The effects of hedgehog ligand neutralising antibody 5E1 in a mouse model of endometriosis
Tóm tắt
Endometriosis is a common and painful condition characterised by the formation of endometrial lesions within the peritoneal cavity. Previous studies have suggested a role for hedgehog signalling in the pathogenesis of endometriosis. We investigated the role of hedgehog signalling in the establishment of endometriosis lesions using 5E1, a hedgehog ligand neutralising antibody, and a mouse model of endometriosis. To mimic the initiation of endometriosis by retrograde menstruation, which is believed to occur in humans, donor mice underwent an artificial menstruation protocol. Fragments of menstrual endometrium were injected into the peritoneal cavity of estrogen primed recipients. Recipients received twice weekly injections of 5E1 or an isotype matched control antibody for three weeks. Lesions were collected and analysed for markers of epithelium, proliferation and apoptosis by immunofluorescence microscopy. Treatment with 5E1 reduced the number of lesions found on the mesentery. No significant changes were found in the size of lesions, abundance of endometrial epithelial cells, proliferation or apoptosis.
Tài liệu tham khảo
Sampson JA. Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. Am J Pathol. 1927;3(2):93–110.
Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99.
Beste MT, PfaffleDoyle N, Prentice EA, Morris SN, Lauffenburger DA, Isaacson KB, et al. Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation. Sci Transl Med. 2014;6(222):222ra16.
Klemmt PAB, Carver JG, Koninckx P, McVeigh EJ, Mardon HJ. Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression. Hum Reprod. 2007;22(12):3139–47.
Feng Y-Z, Shiozawa T, Miyamoto T, Kashima H, Kurai M, Suzuki A, et al. Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells. Clin Cancer Res. 2007;13(5):1389–98.
He Y, Guo Q, Cheng Y, Qu Y, Sun L, Kong C, et al. Abnormal activation of the sonic hedgehog signaling pathway in endometriosis and its diagnostic potency. Fertil Steril. 2018;110(1):128–136.e2.
Heard ME, Simmons CD, Simmen FA, Simmen RCM. Krüppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis. Endocrinology. 2014;155(4):1532–46.
Park SR, Kim SR, Park CH, Lim S, Ha SY, Hong IS, et al. Sonic hedgehog, a novel endogenous damage signal, activates multiple beneficial functions of human endometrial stem cells. Mol Ther. 2020;28(2):452–65.
McKinnon BD, Kocbek V, Nirgianakis K, Bersinger NA, Mueller MD. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. Hum Reprod Update. 2016;22(3):382–403.
Yotova IY, Quan P, Leditznig N, Beer U, Wenzl R, Tschugguel W. Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis. Hum Reprod. 2011;26(4):885–97.
Velarde MC, Aghajanova L, Nezhat CR, Giudice LC. Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fibroblasts of women with endometriosis reduces 3′,5′-cyclic adenosine 5′-monophosphate inhibition of cyclin D1. Endocrinology. 2009;150(10):4701–12.
Ngô C, Nicco C, Leconte M, Chéreau C, Arkwright S, Vacher-Lavenu MC, et al. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J Pathol. 2010;222(2):148–57.
Cinar O, Seval Y, Uz YH, Cakmak H, Ulukus M, Kayisli UA, et al. Differential regulation of Akt phosphorylation in endometriosis. Reprod Biomed Online. 2009;19(6):864–71.
Zanatta A, Rocha AM, Carvalho FM, Pereira RMA, Taylor HS, Motta ELA, et al. The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: A review. J Assist Reprod Genet. 2010;27(12):701–10.
Dimitrov JD. Harnessing the therapeutic potential of ‘Rogue’ antibodies. Trends Pharmacol Sci. 2020;41:409–17.
Beachy PA, Hymowitz SG, Lazarus RA, Leahy DJ, Siebold C. Interactions between hedgehog proteins and their binding partners come into view. Genes Dev. 2010;24:2001–122.
Cucchi D, Occhione MA, Gulino A, De Smaele E. Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma. J Exp Pharmacol. 2012;4:173–85.
Greaves E, Cousins FL, Murray A, Esnal-Zufiaurre A, Fassbender A, Horne AW, et al. A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. Am J Pathol. 2014;184(7):1930–9.
Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009;28:3513.
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82.
Dahmane N, Sánchez P, Gitton Y, Palma V, Sun T, Beyna M, et al. The Sonic hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development. 2001;128(24):5201–12.
Thayer SP, Di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.
Ruiz I, Altaba A, Stecca B, Sánchez P. Hedgehog-Gli signaling in brain tumors: Stem cells and paradevelopmental programs in cancer. Cancer Lett. 2004;204(2):145–57.
Wang LH, La CY, Hua XY, Shin YK, Song YJ, Youn SJ, et al. Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions. Mod Pathol. 2006;19(5):675–83.
Liu H, Zhang W, Wang L, Zhang Z, Xiong W, Zhang L, et al. GLI1 is increased in ovarian endometriosis and regulates migration, invasion and proliferation of human endometrial stromal cells in endometriosis. Ann Transl Med. 2019;7(22):663–663.
Hull ML, Escareno CR, Godsland JM, Doig JR, Johnson CM, Phillips SC, et al. Endometrial-peritoneal interactions during endometriotic lesion establishment. Am J Pathol. 2008;173(3):700–15.
Nakajima T, Iguchi T, Sato T. Hedgehog signaling plays roles in epithelial cell proliferation in neonatal mouse uterus and vagina. Cell Tissue Res. 2012;348(1):239–47.
Heard ME, Velarde MC, Giudice LC, Simmen FA, Simmen RCM. Krüppel-like factor 13 deficiency in uterine endometrial cells contributes to defective steroid hormone receptor signaling but not lesion establishment in a mouse model of endometriosis. Biol Reprod. 2015;92(6):140.