{"paper_id":"6a9d560c-14d8-4ec6-bcd8-c27ef75558a1","body_text":"Abstract\nPhenotypes viewed as distinctive to cancer are often recapitulated in benign disease and consideration of these diseases can inform our understanding of the cancer microenvironment. Endometriosis is an estrogen-dependent inflammatory disease characterized by the presence of “metastatic” endometrium-like glands and stroma, together with hemosiderin and (often) fibrosis outside the uterine lumen. It is most often diagnosed as a result of pain and/or infertility and results in substantial economic and personal costs. However, in contrast to cancer it is typically not dysplastic and rarely causes death, though it increases the risk of several ovarian cancer subtypes. Like cancers, the disease is angiogenesis-dependent and genetic studies demonstrate that the VEGFR2 signaling axis plays a key role in the disease. In addition, molecular studies demonstrate that the immune/inflammatory milieu of endometriosis lesions is more similar to that of endometriosis-associated ovarian cancers (EAOCs) than it is to eutopic endometrium. This is consistent with the dysregulation of a host of immune/inflammatory cells and cytokines in disease tissue in ways that often resemble dysregulation observed in ovarian cancer. However, in contrast to EAOC, pain is often a key early symptom of endometriosis and can accompany even very small lesions. Another key contrast with cancers is the very limited range of medical treatments available. This is partially driven by the much more limited range of side effects that is acceptable for treatment of a non-life-threatening illness in women of childbearing age, but is also a function of the limited study of endometriosis pathophysiology that has occurred thus far.\nAccess this chapter\nTax calculation will be finalised at checkout\nPurchases are for personal use only\nSimilar content being viewed by others\nReferences\nEskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin N Am. 1997;24(2):235–58.\nMissmer SA, Hankinson SE, et al. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160(8):784–96.\nGiudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–98.\nFuldeore M, Yang H, et al. Healthcare utilization and costs in women diagnosed with endometriosis before and after diagnosis: a longitudinal analysis of claims databases. Fertil Steril. 2015;103(1):163–71.\nSimoens S, Dunselman G, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012;27(5):1292–9.\nOzkan S, Arici A. Advances in treatment options of endometriosis. Gynecol Obstet Investig. 2009;67(2):81–91.\nHornstein MD, Hemmings R, et al. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68(5):860–4.\nParazzini F, Fedele L, et al. Postsurgical medical treatment of advanced endometriosis: results of a randomized clinical trial. Am J Obstet Gynecol. 1994;171(5):1205–7.\nTelimaa S, Puolakka J, et al. Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol. 1987;1(1):13–23.\nCandiani GB, Fedele L, et al. Presacral neurectomy for the treatment of pelvic pain associated with endometriosis: a controlled study. Am J Obstet Gynecol. 1992;167(1):100–3.\nHanahan D, Robert A (2011) Hallmarks of cancer: the next generation. Cell 144.\nSampson JA, Albany NY (1927) Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 14.\nSuryawanshi S, Huang X, et al. (2014) Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res 20.\nWendel JRH, Wang X, et al. (2018) The Endometriotic tumor microenvironment in ovarian cancer. Cancers (Basel) 10.\nAnglesio MS, Papadopoulos N, et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med. 2017;376(19):1835–48.\nMcLennan CE, Rydell AH. Extent of endometrial shedding during normal menstruation. Obstet Gynecol. 1965;26(5):605–21.\nYamaguchi M, Yoshihara K, et al. Three-dimensional understanding of the morphological complexity of the human uterine endometrium. iScience. 2021;24(4):102258.\nTempest N, Jansen M, et al. Histological 3D reconstruction and in vivo lineage tracing of the human endometrium. J Pathol. 2020;251(4):440–51.\nBaerwald AR, Pierson RA. Endometrial development in association with ovarian follicular waves during the menstrual cycle. Ultrasound Obstet Gynecol. 2004;24(4):453–60.\nShafrir AL, Farland LV, et al. Risk for and consequences of endometriosis: a critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol. 2018;51:1–15.\nZondervan KT, Becker CM, et al. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.\nSuda K, Nakaoka H, et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 2018;24(7):1777–89.\nFattori V, Ferraz CR, et al. Neuroimmune communication in infection and pain: friends or foes? Immunol Lett. 2021;229:32–43.\nFolkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.\nFerrara N, Gerber HP, et al. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.\nCarmeliet P, Ferreira V, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380(6573):435–9.\nAzar DT. Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2006;104:264–302.\nJohnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care (New Rochelle). 2014;3(10):647–61.\nCarmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.\nSelvaraj D, Gangadharan V, et al. A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell. 2015;27(6):780–96.\nMarcoval J, Moreno A, et al. Angiogenesis and malignant melanoma. Angiogenesis is related to the development of vertical (tumorigenic) growth phase. J Cutan Pathol. 1997;24(4):212–8.\nSapkota Y, Steinthorsdottir V, et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 2017;8:15539.\nForsythe JA, Jiang BH, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9):4604–13.\nShweiki D, Itin A, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359(6398):843–5.\nPugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–84.\nLohela M, Bry M, et al. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21(2):154–65.\nRoskoski R Jr. VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun. 2008;375(3):287–91.\nKoch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2(7):a006502.\nArtini PG, Ruggiero M, et al. Vascular endothelial growth factor and its soluble receptor in benign and malignant ovarian tumors. Biomed Pharmacother. 2008;62(6):373–7.\nPavlakovic H, Becker J, et al. Soluble VEGFR-2: an anti-lymphangiogenic variant of VEGF receptors. Ann N Y Acad Sci. 2010;1207(Suppl 1):E7–15.\nWu FT, Stefanini MO, et al. A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med. 2010;14(3):528–52.\nKumasawa K, Ikawa M, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci USA. 2011;108(4):1451–5.\nAlbertsen HMCR, Ward K. Endometriosis GWAS Replicate Association Near the Kinase Insert Domain Receptor Gene (KDR); 2017 18 May 2017; Vancouver, CA.\nSteinthorsdottir V, Thorleifsson G, et al. Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nat Commun. 2016;7:12350.\nSalmeron K, Aihara T, et al. IL-1alpha induces angiogenesis in brain endothelial cells in vitro: implications for brain angiogenesis after acute injury. J Neurochem. 2016;136(3):573–80.\nAguilo F, Zhou MM, et al. Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. Cancer Res. 2011;71(16):5365–9.\nTraves PG, Luque A, et al. Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game. Mediat Inflamm. 2012;2012:568783.\nZerrouqi A, Pyrzynska B, et al. P14ARF inhibits human glioblastoma-induced angiogenesis by upregulating the expression of TIMP3. J Clin Invest. 2012;122(4):1283–95.\nBurd CE, Jeck WR, et al. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet. 2010;6(12):e1001233.\nYoshino S, Cilluffo R, et al. Single nucleotide polymorphisms associated with abnormal coronary microvascular function. Coron Artery Dis. 2014;25(4):281–9.\nNanda V, Downing KP, et al. CDKN2B regulates TGFbeta signaling and smooth muscle cell investment of hypoxic neovessels. Circ Res. 2016;118(2):230–40.\nPankov R, Yamada KM. Fibronectin at a glance. J Cell Sci. 2002;115(Pt 20):3861–3.\nKuzontkoski PM, Mulligan-Kehoe MJ, et al. Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels. Oncogene. 2010;29(26):3793–802.\nMartini M, Cenci T, et al. Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis. Cancer. 2013;119(5):1004–12.\nNio-Kobayashi J, Narayanan R, et al. Expression and localization of inhibitor of differentiation (ID) proteins during tissue and vascular remodelling in the human corpus luteum. Mol Hum Reprod. 2013;19(2):82–92.\nPowell JE, Fung JN, et al. Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339. Hum Mol Genet. 2016;25(22):5046–58.\nQadir MI, Parveen A, et al. Cdc42: role in cancer management. Chem Biol Drug Des. 2015;86(4):432–9.\nMa J, Xue Y, et al. Role of activated rac1/cdc42 in mediating endothelial cell proliferation and tumor angiogenesis in breast cancer. PLoS One. 2013;8(6):e66275.\nRogers MS, D'Amato RJ. The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006;312(5):561–74.\nRogers MS, D’Amato RJ (2012) Common polymorphisms in angiogenesis. Cold Spring Harb Perspect Med 2(11).\nLi YZ, Wang LJ, et al. Vascular endothelial growth factor gene polymorphisms contribute to the risk of endometriosis: an updated systematic review and meta-analysis of 14 case-control studies. Genet Mol Res. 2013;12(2):1035–44.\nCardoso JV, Abrao MS, et al. Combined effect of vascular endothelial growth factor and its receptor polymorphisms in endometriosis: a case-control study. Eur J Obstet Gynecol Reprod Biol. 2017;209:25–33.\nHolt VL, Weiss NS. Recommendations for the design of epidemiologic studies of endometriosis. Epidemiology. 2000;11(6):654–9.\nZondervan KT, Cardon LR, et al. What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod. 2002;17(6):1415–23.\nTakehara M, Ueda M, et al. Vascular endothelial growth factor A and C gene expression in endometriosis. Hum Pathol. 2004;35(11):1369–75.\nSong WW, Lu H, et al. Expression of vascular endothelial growth factor C and anti-angiogenesis therapy in endometriosis. Int J Clin Exp Pathol. 2014;7(11):7752–9.\nXu H, Zhang T, et al. Vascular endothelial growth factor C is increased in endometrium and promotes endothelial functions, vascular permeability and angiogenesis and growth of endometriosis. Angiogenesis. 2013;16(3):541–51.\nTan CW, Lee YH, et al. (2014) CD26/DPPIV down-regulation in endometrial stromal cell migration in endometriosis. Fertil Steril 102(1): 167–177 e169.\nBraza-Boils A, Mari-Alexandre J, et al. MicroRNA expression profile in endometriosis: its relation to angiogenesis and fibrinolytic factors. Hum Reprod. 2014;29(5):978–88.\nMeng Q, Sun W, et al. Identification of common mechanisms between endometriosis and ovarian cancer. J Assist Reprod Genet. 2011;28(10):917–23.\nvan den Berg LL, Crane LM, et al. Analysis of biomarker expression in severe endometriosis and determination of possibilities for targeted intraoperative imaging. Int J Gynaecol Obstet. 2013;121(1):35–40.\nDi Carlo C, Bonifacio M, et al. Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium. Fertil Steril. 2009;91(6):2315–23.\nMachado DE, Abrao MS, et al. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril. 2008;90(1):148–55.\nRamon LA, Braza-Boils A, et al. microRNAs expression in endometriosis and their relation to angiogenic factors. Hum Reprod. 2011;26(5):1082–90.\nBourlev V, Volkov N, et al. The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction. 2006;132(3):501–9.\nGilabert-Estelles J, Ramon LA, et al. Expression of angiogenic factors in endometriosis: relationship to fibrinolytic and metalloproteinase systems. Hum Reprod. 2007;22(8):2120–7.\nOliveira VA, Abreu LG, et al. Vascular endothelial growth factor in the plasma, follicular fluid and granulosa cells of women with endometriosis submitted to in vitro fertilization – a pilot study. Gynecol Endocrinol. 2005;20(5):284–8.\nTakehara M, Ueda M, et al. Vascular endothelial growth factor A and C gene expression in endometriosis. Hum Pathol. 2004;35(11):1369–75..\nTan XJ, Lang JH, et al. Expression of vascular endothelial growth factor and thrombospondin-1 mRNA in patients with endometriosis. Fertil Steril. 2002;78(1):148–53.\nZhang L, Xiong W, et al. 17 β-Estradiol promotes vascular endothelial growth factor expression via the Wnt/β-catenin pathway during the pathogenesis of endometriosis. Mol Hum Reprod. 2016;22(7):526–35.\nFujishita A, Hasuo A, et al. Immunohistochemical study of angiogenic factors in endometrium and endometriosis. Gynecol Obstet Investig. 1999;48(Suppl 1):36–44.\nMueller MD, Vigne JL, et al. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA. 2000;97(20):10972–7.\nKupker W. Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update. 1998;4(5):719–23.\nNa YJ, Yang SH, et al. Effects of peritoneal fluid from endometriosis patients on the release of vascular endothelial growth factor by neutrophils and monocytes. Hum Reprod. 2006;21(7):1846–55.\nBraza-Boils A, Gilabert-Estelles J, et al. Peritoneal fluid reduces angiogenesis-related microRNA expression in cell cultures of endometrial and endometriotic tissues from women with endometriosis. PLoS One. 2013;8(4):e62370.\nWang HB, Lang JH, et al. Expression of vascular endothelial growth factor receptors in the ectopic and eutopic endometrium of women with endometriosis. Zhonghua Yi Xue Za Zhi. 2005;85(22):1555–9.\nMartin DC. Laparoscopic appearance of endometriosis. 2nd ed. Resurge Press; 2017.\nNisolle M, Casanas-Roux F, et al. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59(3):681–4.\nKhan KN, Masuzaki H, et al. Higher activity by opaque endometriotic lesions than nonopaque lesions. Acta Obstet Gynecol Scand. 2004;83(4):375–82.\nDonnez J, Smoes P, et al. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 1998;13(6):1686–90.\nZhao L, Gu C, et al. Identification of global transcriptome abnormalities and potential biomarkers in eutopic endometria of women with endometriosis: A preliminary study. Biomed Rep. 2017;6(6):654–62.\nPrint C, Valtola R, et al. Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome. Hum Reprod. 2004;19(10):2356–66.\nSharkey AM, Day K, et al. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab. 2000;85(1):402–9.\nVodolazkaia A, El-Aalamat Y, et al. Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis. Hum Reprod. 2012;27(9):2698–711.\nVodolazkaia A, Yesilyurt BT, et al. Vascular endothelial growth factor pathway in endometriosis: genetic variants and plasma biomarkers. Fertil Steril. 2016;105(4):988–96.\nKalu E, Sumar N, et al. Cytokine profiles in serum and peritoneal fluid from infertile women with and without endometriosis. J Obstet Gynaecol Res. 2007;33(4):490–5.\nKianpour M, Nematbakhsh M, et al. Serum and peritoneal fluid levels of vascular endothelial growth factor in women with endometriosis. Int J Fertil Steril. 2013;7(2):96–9.\nPupo-Nogueira A, de Oliveira RM, et al. Vascular endothelial growth factor concentrations in the serum and peritoneal fluid of women with endometriosis. Int J Gynaecol Obstet. 2007;99(1):33–7.\nGagne D, Page M, et al. Levels of vascular endothelial growth factor (VEGF) in serum of patients with endometriosis. Hum Reprod. 2003;18(8):1674–80.\nKim JG, Kim JY, et al. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008;89(1):243–5.\nOthman Eel D, Hornung D, et al. Serum cytokines as biomarkers for nonsurgical prediction of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;137(2):240–6.\nGogacz M, Gałczyński K, et al. Concentration of selected angiogenic factors in serum and peritoneal fluid of women with endometriosis. Polish Gynaecol. 2015;86(3):188–92.\nBourlev V, Iljasova N, et al. Signs of reduced angiogenic activity after surgical removal of deeply infiltrating endometriosis. Fertil Steril. 2010;94(1):52–7.\nWang H, Gorpudolo N, et al. Elevated vascular endothelia growth factor-A in the serum and peritoneal fluid of patients with endometriosis. J Huazhong Univ Sci Technolog Med Sci. 2009;29(5):637–41.\nXavier P, Belo L, et al. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Arch Gynecol Obstet. 2006;273(4):227–31.\nKopuz A, Kurt S, et al. Relation of peritoneal fluid and serum vascular endothelial growth factor levels to endometriosis stage. Clin Exp Obstet Gynecol. 2014;41(5):547–50.\nMohamed ML, El Behery MM, et al. Comparative study between VEGF-A and CA-125 in diagnosis and follow-up of advanced endometriosis after conservative laparoscopic surgery. Arch Gynecol Obstet. 2013;287(1):77–82.\nKhan KN, Masuzaki H, et al. Immunoexpression of hepatocyte growth factor and c-Met receptor in the eutopic endometrium predicts the activity of ectopic endometrium. Fertil Steril. 2003;79(1):173–81.\nFasciani A, D’Ambrogio G, et al. (2001) Vascular endothelial growth factor and interleukin-8 in ovarian cystic pathology. Fertil Steril 75.\nRakhila H, Al-Akoum M, et al. Augmented angiogenic factors expression via FP signaling pathways in peritoneal endometriosis. J Clin Endocrinol Metabol. 2016;101(12):4752–63.\nYerlikaya G, Balendran S, et al. Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis. Eur J Obst Gynecol Reprod Biol. 2016;204:88–98.\nLin SC, Lee HC, et al. Targeting anthrax toxin receptor 2 ameliorates endometriosis progression. Theranostics. 2019;9(3):620–32.\nRogers MS, Christensen KA, et al. Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth. Cancer Res. 2007;67(20):9980–5.\nCryan LM, Bazinet L, et al. 1,2,3,4,6-Penta-O-galloyl-beta-d-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2. J Med Chem. 2013;56(5):1940–5.\nVallve-Juanico J, Houshdaran S, et al. (2019) The endometrial immune environment of women with endometriosis. Hum Reprod Update 25.\nRiccio LDGC, Santulli P, et al. (2018) Immunology of endometriosis. Best Pract Res Clin Obstet Gynaecol 50.\nSymons LK, Miller JE, et al. (2018) The immunopathophysiology of endometriosis. Trends Mol Med 24.\nGonzález-Foruria I, Santulli P, et al. (2015) Soluble ligands for the NKG2D receptor are released during endometriosis and correlate with disease severity. PLoS One 10.\nShen P, Fillatreau S (2015) Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol 15.\nLang GA, Yeaman GR. Autoantibodies in endometriosis sera recognize a Thomsen-Friedenreich-like carbohydrate antigen. J Autoimmun. 2001;16(2):151–61.\nBeste MT, Pfaffle-Doyle N, et al. Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Sci Transl Med. 2014;6(222):222ra216.\nAslan C, Ak H, et al. Overexpression of complement C5 in endometriosis. Clin Biochem. 2014;47(6):496–8.\nDarai E, Detchev R, et al. (2003) Serum and cyst fluid levels of interleukin (IL) -6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Hum Reprod 18.\nSchroder W, Ruppert C, et al. (1994) Concomitant measurements of interleukin-6 (IL-6) in serum and peritoneal fluid of patients with benign and malignant ovarian tumors. Eur J Obstet Gynecol Reprod Biol 56.\nSipak-Szmigiel O, Wlodarski P, et al. (2017) Serum and peritoneal fluid concentrations of soluble human leukocyte antigen, tumor necrosis factor alpha and interleukin 10 in patients with selected ovarian pathologies. J Ovarian Res 10.\nMach P, Blecharz P, et al. (2010) Differences in the soluble HLA-G blood serum concentration levels in patients with ovarian cancer and ovarian and deep endometriosis. Am J Reprod Immunol 63.\nLiu L, Wang L, et al. The role of HLA-G in tumor escape: manipulating the phenotype and function of immune cells. Front Oncol. 2020;10:597468.\nFuruya M, Suyama T, et al. (2007) Up-regulation of CXC chemokines and their receptors: implications for proinflammatory microenvironments of ovarian carcinomas and endometriosis. Hum Pathol 38.\nFuruya M, Yoneyama T, et al. (2011) Differential expression patterns of CXCR3 variants and corresponding CXC chemokines in clear cell ovarian cancers and endometriosis. Gynecol Oncol 122.\nFuruya M, Tanaka R, et al. (2012) Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis. Cancer Biol Ther 13.\nFedele L, Parazzini F, et al. Stage and localization of pelvic endometriosis and pain. Fertil Steril. 1990;53(1):155–8.\nAdamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol. 1990;162(2):568–9.\nHe W, Liu X, et al. Generalized hyperalgesia in women with endometriosis and its resolution following a successful surgery. Reprod Sci. 2010;17(12):1099–111.\nBajaj P, Bajaj P, et al. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003;4(7):372–80.\nMorotti M, Vincent K, et al. Mechanisms of pain in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2017;209:8–13.\nMowers EL, Lim CS, et al. Prevalence of endometriosis during abdominal or laparoscopic hysterectomy for chronic pelvic pain. Obstet Gynecol. 2016;127(6):1045–53.\nZhang G, Dmitrieva N, et al. Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat. Am J Physiol Regul Integr Comp Physiol. 2008;294(1):R162–71.\nBerkley KJ, Dmitrieva N, et al. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci. 2004;101(30):11094–8.\nRocha MG, e Silva JC, et al. TRPV1 expression on peritoneal endometriosis foci is associated with chronic pelvic pain. Reprod Sci. 2011;18(6):511–5.\nPoli-Neto OB, Filho AA, et al. Increased capsaicin receptor TRPV1 in the peritoneum of women with chronic pelvic pain. Clin J Pain. 2009;25(3):218–22.\nTokushige N, Markham R, et al. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21(11):3001–7.\nTokushige N, Markham R, et al. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod. 2006;21(3):782–7.\nGarcía-Manero M, Alcazar JL, et al. Vascular endothelial growth factor (VEGF) and ovarian endometriosis: correlation between VEGF serum levels, VEGF cellular expression, and pelvic pain. Fertil Steril. 2007;88(2):513–5.\nGarcia-Manero M, Santana GT, et al. Relationship between microvascular density and expression of vascular endothelial growth factor in patients with ovarian endometriosis. J Womens Health (Larchmt). 2008;17(5):777–82.\nSerhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128(7):2657–69.\nZondervan KT, Becker CM, et al. Endometriosis. N Engl J Med. 2020;382(13):1244–56.\nShih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006;28(11):1779–802.\nCook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010;60(4):222–43.\nChang J-H, Garg NK, et al. Corneal neovascularization: an anti-VEGF therapy review. Surv Ophthalmol. 2012;57(5):415–29.\nCho SH, Oh YJ, et al. Evaluation of serum and urinary angiogenic factors in patients with endometriosis. Am J Reprod Immunol. 2007;58(6):497–504.\nHull ML, Charnock-Jones DS, et al. Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab. 2003;88(6):2889–99.\nMatalliotakis IM, Goumenou AG, et al. Serum concentrations of growth factors in women with and without endometriosis: the action of anti-endometriosis medicines. Int Immunopharmacol. 2003;3(1):81–9.\nBilotas M, Meresman G, et al. Effect of vascular endothelial growth factor and interleukin-1beta on apoptosis in endometrial cell cultures from patients with endometriosis and controls. J Reprod Immunol. 2010;84(2):193–8.\nTesone M, Bilotas M, et al. The role of GnRH analogues in endometriosis-associated apoptosis and angiogenesis. Gynecol Obstet Investig. 2008;66(Suppl 1):10–8.\nHuang F, Wang H, et al. Effect of GnRH-II on the ESC proliferation, apoptosis and VEGF secretion in patients with endometriosis in vitro. Int J Clin Exp Pathol. 2013;6(11):2487–96.\nMeresman GF, Bilotas MA, et al. Effect of GnRH analogues on apoptosis and release of interleukin-1beta and vascular endothelial growth factor in endometrial cell cultures from patients with endometriosis. Hum Reprod. 2003;18(9):1767–71.\nDogan E, Saygili U, et al. Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril. 2004;82(Suppl 3):1115–20.\nLiu S, Xin X, et al. Efficacy of anti-VEGF/VEGFR agents on animal models of endometriosis: a systematic review and meta-analysis. PLoS One. 2016;11(11):e0166658.\nOzer H, Boztosun A, et al. The efficacy of bevacizumab, sorafenib, and retinoic acid on rat endometriosis model. Reprod Sci. 2013;20(1):26–32.\nSoysal D, Kızıldağ S, et al. (2014) A novel angiogenesis inhibitor bevacizumab induces apoptosis in the rat endometriosis model. Balkan J Med Genet 17(2).\nRicci AG, Olivares CN, et al. Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis. Reprod Sci. 2011;18(7):614–22.\nSevket O, Sevket A, et al. The effects of ranibizumab on surgically induced endometriosis in a rat model: a preliminary study. Reprod Sci. 2013;20(10):1224–9.\nLaschke MW, Elitzsch A, et al. Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod. 2006;21(1):262–8.\nYildiz C, Kacan T, et al. Effects of pazopanib, sunitinib, and sorafenib, anti-VEGF agents, on the growth of experimental endometriosis in rats. Reprod Sci. 2015;22(11):1445–51.\nAbbas MA, Disi AM, et al. Sunitinib as an anti-endometriotic agent. Eur J Pharm Sci. 2013;49(4):732–6.\nPala HG, Erbas O, et al. The effects of sunitinib on endometriosis. J Obstet Gynaecol. 2015;35(2):183–7.\nFallon EM, Nehra D, et al. Sunitinib reduces recurrent pelvic adhesions in a rabbit model. J Surg Res. 2012;178(2):860–5.\nMeisel JA, Fallon EM, et al. Sunitinib inhibits postoperative adhesions in a rabbit model. Surgery. 2011;150(1):32–8.\nKim S, Lee S, et al. Inhibition of intra-abdominal adhesion formation with the angiogenesis inhibitor sunitinib. J Surg Res. 2008;149(1):115–9.\nMoggio A, Pittatore G, et al. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6):1521–1530 e1522.\nLeconte M, Santulli P, et al. Inhibition of MAPK and VEGFR by sorafenib controls the progression of endometriosis. Reprod Sci. 2015;22(9):1171–80.\nMir O, Ropert S, et al. Clinical activity of sunitinib and regorafenib in endometriosis. Mayo Clin Proc. 2019;94(12):2591–3.\nBasu S, Nagy JA, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 2001;7(5):569–74.\nNovella-Maestre E, Carda C, et al. Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium: a novel molecular target for endometriosis therapy. Biol Reprod. 2010;83(5):866–73.\nDelgado-Rosas F, Gomez R, et al. The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis. Reproduction. 2011;142(5):745–55.\nNovella-Maestre E, Carda C, et al. Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis. Hum Reprod. 2009;24(5):1025–35.\nGomez R, Abad A, et al. Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia. Fertil Steril. 2011;95(3):882–888 e881.\nNakamura DS, Edwards AK, et al. Thrombospondin-1 mimetic peptide ABT-898 affects neovascularization and survival of human endometriotic lesions in a mouse model. Am J Pathol. 2012;181(2):570–82.\nNakamura DS, Edwards AK, et al. Compatibility of a novel thrombospondin-1 analog with fertility and pregnancy in a xenograft mouse model of endometriosis. PLoS One. 2015;10(3):e0121545.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEditor information\nEditors and Affiliations\nRights and permissions\nCopyright information\n© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG\nAbout this chapter\nCite this chapter\nRogers, M.S. (2022). The Role of the Microenvironment in Endometriosis: Parallels and Distinctions to Cancer. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_28\nDownload citation\nDOI: https://doi.org/10.1007/978-3-030-98950-7_28\nPublished:\nPublisher Name: Springer, Cham\nPrint ISBN: 978-3-030-98949-1\nOnline ISBN: 978-3-030-98950-7\neBook Packages: MedicineMedicine (R0)","source_license":"CC0","license_restricted":false}