Eph receptors in cancer and endometriosis

Faizullin L.Z., Muftaydinоva Sh.R., Buralkina N.A., Chuprynin V.D.

Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia
The mechanism of endometriosis is complex and controlled by various factors, most of which are based on cell proliferation, tissue invasion, neovascularization, and apoptosis inhibition. Women with endometriosis have an increased incidence of malignant neoplasms of different localization, which indicates the similarity of their pathogenesis and common environmental, molecular, and genetic risk factors. The presence of general characteristics of the development of the ectopic endometrium, especially in deep infiltrative endometriosis, and cancer may suggest not only the same mechanism of pathogenesis, but also common approaches to therapy. Therefore, it cannot be ruled out that many factors used today as a target for cancer therapy may also manifest themselves similarly in endometriosis. In this regard, of particular interest are the ephrin (Eph) receptors, which belong to the largest family of receptor tyrosine kinases that are expressed on the surface of epithelial cells during their active division. In addition to their involvement in the processes of embryonic development, Eph receptors play an important role in tumor angiogenesis, metastasis, and cancer stem cell regeneration. In cancer cells, many ephrins exhibit abnormally high levels of expression, the suppression of which is accompanied by the inhibition of the tumor process. In this connection, it is of interest to analyze the expression of Eph in endometriosis and to assess the possibility of using it as a target for treating endometriosis as in cancer.
Conclusion. The studies indicate the prospects of using Eph receptors as a target for the pathogenetic therapy and prevention of recurrent endometriosis and, first of all, severe infiltrative forms.

Keywords

endometriosis
cancer
Eph-receptors
ephrins
targeted therapy

References

  1. Herreros-Villanueva M., Chen C.C., Tsai E.M., Er T.K. Endometriosis-associated ovarian cancer: What have we learned so far? Clin. Chim. Acta. 2019; 493: 63-72. https://dx.doi.org/10.1016/j.cca.2019.02.016.
  2. Kajiyama H., Suzuki S., Yoshihara M., Tamauchi S., Yoshikawa N., Niimi K. et al. Endometriosis and cancer. Free Radic. Biol. Med. 2019; 133: 186‐92. https://dx.doi.org/10.1016/j.freeradbiomed.2018.12.015.
  3. Samani E.N., Mamillapalli R., Li F., Mutlu L., Hufnagel D., Krikun G., Taylor H.S. Micrometastasis of endometriosis to distant organs in a murine model. Oncotarget. 2017; 10(23): 2282-91. https://dx.doi.org/10.18632/oncotarget.16889. eCollection 2019 Mar 19.
  4. Ruderman R., Pavone M.E. Ovarian cancer in endometriosis: an update on the clinical and molecular aspects. Minerva Ginecol. 2017; 69(3): 286‐94. https://dx.doi.org/10.23736/S0026-4784.17.04042-4.
  5. Wei J.J., William J., Bulun S. Endometriosis and ovarian cancer: a review of clinical, pathologic, and molecular aspects. Int. J. Gynecol. Pathol. 2011; 30(6): 553-68. https://dx.doi.org/10.1097/PGP.0b013e31821f4b85.
  6. Nezhat F.R., Apostol R., Nezhat C., Pejovic T. New insights in the pathophysiology of ovarian cancer and implications for screening and prevention. Am. J. Obstet. Gynecol. 2015; 213(3): 262-7. https://dx.doi.org/10.1016/j.ajog.2015.03.044.
  7. Yang C., Oh H.K., Kim D. Müllerian adenosarcoma arising from rectal endometriosis. Ann. Coloproctol. 2014; 30(5): 232‐6. https://dx.doi.org/10.3393/ac.2014.30.5.232.
  8. Masand R.P., Euscher E.D., Deavers M.T., Malpica A. Endometrioid stromal sarcoma: a clinicopathologic study of 63 cases. Am. J. Surg. Pathol. 2013; 37(11): 1635-47. https://dx.doi.org/10.1097/PAS.0000000000000083.
  9. Anglesio M.S., Bashashati A., Wang Y.K., Senz J., Ha G., Yang W. et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J. Pathol. 2015; 236(2): 201-9. https://dx.doi.org/10.1002/path.4516.
  10. Yu H.C., Lin C.Y., Chang W.C., Shen B.J., Chang W.P., Chuang C.M. Increased association between endometriosis and endometrial cancer: a nationwide population-based retrospective cohort study. Int. J. Gynecol. Cancer. 2015; 25(3): 447‐52. https://dx.doi.org/10.1097/IGC.0000000000000384.
  11. Samartzis E.P., Noske A., Dedes K.J., Fink D., Imesch P. ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas. Int. J. Mol. Sci. 2013; 14(9): 18824‐49. https://dx.doi.org/10.3390/ijms140918824.
  12. Borghese B., Zondervan K.T., Abrao M.S., Chapron C., Vaiman D. Recent insights on the genetics and epigenetics of endometriosis. Clin. Genet. 2017; 91(2):254-64. https://dx.doi.org/10.1111/cge.12897.
  13. Anglesio M.S., Papadopoulos N., Ayhan A., Nazeran T.M., Noë M., Horlings H.M. et al. Cancer-associated mutations in endometriosis without cancer. N. Engl. J. Med. 2017; 376(19): 1835-48. https://dx.doi.org/10.1056/NEJMoa1614814.
  14. Grassi T., Calcagno A., Marzinotto S., Londero A.P., Orsaria M., Canciani G.N. et al. Mismatch repair system in endometriotic tissue and eutopic endometrium of unaffected women. Int. J. Clin. Exp. Pathol. 2015; 8(2): 1867-77.
  15. Jiang L., Yan Y., Liu Z., Wang Y. Inflammation and endometriosis. Front. Biosci. (Landmark Ed). 2016; 21: 941‐8. https://dx.doi.org/10.2741/4431.
  16. Samimi M., Pourhanifeh M.H., Mehdizadehkashi A., Eftekhar T., Asemi Z. The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression. J. Cell. Physiol. 2019; 234(11): 19384-92. https://dx.doi.org/10.1002/jcp.28666.
  17. Symons L.K., Miller J.E., Kay V.R., Marks R.M., Liblik K., Koti M., Tayade C. The immunopathophysiology of endometriosis. Trends Mol. Med. 2018; 24(9): 748-62. https://dx.doi.org/10.1016/j.molmed.2018.07.004.
  18. Sikora J., Smycz‐Kubanska M., Mielczarek‐Palacz A., Kondera‐Anasz Z. Abnormal peritoneal regulation of chemokine activation – the role of IL‐8 in pathogenesis of endometriosis. Am. J. Reprod. Immunol. 2017; 77(4): e12622. https://dx.doi.org/10.1111/aji.12622.
  19. Taylor H., Campbell J., Nobes C.D. Ephs and ephrins. Curr. Biol. 2017; 27(3): R90-5. https://dx.doi.org/10.1016/j.cub.2017.01.003.
  20. Kania A., Klein R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol. 2016; 17(4): 240-56. https://dx.doi.org/10.1038/nrm.2015.16.
  21. Pasquale E.B. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat. Rev. Cancer. 2010; 10(3): 165-80. https://dx.doi.org/10.1038/nrc2806.
  22. Fagotto F., Winklbauer R., Rohani N. Ephrin-Eph signaling in embryonic tissue separation. Cell Adh. Migr. 2014; 8(4): 308-26. https://dx.doi.org/10.4161/19336918.2014.970028.
  23. Liang L.Y., Patel O., Janes P.W., Murphy J.M., Lucet I.S. Eph receptor signalling: from catalytic to non-catalytic functions. Oncogene. 2019; 38(39): 6567‐84. https://dx.doi.org/10.1038/s41388-019-0931-2.
  24. Chen J. Regulation of tumor initiation and metastatic progression by Eph receptor tyrosine kinases. Adv. Cancer Res. 2012; 114: 1-20. https://dx.doi.org/10.1016/B978-0-12-386503-8.00001-6.
  25. Kaenel P., Mosimann M., Andres A.C. The multifaceted roles of Eph/Ephrin signaling in breast cancer. Cell Adh. Migr. 2012; 6(2): 138-47. https://dx.doi.org/10.4161/cam.20154.
  26. Ieguchi K., Maru Y. Roles of EphA1/A2 and ephrin-A1 in cancer. Cancer Sci. 2019; 110(3): 841-8. https://dx.doi.org/10.1111/cas.13942.
  27. Yang N.Y., Fernandez C., Richter M., Xiao Z., Valencia F., Tice D.A., Pasquale E.B. Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells. Cell. Signals. 2011; 23(1): 201-12. https://dx.doi.org/10.1016/j.cellsig.2010.09.004.
  28. Miao H., Gale N.W., Guo H., Qian J., Petty A., Kaspar J. et al. EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties. Oncogene. 2015; 34(5): 558-67. https://dx.doi.org/10.1038/onc.2013.590.
  29. Tarasov V.V., Svistunov A.A., Chubarev V.N., Zatsepilova T.A., Preferanskaya N.G., Stepanova O.I. et al. Feasibility of targeting glioblastoma stem cells: from concept to clinical trials. Curr. Top. Med. Chem. 2019; 19(32): 2974-84. https://dx.doi.org/10.2174/1568026619666191112140939.
  30. Cui Y., Wu B.O., Flamini V., Evans B.A.J., Zhou D., Jiang W.G. Knockdown of EPHA1 using CRISPR/CAS9 suppresses aggressive properties of ovarian cancer cells. Anticancer Res. 2017; 37(8): 4415-24. https://dx.doi.org/10.21873/anticanres.11836.
  31. Janes P.W., Slape C.I., Farnsworth R.H., Atapattu L., Scott A.M., Vail M.E. EphA3 biology and cancer. Growth Factors. 2014; 32(6): 176‐89. https://dx.doi.org/10.3109/08977194.2014.982276.
  32. Lv X.Y., Wang J., Huang F., Wang P., Zhou J.G., Wei B., Li S.H. EphA3 contributes to tumor growth and angiogenesis in human gastric cancer cells. Oncol. Rep. 2018; 40(4): 2408-16. https://dx.doi.org/10.3892/or.2018.6586.
  33. Toyama M., Hamaoka Y., Katoh H. EphA3 is up-regulated by epidermal growth factor and promotes formation of glioblastoma cell aggregates. Biochem. Biophys. Res. Commun. 2019; 508(3): 715-21. https://dx.doi.org/10.1016/j.bbrc.2018.12.002.
  34. Peng J., Wang Q., Liu H., Ye M., Wu X., Guo L. EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway. Tumour Biol. 2016; 37(9): 11959-71. https://dx.doi.org/10.1007/s13277-016-5048-4.
  35. Liu C., Huang H., Wang C., Kong Y., Zhang H. Involvement of ephrin receptor A4 in pancreatic cancer cell motility and invasion. Oncol. Lett. 2014; 7(6): 2165-9. https://dx.doi.org/10.3892/ol.2014.2011.
  36. Saintigny P., Peng S., Zhang L., Sen B., Wistuba I.I., Lippman S.M. et al. Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion. Mol. Cancer Ther. 2012; 11(9): 2021-32. https://dx.doi.org/10.1158/1535-7163.MCT-12-0030.
  37. Giaginis C., Tsoukalas N., Bournakis E., Alexandrou P., Kavantzas N., Patsouris E., Theocharis S. Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival. BMC Clin. Pathol. 2014; 14(1): 8. https://dx.doi.org/10.1186/1472-6890-14-8.
  38. Zhang W., Wei X., Guo S., Wang J., Liu J., Wang H. Differential expression of EphA5 protein in gastric carcinoma and its clinical significance. Oncol. Lett. 2019; 17(6): 5147‐53. https://dx.doi.org/10.3892/ol.2019.10167.
  39. Li R., Sun Y., Jiang A., Wu Y., Li C., Jin M. et al. Knockdown of ephrin receptor A7 suppresses the proliferation and metastasis of A549 human lung cancer cells. Mol. Med. Rep. 2016; 13(4): 3190-6. https://dx.doi.org/10.3892/mmr.2016.4904.
  40. Chen Y., Zhang H., Zhang Y. Targeting receptor tyrosine kinase EphB4 in cancer therapy. Semin. Cancer Biol. 2019; 56: 37-46. https://dx.doi.org/10.1016/j.semcancer.2017.10.002.
  41. Nikas I., Ryu H.S., Theocharis S. Viewing the Eph receptors with a focus on breast cancer heterogeneity. Cancer Lett. 2018; 434: 160‐71. https://dx.doi.org/10.1016/j.canlet.2018.07.030.
  42. Mateo-Lozano S., Bazzocco S., Rodrigues P., Mazzolini R., Andretta E., Dopeso H. et al. Loss of the EPH receptor B6 contributes to colorectal cancer metastasis. Sci. Rep. 2017; 7: 43702. https://dx.doi.org/10.1038/srep43702.
  43. El Zawily A., McEwen E., Toosi B., Vizeacoumar F.S., Freywald T., Vizeacoumar F.J., Freywald A. The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment. Sci. Rep. 2017; 7(1): 14767. https://dx.doi.org/10.1038/s41598-017-15200-3.
  44. Fujiiwara H., Tatsumi K., Kosaka K., Yoshioka S., Fujiwara H., Fujii S. Eph-ephrin A system regulates murine blastocyst attachment and spreading. Dev. Dyn. 2006; 235(12): 3250-8. https://dx.doi.org/10.1002/dvdy.20977.
  45. Fujiwara H., Yoshioka S., Tatsumi K., Kosaka K., Satoh Y., Nishioka Y. et al. Human endometrial epithelial cells express ephrin A1: possible interaction between human blastocysts and endometrium via Eph-ephrin system. J. Clin. Endocrinol. Metab. 2002; 87(12): 5801-7. https://dx.doi.org/10.1210/jc.2002-020508.
  46. Fujii H., Fujiwara H., Horie A., Sato Y., Konishi I. Ephrin A1 induces intercellular dissociation in Ishikawa cells: possible implication of the Eph-ephrin A system in human embryo implantation. Hum. Reprod. 2011; 26(2): 299‐306. https://dx.doi.org/10.1093/humrep/deq340.
  47. Shchegolev A., Muftaydinova S., Fayzullina N.M., Buralkina N., Fayzullin L.Z., Chuprynin V.D. Overexpression of ephrin receptor a2 in the ectopic endometrium of patients with deep infiltrative endometriosis. Virchow’s Archiv. 2019; 475(Suppl. 1): S318.
  48. Kao L.C., Germeyer A., Tulac S., Lobo S., Yang J.P., Taylor R.N. et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003; 144(7): 2870-81. https://dx.doi.org/10.1210/en.2003-0043.
  49. Xu H., Gao Y., Shu Y., Wang Y., Shi Q. EPHA3 enhances macrophage autophagy and apoptosis by disrupting the mTOR signaling pathway in mice with endometriosis. Biosci. Rep. 2019; 39(7): BSR20182274. https://dx.doi.org/10.1042/BSR20182274.
  50. Saha N., Robev D., Mason E.O., Himanen J.P., Nikolov D.B. Therapeutic potential of targeting the Eph/ephrin signaling complex. Int. J. Biochem. Cell Biol. 2018; 105: 123-33. https://dx.doi.org/10.1016/j.biocel.2018.10.006.
  51. Lodola A., Giorgio C., Incerti M., Zanotti I., Tognolini M. Targeting Eph/ephrin system in cancer therapy. Eur. J. Med. Chem. 2017; 142: 152-62. https://dx.doi.org/10.1016/j.ejmech.2017.07.029.
  52. Zondervan K.T., Becker C.M., Missmer S.A. Endometriosis. N. Engl. J. Med. 2020; 382(13): 1244‐56. https://dx.doi.org/10.1056/NEJMra1810764.
  53. Arcoverde F.V.L., Andres M.P., Borrelli G.M., Barbosa P.A., Abrao M.S., Kho R.M. Surgery for endometriosis improves major domains of quality of life: a systematic review and meta-analysis. J. Minim. Invasive Gynecol. 2019; 26: 266-78.
  54. Bendifallah S., Vesale E., Daraï E., Thomassin-Naggara I., Bazot M., Tuech J.J. et al. Recurrence after surgery for colorectal endometriosis: A systematic review and meta-analysis. J. Minim. Invasive Gynecol. 2020; 27(2): 441-51. e2. https://dx.doi.org/10.1016/j.jmig.2019.09.791.
  55. Rudzitis-Auth J., Fuß S.A., Becker V., Menger M.D., Laschke M.W. Inhibition of erythropoietin-producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions. Br. J. Pharmacol. 2020; 177(14): 3225-39. https://dx.doi.org/10.1111/bph.15044.

Received 18.12.2020

Accepted 27.01.2021

About the Authors

Leonid Z. Faizullin, Cand. Bio. Sci., leading researcher, Laboratory of Molecular Genetic Methods, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. Tel.: +7(916)710-67-89. E-mail: l_faizullin@oparina 4. 4, Oparina str., Moscow, 117997, Russia.
Shakhnoza K. Muftaydiniva, PhD student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. Tel.: +7(967)133-42-08. E-mail: shaxnozka_87@mail.ru. 4, Oparina str., Moscow, 117997, Russia.
Natalia A. Buralkina, Dr. Med. Sci., senior researcher, Surgical Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. Tel.: +7(926)405-62-83. E-mail: n_buralkina@oparina4.ru. 4, Oparina str., Moscow, 117997, Russia.
Vladimir D. Chuprynin, PhD/Med, Head of the Surgery department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology,
Ministry of Health of Russia. Tel.: +7(495)438-78-33. E-mail: v_chuprynin@oparina4.ru. 4, Oparina str., Moscow, 117997, Russia.

For citation: Faizullin L.Z., Muftaydinоva Sh.R., Buralkina N.A., Chuprynin V.D. Eph receptors in cancer and endometriosis.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 4: 48-54 (in Russian)
https://dx.doi.org/10.18565/aig.2021.4.48-54

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.