Endometriosis Leads to an Increased Trefoil Factor 3 Concentration in the Peritoneal Cavity but Does Not Alter Systemic Levels

This study analyzed whether trefoil factor 3 (TFF3) is locally elevated and correlated with common biomarkers and inflammatory processes in endometriosis. Peritoneal fluid (PF) was obtained from 50 women and serum from 124 women with or without endometriosis. Experimental endometriosis was induced in female C57BL/6 mice by syngeneic transplantation of uterine tissue to the abdominal wall. Levels of TFF3 in PF of women with endometriosis were significantly increased (P <.05) and correlated with local levels of known biomarkers for endometriosis: cancer antigen (CA) 125, CA-19–9, interleukin 8, monocyte chemotactic protein 1, and matrix metalloproteinase 7. Serum levels of TFF3 in women were significantly influenced by the menstrual cycle but were independent from disease state. In mice, local TFF3 levels were significantly elevated in early endometriosis (up to 4 weeks after transplantation, P <.001) and corresponded to increases in spleen weight as marker for systemic inflammation. This study provides the first evidence that TFF3 is locally elevated in the peritoneal cavity in endometriosis and might play a role in disease pathogenesis and its associated inflammatory processes. Furthermore, the results show that TFF3 is regulated through the menstrual cycle. With respect to animal models, syngeneic mouse model does reflect local TFF3 upregulation in the peritoneal cavity affected by endometriosis. Similar content being viewed by others

May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010;16(6):651–674. Luisi S, Pinzauti S, Regini C, Petraglia F. Serum markers for the noninvasive diagnosis of endometriosis. Womens Health. 2015;11(5):603–610. Taupin D, Podolsky DK. Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol. 2003;4(9):721–732. Wong WM, Poulsom R, Wright NA. Trefoil peptides. Gut. 1999;44(6):890–895. Liu D, el-Hariry I, Karayiannakis AJ, et al. Phosphorylation of beta-catenin and epidermal growth factor receptor by intestinal trefoil factor. Lab Invest. 1997;77(6):557–563. McKenzie C, Marchbank T, Playford RJ, Otto W, Thim L, Parsons ME. Pancreatic spasmolytic polypeptide protects the gastric mucosa but does not inhibit acid secretion or motility. Am J Physiol. 1997;273(1 pt 1):G112–G117. Taupin D, Wu DC, Jeon WK, Devaney K, Wang TC, Podolsky DK. The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation. J Clin Invest. 1999;103(9):R31–R38. Goke MN, Cook JR, Kunert KS, Fini ME, Gipson IK, Podolsky DK. Trefoil peptides promote restitution of wounded corneal epithelial cells. Exp Cell Res. 2001;264(2):337–344. Kjellev S. The trefoil factor family—small peptides with multiple functionalities. Cell Mol Life Sci. 2009;66(8):1350–1369. Dignass A, Lynch-Devaney K, Kindon H, Thim L, Podolsky DK. Trefoil peptides promote epithelial migration through a transforming growth factor beta-independent pathway. J Clin Invest. 1994;94(1):376–383. Taupin DR, Kinoshita K, Podolsky DK. Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. Proc Natl Acad Sci U S A. 2000;97(2):799–804. Emami S, Le Floch N, Bruyneel E, et al. Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial cells. FASEB J. 2001;15(2):351–361. Cook GA, Familari M, Thim L, Giraud AS. The trefoil peptides TFF2 and TFF3 are expressed in rat lymphoid tissues and participate in the immune response. FEBS Lett. 1999;456(1):155–159. Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 1996;274(5285):262–265. Wiede A, Jagla W, Welte T, Kohnlein T, Busk H, Hoffmann W. Localization of TFF3, a new mucus-associated peptide of the human respiratory tract. Am J Respir Crit Care Med. 1999; 159(4 pt 1):1330–1335. Jagla W, Wiede A, Hinz M, et al. Secretion of TFF-peptides by human salivary glands. Cell Tissue Res. 1999;298(1):161–166. Langer G, Jagla W, Behrens-Baumann W, Walter S, Hoffmann W. Secretory peptides TFF1 and TFF3 synthesized in human conjunctival goblet cells. Invest Ophthalmol Vis Sci. 1999;40(10):2220–2224. Madsen J, Nielsen O, Tornoe I, Thim L, Holmskov U. Tissue localization of human trefoil factors 1, 2, and 3. J Histochem Cytochem. 2007;55(5):505–513. Thim L, Madsen F, Poulsen SS. Effect of trefoil factors on the viscoelastic properties of mucus gels. Eur J Clin Invest. 2002;32(7):519–527. May FE, Westley BR. Expression of human intestinal trefoil factor in malignant cells and its regulation by oestrogen in breast cancer cells. J Pathol. 1997;182(4):404–413. Pichon MF, Milgrom E. Clinical significance of the estrogen regulated pS2 protein in mammary tumors. Crit Rev Oncol Hematol. 1993;15(1):13–21. Du TY, Luo HM, Qin HC, et al. Circulating serum trefoil factor 3 (TFF3) is dramatically increased in chronic kidney disease. PloS One. 2013;8(11):e80271. Srivastava S, Kedia S, Kumar S, et al. Serum human trefoil factor 3 is a biomarker for mucosal healing in ulcerative colitis patients with minimal disease activity. J Crohns Colitis. 2015;9(7):575–579. Bignotti E, Ravaggi A, Tassi RA, et al. Trefoil factor 3: a novel serum marker identified by gene expression profiling in highgrade endometrial carcinomas. Br J Cancer. 2008;99(5):768–773. Mhawech-Fauceglia P, Wang D, Samrao D, Liu S, DuPont NC, Pejovic T. Trefoil factor family 3 (TFF3) expression and its interaction with estrogen receptor (ER) in endometrial adenocarci-noma. Gynecol Oncol. 2013;130(1):174–180. Wiede A, Hinz M, Canzler E, Franke K, Quednow C, Hoffmann W. Synthesis and localization of the mucin-associated TFF-peptides in the human uterus. Cell Tissue Res. 2001;303(1):109–115. Revised American Fertility Society classification of endometriosis. Fertil Steril. 1985;43(3):351–352. Wang F, Flanagan J, Su N, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012;14(1):22–29. Laschke MW, Korbel C, Rudzitis-Auth J, et al. High-resolution ultrasound imaging: a novel technique for the noninvasive in vivo analysis of endometriotic lesion and cyst formation in small animal models. Am J Pathol. 2010;176(2):585–593. Matalliotakis IM, Goumenou AG, Mulayim N, Karkavitsas N, Koumantakis EE. High concentrations of the CA-125, CA 19–9 and CA 15–3 in the peritoneal fluid between patients with and without endometriosis. Arch Gynecol Obstet. 2005;271(1):40–45. Muyldermans M, Cornillie FJ, Koninckx PR. CA125 and endo-metriosis. Hum Reprod Update. 1995;1(2):173–187. Bersinger NA, Dechaud H, McKinnon B, Mueller MD. Analysis of cytokines in the peritoneal fluid of endometriosis patients as a function of the menstrual cycle stage using the Bio-Plex(R) platform. Arch Physiol Biochem. 2012;118(4):210–218. Akoum A, Lemay A, McColl S, Turcot-Lemay L, Maheux R. Elevated concentration and biologic activity of monocyte chemo-tactic protein-1 in the peritoneal fluid of patients with endome-triosis. Fertil Steril. 1996;66(1):17–23. Jolicoeur C, Boutouil M, Drouin R, Paradis I, Lemay A, Akoum A. Increased expression of monocyte chemotactic protein-1 in the endometrium of women with endometriosis. Am J Pathol. 1998;152(1):125–133. Rodrigues S, Nguyen QD, Faivre S, et al. Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygen-ase- and thromboxane A2 receptor- dependent signaling pathways. FASEB J. 2001;15(9):1517–1528. Rodrigues S, Van Aken E, Van Bocxlaer S, et al. Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. FASEB J. 2003;17(1):7–16. Tan XD, Chen YH, Liu QP, Gonzalez-Crussi F, Liu XL. Prosta-noids mediate the protective effect of trefoil factor 3 in oxidant-induced intestinal epithelial cell injury: role of cyclooxygenase-2. J Cell Sci. 2000;113(pt 12):2149–2155. McComb J, Gould T, Chlipala E, et al. Antiarthritic activity of soluble tumor necrosis factor receptor type I forms in adjuvant arthritis: correlation of plasma levels with efficacy. J Rheumatol. 1999;26(6):1347–1351. Siegmund B, Rieder F, Albrich S, et al. Adenosine kinase inhibitor GP515 improves experimental colitis in mice. J Pharmacol Exp Ther. 2001;296(1):99–105. Samson MH, Vestergaard EM, Milman N, Poulsen SS, Nexo E. Circulating serum trefoil factors increase dramatically during pregnancy. Scand J Clin Lab Invest. 2008;68(5):369–374. Evans J, Salamonsen LA. Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord. 2012;13(4):277–288. Markee JE. Menstruation in intraocular endometrial transplants in the Rhesus monkey. Am J Obstet Gynecol. 1978;131(5):558–559. Furuta GT, Turner JR, Taylor CT, et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med. 2001;193(9):1027–1034. Hernandez C, Santamatilde E, McCreath KJ, et al. Induction of trefoil factor (TFF)1, TFF2 and TFF3 by hypoxia is mediated by hypoxia inducible factor-1: implications for gastric mucosal healing. Br J Pharmacol. 2009;156(2):262–272. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Henze, D., Doecke, WD., Hornung, D. et al. Endometriosis Leads to an Increased Trefoil Factor 3 Concentration in the Peritoneal Cavity but Does Not Alter Systemic Levels. Reprod. Sci. 24, 258–267 (2017). https://doi.org/10.1177/1933719116653676 Published: Issue date: DOI: https://doi.org/10.1177/1933719116653676