis in \nperitoneal dialysis. Biomed Res Int 2015; 2015: 134708. \n \n33. Kawka E, Witowski J, Fouqet N , et al. Regulation of chemokine CCL5 \nsynthesis in human peritoneal fibroblasts: a key role of IFN-gamma. \nMediators Inflamm 2014; 2014: 590654. \n \n34. Burgess JK, Mauad T, Tjin G , et al. The extracellular matrix - the \nunder-recognized element in lung disease? J Pathol 2016; 240: 397-\n409. \n35. diZerega GS. Biochemical events in peritoneal tissue repair. Eur J Surg \nSuppl 1997: 10-16. \n \n36. Doni A, Garlanda C, Mantovani A. PTX3 orchestrates tissue repair. \nOncotarget 2015; 6: 30435-30436. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n37. Cappuzzello C, Doni A, Dander E , et al. Mesenchymal Stromal Cell-\nDerived PTX3 Promotes Wound Healing via Fibrin Remodeling. J \nInvest Dermatol 2015. \n \n38. Vezzoli M, Sciorati C, Campana L , et al. The clearance of cell \nremnants and the regeneration of the injured muscle depend on \nsoluble pattern recognition receptor PTX3. Mol Med 2016; 22. \n \n39. Saed GM, Diamond MP. Molecular characterization of postoperative \nadhesions: the adhesion phenotype. J Am Assoc Gynecol Laparosc \n2004; 11: 307-314. \n \n40. Roulis M, Flavell RA. Fibroblasts and myofibroblasts of the intestinal \nlamina propria in physiology and disease. Differentiation 2016; 92: 116-\n131. \n \n41. Nicolosi PA, Tombetti E, Maugeri N , et al. Vascular Remodelling and \nMesenchymal Transition in Systemic Sclerosis. Stem Cells Int 2016; \n2016: 4636859. \n \n42. Fallowfield JA. Future mechanistic strategies for tackling fibrosis--an \nunmet need in liver disease. Clin Med (Lond) 2015; 15 Suppl 6: s83-\n87. \n \n43. Mohammed AR, Babu S. Serositis and inflammatory bowel disease. Br \nJ Hosp Med (Lond) 2008; 69: 296-297. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n44. Karadag O, Tufan A, Yazisiz V , et al. The factors considered as trigger \nfor the attacks in patients with familial Mediterranean fever. Rheumatol \nInt 2013; 33: 893-897. \n \n45. Akar S, Soyturk M, Onen F , et al. The relations between attacks and \nmenstrual periods and pregnancies of familial Mediterranean fever \npatients. Rheumatol Int 2006; 26: 676-679. \n \n46. Baroni G, Schuinski A, de Moraes TP , et al. Inflammation and the \nperitoneal membrane: causes and impact on structure and function \nduring peritoneal dialysis. Mediators Inflamm 2012; 2012: 912595. \n \n47. Rees F. Early Clinical Features in Systemic Lupus Erythematosus: Can \nThey Be Used to Achieve Earlier Diagnosis? A Risk Prediction Model. \nArthritis Care Research 2016. \n48. Bridda A, Padoan I, Mencarelli R , et al. Peritoneal mesothelioma: a \nreview. MedGenMed 2007; 9: 32. \n \n49. Carbone M, Ly BH, Dodson RF , et al. Malignant mesothelioma: facts, \nmyths, and hypotheses. J Cell Physiol 2012; 227: 44-58. \n \n50. Cottone L, Valtorta S, Capobianco A , et al. Evaluation of the role of \ntumor-associated macrophages in an experimental model of peritoneal \ncarcinomatosis using (18)F-FDG PET. J Nucl Med 2011; 52: 1770-\n1777. \n \n51. Vercellini P, Vigano P, Somigliana E , et al. Endometriosis: \npathogenesis and treatment. Nat Rev Endocrinol 2014; 10: 261-275. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n52. O DF, Roskams T, Van den Eynde K , et al. The Presence of \nEndometrial Cells in Peritoneal Fluid of Women With and Without \nEndometriosis. Reprod Sci 2017; 24: 242-251. \n \n53. Mezawa Y, Orimo A. The roles of tumor- and metastasis-promoting \ncarcinoma-associated fibroblasts in human carcinomas. Cell Tissue \nRes 2016; 365: 675-689. \n \n54. Wang X, Page-McCaw A. A matrix metalloproteinase mediates long-\ndistance attenuation of stem cell proliferation. J Cell Biol 2014; 206: \n923-936. \n \n55. Lopez JI, Mouw JK, Weaver VM. Biomechanical regulation of cell \norientation and fate. Oncogene 2008; 27: 6981-6993. \n \n56. Engler AJ, Chan M, Boettiger D , et al. A novel mode of cell detachment \nfrom fibrillar fibronectin matrix under shear. J Cell Sci 2009; 122: 1647-\n1653. \n \n57. Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the \ncollagen scaffold and tumor evolution. Curr Opin Cell Biol 2010; 22: \n697-706. \n \n58. Daley WP, Yamada KM. ECM-modulated cellular dynamics as a \ndriving force for tissue morphogenesis. Curr Opin Genet Dev 2013; 23: \n408-414. \n \n59. Palucka AK, Coussens LM. The Basis of Oncoimmunology. Cell 2016; \n164: 1233-1247. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n60. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: \n860-867. \n \n61. Gazvani R, Templeton A. Peritoneal environment, cytokines and \nangiogenesis in the pathophysiology of endometriosis. Reproduction \n2002; 123: 217-226. \n \n62. Capobianco A, Rovere-Querini P. Endometriosis, a disease of the \nmacrophage. Front Immunol 2013; 4: 9. \n \n63. Solinas G, Marchesi F, Garlanda C , et al. Inflammation-mediated \npromotion of invasion and metastasis. Cancer Metastasis Rev 2010; \n29: 243-248. \n \n64. Cassetta L, Pollard JW. Cancer im munosurveillance: role of patrolling \nmonocytes. Cell Res 2016; 26: 3-4. \n \n65. Murdoch C, Muthana M, Coffelt SB , et al. The role of myeloid cells in \nthe promotion of tumour angiogenesis. Nat Rev Cancer 2008; 8: 618-\n631. \n \n66. Hamm A, Prenen H, Van Delm W , et al. Tumour-educated circulating \nmonocytes are powerful candidate biomarkers for diagnosis and \ndisease follow-up of colorectal cancer. Gut 2016; 65: 990-1000. \n \n67. Wang Y, Nakayama M, Pitulescu ME , et al. Ephrin-B2 controls VEGF-\ninduced angiogenesis and lymphangiogenesis. Nature 2010; 465: 483-\n486. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n68. Kimura Y, Sumiyoshi M, Baba K. Antitumor and Antimetastatic Activity \nof Synthetic Hydroxystilbenes Through Inhibition of \nLymphangiogenesis and M2 Macrophage Differentiation of Tumor-\nassociated Macrophages. Anticancer Res 2016; 36: 137-148. \n \n69. Henze AT, Mazzone M. The impact of hypoxia on tumor-associated \nmacrophages. J Clin Invest 2016; 126: 3672-3679. \n \n70. Mantovani A, Marchesi F, Malesci A , et al. Tumour-associated \nmacrophages as treatment targets in oncology. Nat Rev Clin Oncol \n2017; 14: 399-416. \n \n71. Lousse JC, Van Langendonckt A, Defrere S , et al. Peritoneal \nendometriosis is an inflammatory disease. Front Biosci (Elite Ed) 2012; \n4: 23-40. \n \n72. Bacci M, Capobianco A, Monno A , et al. Macrophages are alternatively \nactivated in patients with endometriosis and required for growth and \nvascularization of lesions in a mouse model of disease. Am J Pathol \n2009; 175: 547-556. \n \n73. Capobianco A, Monno A, Cottone L , et al. Proangiogenic Tie2(+) \nmacrophages infiltrate human and murine endometriotic lesions and \ndictate their growth in a mouse model of the disease. Am J Pathol \n2011; 179: 2651-2659. \n \n74. Carmignani CP, Sugarbaker TA, Bromley CM , et al. Intraperitoneal \ncancer dissemination: mechanisms of the patterns of spread. Cancer \nMetastasis Rev 2003; 22: 465-472. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n75. Lemoine L, Sugarbaker P, Van der Speeten K. Pathophysiology of \ncolorectal peritoneal carcinomatosis: Role of the peritoneum. World J \nGastroenterol 2016; 22: 7692-7707. \n \n76. Worzfeld T, Pogge von Strandmann E, Huber M , et al. The Unique \nMolecular and Cellular Microenvironment of Ovarian Cancer. Front \nOncol 2017; 7: 24. \n \n77. Lengyel E. Ovarian cancer development and metastasis. Am J Pathol \n2010; 177: 1053-1064. \n \n78. Sodek KL, Murphy KJ, Brown TJ , et al. Cell-cell and cell-matrix \ndynamics in intraperitoneal cancer metastasis. Cancer Metastasis Rev \n2012; 31: 397-414. \n \n79. Zhao YC, Ni XJ, Li Y , et al. Peritumoral lymphangiogenesis induced by \nvascular endothelial growth factor C and D promotes lymph node \nmetastasis in breast cancer patients. World J Surg Oncol 2012; 10: \n165. \n \n80. Bokor A, Debrock S, Drijkoningen M , et al. Quantity and quality of \nretrograde menstruation: a case control study. Reprod Biol Endocrinol \n2009; 7: 123. \n \n81. Bulun SE. Endometriosis. N Engl J Med 2009; 360: 268-279. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n82. Bulun SE, Monsivais D, Kakinuma T , et al. Molecular biology of \nendometriosis: from aromatase to genomic abnormalities. Semin \nReprod Med 2015; 33: 220-224. \n \n83. Carvalho LF, Samadder AN, Agarwal A , et al. Oxidative stress \nbiomarkers in patients with endometriosis: systematic review. Arch \nGynecol Obstet 2012; 286: 1033-1040. \n \n84. Donnez J, Binda MM, Donnez O , et al. Oxidative stress in the pelvic \ncavity and its role in the pathogenesis of endometriosis. Fertil Steril \n2016; 106: 1011-1017. \n \n85. Turkyilmaz E, Yildirim M, Cendek BD , et al. Evaluation of oxidative \nstress markers and intra-extracellular antioxidant activities in patients \nwith endometriosis. Eur J Obstet Gynecol Reprod Biol 2016; 199: 164-\n168. \n86. Da Broi MG, Navarro PA. Oxidative stress and oocyte quality: \nethiopathogenic mechanisms of minimal/mild endometriosis-related \ninfertility. Cell Tissue Res 2016; 364: 1-7. \n \n87. Gozzelino R, Arosio P. Iron Homeostasis in Health and Disease. Int J \nMol Sci 2016; 17. \n \n88. Defrere S, Lousse JC, Gonzalez-Ramos R , et al. Potential involvement \nof iron in the pathogenesis of peritoneal endometriosis. Mol Hum \nReprod 2008; 14: 377-385. \n \n89. Augoulea A, Alexandrou A, Creatsa M , et al. Pathogenesis of \nendometriosis: the role of genetics, inflammation and oxidative stress. \nArch Gynecol Obstet 2012; 286: 99-103. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n90. Santanam N, Zoneraich N, Parthasarathy S. Myeloperoxidase as a \nPotential Target in Women With Endometriosis Undergoing IVF. \nReprod Sci 2017; 24: 619-626. \n \n91. Alvarado-Diaz CP, Nunez MT, Devoto L , et al. Endometrial expression \nand in vitro modulation of the iron transporter divalent metal \ntransporter-1: implications for endometriosis. Fertil Steril 2016; 106: \n393-401. \n \n92. Nassif J, Abbasi SA, Nassar A , et al. The role of NADPH-derived \nreactive oxygen species production in the pathogenesis of \nendometriosis: a novel mechanistic approach. J Biol Regul Homeost \nAgents 2016; 30: 31-40. \n \n93. McKinnon BD, Kocbek V, Nirgianakis K , et al. Kinase signalling \npathways in endometriosis: potential targets for non-hormonal \ntherapeutics. Hum Reprod Update 2016; 22. \n \n94. Rishi G, Secondes ES, Wallace DF , et al. Normal systemic iron \nhomeostasis in mice with macrophage-specific deletion of transferrin \nreceptor 2. Am J Physiol Gastrointest Liver Physiol 2016; 310: G171-\n180. \n \n95. Jiang L, Chew SH, Nakamura K , et al. Dual preventive benefits of iron \nelimination by desferal in asbestos-induced mesothelial \ncarcinogenesis. Cancer Sci 2016; 107: 908-915. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n96. Pirdel L, Pirdel M. Role of iron overload-induced macrophage \napoptosis in the pathogenesis of peritoneal endometriosis. \nReproduction 2014; 147: R199-207. \n \n97. Lousse JC, Defrere S, Van Langendonckt A , et al. Iron storage is \nsignificantly increased in peritoneal macrophages of endometriosis \npatients and correlates with iron overload in peritoneal fluid. Fertil Steril \n2009; 91: 1668-1675. \n98. Xiu-li W, Wen-jun C, Hui-hua D , et al. ERB-041, a selective ER beta \nagonist, inhibits iNOS production in LPS-activated peritoneal \nmacrophages of endometriosis via suppression of NF-kappaB \nactivation. Mol Immunol 2009; 46: 2413-2418. \n \n99. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: \nthe good, the bad, and ugly. Am J Physiol 1996; 271: C1424-1437. \n \n100. Detmers PA, Hernandez M, Mudgett J , et al. Deficiency in inducible \nnitric oxide synthase results in reduced atherosclerosis in \napolipoprotein E-deficient mice. J Immunol 2000; 165: 3430-3435. \n \n101. Kanda M, Kodera Y. Molecular mechanisms of peritoneal \ndissemination in gastric cancer. World J Gastroenterol 2016; 22: 6829-\n6840. \n \n102. Nair AS, Nair HB, Lucidi RS , et al. Modeling the early endometriotic \nlesion: mesothelium-endometrial cell co-culture increases endometrial \ninvasion and alters mesothelial and endometrial gene transcription. \nFertil Steril 2008; 90: 1487-1495. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n103. Fassbender A, Overbergh L, Verdrengh E , et al. How can \nmacroscopically normal peritoneum contribute to the pathogenesis of \nendometriosis? Fertil Steril 2011; 96: 697-699. \n \n104. Robinson-Smith TM, Isaacsohn I, Mercer CA , et al. Macrophages \nmediate inflammation-enhanced metastasis of ovarian tumors in mice. \nCancer Res 2007; 67: 5708-5716. \n \n105. Cottone L, Capobianco A, Gualteroni C , et al. Leukocytes recruited by \ntumor-derived HMGB1 sustain peritoneal carcinomatosis. \nOncoimmunology 2016; 5: e1122860. \n \n106. Wu T, Zhang W, Yang G , et al. HMGB1 overexpression as a \nprognostic factor for survival in cancer: a meta-analysis and systematic \nreview. Oncotarget 2016; 7: 50417-50427. \n \n107. Jube S, Rivera ZS, Bianchi ME , et al. Cancer cell secretion of the \nDAMP protein HMGB1 supports progression in malignant \nmesothelioma. Cancer Res 2012; 72: 3290-3301. \n \n108. Cottone L, Capobianco A, Gualteroni C , et al. 5-Fluorouracil causes \nleukocytes attraction in the peritoneal cavity by activating autophagy \nand HMGB1 release in colon carcinoma cells. Int J Cancer 2015; 136: \n1381-1389. \n \n109. Yang H, Rivera Z, Jube S , et al. Programmed necrosis induced by \nasbestos in human mesothelial cells causes high-mobility group box 1 \nprotein release and resultant inflammation. Proc Natl Acad Sci U S A \n2010; 107: 12611-12616. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n110. Qi F, Okimoto G, Jube S , et al. Continuous exposure to chrysotile \nasbestos can cause transformation of human mesothelial cells via \nHMGB1 and TNF-alpha signaling. Am J Pathol 2013; 183: 1654-1666. \n \n111. Napolitano A, Antoine DJ, Pellegrini L , et al. HMGB1 and Its \nHyperacetylated Isoform are Sensitive and Specific Serum Biomarkers \nto Detect Asbestos Exposure and to Identify Mesothelioma Patients. \nClin Cancer Res 2016; 22: 3087-3096. \n \n112. Pellegrini L, Xue J, Larson D , et al. HMGB1 targeting by ethyl pyruvate \nsuppresses malignant phenotype of human mesothelioma. Oncotarget \n2017; 8: 22649-22661. \n \n113. Yang T, Peleli M, Zollbrecht C , et al. Inorganic nitrite attenuates \nNADPH oxidase-derived superoxide generation in activated \nmacrophages via a nitric oxide-dependent mechanism. Free Radic Biol \nMed 2015; 83: 159-166. \n \n114. Li W, Wu K, Zhao E , et al. HMGB1 recruits myeloid derived suppressor \ncells to promote peritoneal dissemination of colon cancer after \nresection. Biochem Biophys Res Commun 2013; 436: 156-161. \n \n115. Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer Immunol \nRes 2017; 5: 3-8. \n \n116. Manfredi AA, Covino C, Rovere-Querini P , et al. Instructive influences \nof phagocytic clearance of dying cells on neutrophil extracellular trap \ngeneration. Clin Exp Immunol 2015; 179: 24-29. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n117. Manfredi AA, Baldini M, Camera M , et al. Anti-TNFalpha agents curb \nplatelet activation in patients with rheumatoid arthritis. Ann Rheum Dis \n2016; 75: 1511-1520 \n. \n118. Incerti E, Tombetti E, Fallanca F , et al. 18F-FDG PET reveals unique \nfeatures of large vessel inflammation in patients with Takayasu's \narteritis. Eur J Nucl Med Mol Imaging 2017; 44: 1109-1118. \n \n119. Qian BZ, Pollard JW. Macrophage diversity enhances tumor \nprogression and metastasis. Cell 2010; 141: 39-51. \n \n120. De Palma M, Naldini L. Angiopoietin-2 TIEs up macrophages in tumor \nangiogenesis. Clin Cancer Res 2011; 17: 5226-5232. \n \n121. De Palma M, Naldini L. Tie2-expressing monocytes (TEMs): novel \ntargets and vehicles of anticancer therapy? Biochimica et biophysica \nacta 2009; 1796: 5-10. \n \n122. Squadrito ML, De Palma M. Macrophage regulation of tumor \nangiogenesis: implications for cancer therapy. Mol Aspects Med 2011; \n32: 123-145. \n123. Du R, Lu KV, Petritsch C , et al. HIF1alpha induces the recruitment of \nbone marrow-derived vascular modulatory cells to regulate tumor \nangiogenesis and invasion. Cancer cell 2008; 13: 206-220. \n \n124. Girling JE, Rogers PA. Regulation of endometrial vascular remodelling: \nrole of the vascular endothelial growth factor family and the \nangiopoietin-TIE signalling system. Reproduction 2009; 138: 883-893. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n125. Mints M, Blomgren B, Palmblad J. Expression of angiopoietins 1, 2 and \ntheir common receptor tie-2 in relation to the size of endothelial lining \ngaps and expression of VEGF and VEGF receptors in idiopathic \nmenorrhagia. Fertil Steril 2010; 94: 701-707. \n \n126. Elsheikh E, Sylven C, Ericzon BG , et al. Cyclic variability of stromal \ncell-derived factor-1 and endothelial progenitor cells during the \nmenstrual cycle. Int J Mol Med 2011; 27: 221-226. \n \n127. Lash GE, Pitman H, Morgan HL , et al. Decidual macrophages: key \nregulators of vascular remodeling in human pregnancy. J Leukoc Biol \n2016; 100: 315-325. \n \n128. McLaren J, Prentice A, Charnock-Jones DS , et al. Vascular endothelial \ngrowth factor is produced by peritoneal fluid macrophages in \nendometriosis and is regulated by ovarian steroids. J Clin Invest 1996; \n98: 482-489. \n \n129. Cakmak H, Guzeloglu-Kayisli O, Kayisli UA , et al. Immune-endocrine \ninteractions in endometriosis. Front Biosci (Elite Ed) 2009; 1: 429-443. \n \n130. Pellegrini C, Gori I, Achtari C , et al. The expression of estrogen \nreceptors as well as GREB1, c-MYC, and cyclin D1, estrogen-\nregulated genes implicated in proliferation, is increased in peritoneal \nendometriosis. Fertil Steril 2012; 98: 1200-1208. \n \n131. Yamaguchi K, Mandai M, Toyokuni S , et al. Contents of endometriotic \ncysts, especially the high concentration of free iron, are a possible \ncause of carcinogenesis in the cysts through the iron-induced \npersistent oxidative stress. Clin Cancer Res 2008; 14: 32-40. \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \n132. Yamaguchi K, Mandai M, Oura T , et al. Identification of an ovarian \nclear cell carcinoma gene signature that reflects inherent disease \nbiology and the carcinogenic processes. Oncogene 2010; 29: 1741-\n1752. \n \n133. Wei JJ, William J, Bulun S. Endometriosis and ovarian cancer: a review \nof clinical, pathologic, and molecular aspects. Int J Gynecol Pathol \n2011; 30: 553-568. \n \n134. Giudice LC, Kao LC. Endometriosis. Lancet 2004; 364: 1789-1799. \n135. Miselis NR, Wu ZJ, Van Rooijen N , et al. Targeting tumor-associated \nmacrophages in an orthotopic murine model of diffuse malignant \nmesothelioma. Mol Cancer Ther 2008; 7: 788-799. \n \n136. Liu G, Ma H, Qiu L , et al. Phenotypic and functional switch of \nmacrophages induced by regulatory CD4+CD25+ T cells in mice. \nImmunol Cell Biol 2011; 89: 130-142. \n \n137. De Palma M, Venneri MA, Galli R , et al. Tie2 identifies a hematopoietic \nlineage of proangiogenic monocytes required for tumor vessel \nformation and a mesenchymal population of pericyte progenitors. \nCancer Cell 2005; 8: 211-226. \n \n138. Gordon S, Martinez FO. Alternative activation of macrophages: \nmechanism and functions. Immunity 2010; 32: 593-604. \n \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nFig\n \nFig\nper\nwhi\nthes\nmes\ncon\nsitu\nFig\ndam\nass\nby i\nUnd\nthes\narch\nunr\nnor\nure legen\nure 1. Ana\nritoneum co\nle the visc\nse two laye\nsothelial ce\nnnective tis\nuated direc\nure 2. Per\nmage. Dam\nsociated mo\ninvading o\nder physio\nse triggers\nhitecture is\nrelenting tis\nrmal tissue\nds \natomy and\nover the ab\nceral layer l\ners is refer\nells is refer\nssue and p\nctly beneath\nritoneal in\nmage-asso\nolecular pa\nrganisms e\nlogical con\ns are elimin\ns restored.\nssue repair\n function a\nd organiza\nbdomen: th\nlines the a\nrred to as t\nrred to as t\neritoneum\nh the abdo\nflammatio\nociated mo\natterns (PA\nelicit an inf\nnditions (A)\nnated, infla\n However,\nr process l\nand ultimat\nation of th\nhe parietal\nbdominal v\nthe periton\nthe periton\n are referre\nominal mus\non fosters\nlecular pat\nAMPs) rele\nflammatory\n), the respo\nammation r\n if the mole\neads to fib\nely leading\ne peritone\nl layer lines\nviscera. Th\nneal cavity.\nneum and c\ned to as th\nsculature.\n homeost\ntterns (DAM\neased by d\ny reaction i\nonse is org\nresolves qu\necular trigg\nbrosis or sc\ng to organ \neum. (A) T\ns the abdo\nhe narrow s\n (B) The la\ncollectively\nhe serosa. \nasis and/o\nMPs) and \nead and dy\nin the perit\nganized an\nuickly and \ngers persis\ncarring, im\nfailure and\nTwo layers \nminal wall,\nspace with\nayer of \ny, the \nThe seros\nor tissue \npathogen-\nying cells a\ntoneal cavi\nnd controlle\nnormal tiss\nst (B), the \npairing \nd death. \nof \n, \nhin \na is \n \nand \nity. \ned, \nsue \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\nFig\nand\n(ligh\nenv\nTie2\nand\nves\nDA\n \nure 3.  Co\nd neoplast\nht brown) o\nvironment; \n2-expressi\nd attach firm\nssels and g\nMP/alarmi\nommon inf\ntic periton\nor cancer c\n(ii) attract \nng macrop\nmly, via int\ngrow, both \nn, HMGB1\nflammator\nneal lesion\ncells (gree\ninflammato\nphages, TE\ntegrins, to \nprocesses\n. \nry themes\nns. To yield\nn) must: (i)\nory phagoc\nEM); (iii) ad\nthe basem\ns being dep\n in the est\nd lesions, e\n) survive th\ncytes (mac\ndhere to th\nment memb\npendent on\ntablishme\nexfoliated \nhe peritone\ncrophages\nhe surface \nbrane; (iv) a\nn the proto\nent of ecto\nendometria\neal \n, Mφ and \nof the sero\nattract nov\notypic \n \nopic \nal  \nosa \nvel \nThis article is protected by copyright. All rights reserved.\n\nAccepted Article\n \nThis article is protected by copyright. All rights reserved.","source_license":"CC0","license_restricted":false}