Virchows Archiv

, Volume 461, Issue 5, pp 589–599

Survivin, MMP-2, MT1-MMP, and TIMP-2: their impact on survival, implantation, and proliferation of endometriotic tissues

  • Ambrogio P. Londero
  • Angelo Calcagno
  • Tiziana Grassi
  • Stefania Marzinotto
  • Maria Orsaria
  • Carlo Alberto Beltrami
  • Diego Marchesoni
  • Laura Mariuzzi
Original Article


In order to study survivin, matrix metalloproteinases (MMP-2), membranous type 1 matrix metalloproteinase (MT1-MMP), and tissue inhibitor metalloproteinase-2 (TIMP-2) expression immunohistochemically in endometriotic tissues and normal endometrium, our retrospective study considered 194 patients affected by endometriosis and 71 patients with normal endometrium. Tissue microarrays were created from paraffin-embedded blocks; immunohistochemistry was used to assess protein expression. In endometriotic tissues, survivin was expressed at a higher level than in normal endometrium; its glandular expression level was higher in non-ovarian than in ovarian endometriotic tissues and lower in stromal components. Endometrial tissues from women without endometriosis and endometriotic tissues had different matrix metalloproteinase expression profiles. MMP-2 and MT1-MMP correlated with TIMP-2 in endometriotic tissues. Furthermore, in endometriotic tissues, expression of survivin, aurora B kinase, and Ki-67 showed a significant positive correlation, which indicates a role in cellular proliferation that could be closely linked to its anti-apoptotic activity in endometriosis development. Our results imply a role for matrix metalloproteinases in endometriosis invasiveness; correlation of their expression with that of TIMP-2 underscores its possible key regulatory role.


Endometriosis Survivin Matrix metalloproteinase-2 Membranous type 1 matrix metalloproteinase Tissue inhibitor metalloproteinase-2 Tissue microarrays 



Aurora B kinase


Adenomatous polyposis coli


American Society of Reproductive Medicine


Endometriotic tissue


Inhibitor of apoptosis protein


Interquartile range


Matrix metalloproteinase-2


Matrix metalloproteinase


Membranous type 1 matrix metalloproteinase


Progesterone receptor


Tissue inhibitor metalloproteinase-2


Tissue microarray

Supplementary material

428_2012_1301_MOESM1_ESM.pdf (215 kb)
ESM 1(PDF 215 kb)


  1. 1.
    Leyendecker G, Kunz G, Noe M, Herbertz M, Mall G (1998) Endometriosis: a dysfunction and disease of the archimetra. Hum Reprod Update 4:752–762PubMedCrossRefGoogle Scholar
  2. 2.
    Fujino K, Ueda M, Takehara M et al (2006) Transcriptional expression of survivin and its splice variants in endometriosis. Mol Hum Reprod 12:383–388. doi:10.1093/molehr/gal042 PubMedCrossRefGoogle Scholar
  3. 3.
    Fauvet R, Poncelet C, Hugol D, Lavaur A, Feldmann G, Daraï E (2003) Expression of apoptosis-related proteins in endometriomas and benign and malignant ovarian tumours. Virchows Arch 443:38–43. doi:10.1007/s00428-003-0813-3 PubMedCrossRefGoogle Scholar
  4. 4.
    Ueda M, Yamashita Y, Takehara M et al (2002) Survivin gene expression in endometriosis. J Clin Endocrinol Metab 87:3452–3459PubMedCrossRefGoogle Scholar
  5. 5.
    Imai A, Takagi A, Tamaya T (2000) Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro. Am J Obstet Gynecol 182:1142–1146PubMedCrossRefGoogle Scholar
  6. 6.
    Gebel HM, Braun DP, Tambur A, Frame D, Rana N, Dmowski WP (1998) Spontaneous apoptosis of endometrial tissue is impaired in women with endometriosis. Fertil Steril 69:1042–1047PubMedCrossRefGoogle Scholar
  7. 7.
    Ai Z, Yin L, Zhou X, Zhu Y, Zhu D, Yu Y, Feng Y (2006) Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. Cancer 107:746–756. doi:10.1002/cncr.22044 PubMedCrossRefGoogle Scholar
  8. 8.
    Kelly AE, Ghenoiu C, Xue JZ, Zierhut C, Kimura H, Funabiki H (2010) Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. Science 330:235–239. doi:10.1126/science.1189505 PubMedCrossRefGoogle Scholar
  9. 9.
    Musacchio A (2010) Molecular biology. Surfing chromosomes (and Survivin). Science 330:183–184, doi:10.1126/science.1197261.Google Scholar
  10. 10.
    Chu Y, Yao PY, Wang W et al (2010) Aurora B kinase activation requires survivin priming phosphorylation by PLK1. J Mol Cell Biol. doi:10.1093/jmcb/mjq037
  11. 11.
    Chung HW, Lee JY, Moon HS, Hur SE, Park MH, Wen Y, Polan ML (2002) Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil Steril 78:787–795PubMedCrossRefGoogle Scholar
  12. 12.
    Will H, Atkinson SJ, Butler GS, Smith B, Murphy G (1996) The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. J Biol Chem 271:17119–17123PubMedCrossRefGoogle Scholar
  13. 13.
    Zucker S, Drews M, Conner C et al (1998) Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J Biol Chem 273:1216–1222PubMedCrossRefGoogle Scholar
  14. 14.
    Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI (1995) Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 270:5331–5338PubMedCrossRefGoogle Scholar
  15. 15.
    Murphy G (2011) Tissue inhibitors of metalloproteinases. Genome Biol 12:233. doi:10.1186/gb-2011-12-11-233 PubMedCrossRefGoogle Scholar
  16. 16.
    Kokorine I, Marbaix E, Henriet P, Okada Y, Donnez J, Eeckhout Y, Courtoy PJ (1996) Focal cellular origin and regulation of interstitial collagenase (matrix metalloproteinase-1) are related to menstrual breakdown in the human endometrium. J Cell Sci 109(Pt 8):2151–2160PubMedGoogle Scholar
  17. 17.
    Osteen KG, Keller NR, Feltus FA, Melner MH (1999) Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol Obstet Invest 48(Suppl 1):2–13PubMedCrossRefGoogle Scholar
  18. 18.
    Bruner-Tran KL, Eisenberg E, Yeaman GR, Anderson TA, McBean J, Osteen KG (2002) Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab 87:4782–4791PubMedCrossRefGoogle Scholar
  19. 19.
    Uzan C, Cortez A, Dufournet C, Fauvet R, Siffroi JP, Daraï E (2004) Eutopic endometrium and peritoneal, ovarian and bowel endometriotic tissues express a different profile of matrix metalloproteinases-2, -3 and -11, and of tissue inhibitor metalloproteinases-1 and -2. Virchows Arch 445:603–609. doi:10.1007/s00428-004-1117-y PubMedCrossRefGoogle Scholar
  20. 20.
    Ria R, Loverro G, Vacca A, Ribatti D, Cormio G, Roccaro AM, Selvaggi L (2002) Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas. Eur J Clin Invest 32:199–206PubMedCrossRefGoogle Scholar
  21. 21.
    Calcagno A, Grassi T, Mariuzzi L et al (2011) Expression patterns of Aurora A and B kinases, Ki-67 and the estrogen and progesterone receptors determined using an endometriosis tissue microarray model. Hum Reprod 26:2731–2741. doi:10.1093/humrep/der264 PubMedCrossRefGoogle Scholar
  22. 22.
    Noyes R, Hertig A, Rock J (1950) Dating the endometrial biopsy. Fertil Steril 1:3–25Google Scholar
  23. 23.
    ASRM (1997) Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 67:817–821CrossRefGoogle Scholar
  24. 24.
    Dilly M, Hambruch N, Shenavai S et al (2011) Expression of matrix metalloproteinase (MMP)-2, MMP-14 and tissue inhibitor of matrix metalloproteinase (TIMP)-2 during bovine placentation and at term with or without placental retention. Theriogenology 75:1104–1114. doi:10.1016/j.theriogenology.2010.11.019 PubMedCrossRefGoogle Scholar
  25. 25.
    Mazzoni A, Pashley DH, Tay FR et al (2009) Immunohistochemical identification of MMP-2 and MMP-9 in human dentin: correlative FEI-SEM/TEM analysis. J Biomed Mater Res A 88:697–703. doi:10.1002/jbm.a.31920 PubMedGoogle Scholar
  26. 26.
    Zhang H, Li M, Zheng X, Sun Y, Wen Z, Zhao X (2009) Endometriotic stromal cells lose the ability to regulate cell-survival signaling in endometrial epithelial cells in vitro. Mol Hum Reprod 15:653–663. doi:10.1093/molehr/gap069 PubMedCrossRefGoogle Scholar
  27. 27.
    Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315–5320PubMedGoogle Scholar
  28. 28.
    Konno R, Yamakawa H, Utsunomiya H, Ito K, Sato S, Yajima A (2000) Expression of survivin and Bcl-2 in the normal human endometrium. Mol Hum Reprod 6:529–534PubMedCrossRefGoogle Scholar
  29. 29.
    Donjacour AA, Cunha GR (1991) Stromal regulation of epithelial function. Cancer Treat Res 53:335–364PubMedCrossRefGoogle Scholar
  30. 30.
    Gaide Chevronnay HP, Selvais C, Emonard H, Galant C, Marbaix E, Henriet P (2012) Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta 1824:146–156. doi:10.1016/j.bbapap. 2011.09.003 PubMedCrossRefGoogle Scholar
  31. 31.
    Sotnikova NY, Antsiferova YS, Posiseeva LV, Shishkov DN, Posiseev DV, Filippova ES (2010) Mechanisms regulating invasiveness and growth of endometriosis lesions in rat experimental model and in humans. Fertil Steril 93:2701–2705. doi:10.1016/j.fertnstert.2009.11.024 PubMedCrossRefGoogle Scholar
  32. 32.
    Di Carlo C, Bonifacio M, Tommaselli GA, Bifulco G, Guerra G, Nappi C (2009) Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium. Fertil Steril 91:2315–2323. doi:10.1016/j.fertnstert.2008.03.079 PubMedCrossRefGoogle Scholar
  33. 33.
    Wenzl RJ, Heinzl H (1998) Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest 45:253–257PubMedCrossRefGoogle Scholar
  34. 34.
    Mönckedieck V, Sannecke C, Husen B et al (2009) Progestins inhibit expression of MMPs and of angiogenic factors in human ectopic endometrial lesions in a mouse model. Mol Hum Reprod 15:633–643. doi:10.1093/molehr/gap063 PubMedCrossRefGoogle Scholar
  35. 35.
    Bruner-Tran KL, Zhang Z, Eisenberg E, Winneker RC, Osteen KG (2006) Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget. J Clin Endocrinol Metab 91:1554–1560. doi:10.1210/jc.2005-2024 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ambrogio P. Londero
    • 1
  • Angelo Calcagno
    • 1
  • Tiziana Grassi
    • 1
  • Stefania Marzinotto
    • 2
  • Maria Orsaria
    • 2
  • Carlo Alberto Beltrami
    • 2
  • Diego Marchesoni
    • 1
  • Laura Mariuzzi
    • 2
  1. 1.Clinic of Obstetrics and GynecologyUniversity of UdineUdineItaly
  2. 2.Institute of PathologyUniversity of UdineUdineItaly

Personalised recommendations