Стволовые свойства опухолевых клеток асцитической жидкости у больных раком яичника: ключ к управлению распространением процесса

Рак яичника принято рассматривать как наиболее злокачественную и агрессивную опухоль женской репродуктивной системы, что во многом связано с ранним развитием злокачественного асцита и перитонеального канцероматоза. Опухолевые клетки, представляющие первичный очаг, а также содержащиеся в составе асцитической жидкости, крайне гетерогенны с морфологической, иммуногистохимической и молекулярно-генетической позиций. Значимую роль в процессах самообновления опухоли, ее дифференцировки, метастазирования и развития химиорезистенстности играют опухолевые стволовые клетки.

Настоящий обзор направлен на обобщение имеющихся данных о стволовых опухолевых клетках рака яичников и их роли в опухолевой прогрессии. При написании обзора проведен биоинформационный поиск в универсальных базах данных PubMed, NCBI, Google Scholar и eLibrary с применением следующих ключевых слов для поиска: cancer stem cells, ovarian cancer, malignant ascites, hemoresistance и т.п.

Представленные данные позволяют всесторонне охарактеризовать роль стволовых свойств опухолевых клеток рака яичника. Изложена актуальная информация о молекулярно-биологических параметрах стволовых опухолевых клеток рака яичника, представляющих клеточный компонент злокачественного асцита, с приведением данных собственных исследований. Отражены современные представления о механизмах формирования клеточных сфероидов и их вкладе в прогрессирование опухолевого процесса.

Опухолевые стволовые клетки являются крайне перспективной мишенью в создании будущих терапевтических стратегий, основанных на изучении сигнальных путей в стволовых клетках рака яичников, механизмах образования сфероидов, а также вкладе иммунных клеток в приобретение стволовых свойств опухоли.

1. Motohara T., Masuda K., Morotti M., Zheng Y., El-Sahhar S., Chong K.Y. et al. An evolving story of the metastatic voyage of ovarian cancer cells: Cellular and molecular orchestration of the adipose-rich metastatic microenvironment. Oncogene. 2019;38(16):2885–2898. DOI: 10.1038/s41388-018-0637-x.

2. Ahmed N., Abubaker K., Findlay J.K. Ovarian cancer stem cells: Molecular concepts and relevance as therapeutic targets. Mol. Asp. Med. 2014;39:110–125. DOI: 10.1016/j.mam.2013.06.002.

3. Horst D., Kriegl L., Engel J., Kirchner T., Jung A. Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Investigation. 2009;27(8):844–850. DOI: 10.1080/07357900902744502.

4. Yan Y., Zuo X., Wei D. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target. Stem Cells Translational Medicine. 2015;4(9):1033–1043. DOI: 10.5966/sctm.2015-0048.

5. Lee Y.J., Wu C.C., Li J.W., Ou C.C., Hsu S.C., Tseng H.H. et al. A rational approach for cancer stem-like cell isolation and characterization using CD44 and prominin-1(CD133) as selection markers. Oncotarget. 2016;7(48):78499–78515. DOI: 10.18632/oncotarget.12100.

6. Gao M.Q., Choi Y.P., Kang S., Youn J.H., Cho N.H. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 2010;29(18):2672–2680. DOI: 10.1038/onc.2010.35.

7. Zhang S., Balch C., Chan M.W., Lai H.C., Matei D., Schilder J.M. et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008;68(11):4311–4320. DOI: 10.1158/0008-5472.CAN08-0364.

8. Li Z., Block M.S., Vierkant R.A., Fogarty Z.C., Winham S.J., Visscher D.W. et al. The inflammatory microenvironment in epithelial ovarian cancer: a role for TLR4 and MyD88 and related proteins. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2016;37(10):13279–13286. DOI: 10.1007/s13277-016-5163-2.

9. Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C., Maschera B. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biology. 2000;2(6):346–351. DOI: 10.1038/35014038.

10. López J., Valdez-Morales F.J., Benítez-Bribiesca L., Cerbón M., Carrancá A.G. Normal and cancer stem cells of the human female reproductive system. Reproductive Biology and Endocrinology. 2013;11:53. DOI: 10.1186/1477-7827-11-53.

11. Spizzo G., Went P., Dirnhofer S., Obrist P., Moch H., Baeuerle P.A. et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecologic Oncology. 2006;103(2):483–488. DOI: 10.1016/j.ygyno.2006.03.035.

12. Chang B., Liu G., Xue F., Rosen D.G., Xiao L., Wang X. et al. ALDH1 expression correlates with favorable prognosis in ovarian cancers. Modern Pathology: an Official Journal of the United States and Canadian Academy of Pathology. 2009;22(6):817–823. DOI: 10.1038/modpathol.2009.35.

13. Deng S., Yang X., Lassus H., Liang S., Kaur S., Ye Q. et al. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One. 2010;5(4):e10277. DOI: 10.1371/journal.pone.0010277.

14. Cioffi M., D’Alterio C., Camerlingo R., Tirino V., Consales C., Riccio A. et al. Identification of a distinct population of CD133(+)CXCR4(+) cancer stem cells in ovarian cancer. Sci. Report. 2015;5:10357. DOI: 10.1038/srep10357.

15. Kajiyama H., Shibata K., Terauchi M., Ino K., Nawa A., Kikkawa F. Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. International Journal of Cancer. 2008;122(1):91–99. DOI: 10.1002/ijc.23083.

16. Krohn A., Song Y.H., Muehlberg F., Droll L., Beckmann C., Alt E. CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro. Cancer Letters. 2009;280(1):65–71. DOI: 10.1016/j.canlet.2009.02.005.

17. Rodda D.J., Chew J.L., Lim L.H., Loh Y.H., Wang B., Ng H.H. et al. Transcriptional regulation of nanog by OCT4 and SOX2. J. Biol. Chem. 2005;280(26):247317. DOI: 10.1074/jbc.M502573200.

18. Alemohammad H., Asadzadeh Z., Motafakker Azad R., Hemmat N., Najafzadeh B., Vasefifar P. et al. Signaling pathways and microRNAs, the orchestrators of NANOG activity during cancer induction. Life Sci. 2020;260:118337. DOI: 10.1016/j.lfs.2020.118337.

19. Lin F.K., Chui Y.L. Generation of induced pluripotent stem cells from mouse cancer cells. Cancer Biother. Radiopharm. 2012;27(10):694–700. DOI: 10.1089/cbr.2012.1227.

20. Kaufhold S., Garbán H., Bonavida B. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J. Exp. Clin. Cancer Res. 2016;35:84. DOI: 10.1186/s13046-016-0359-2.

21. Stevanovic M., Zuffardi O., Collignon J., Lovell-Badge R., Goodfellow P. The cDNA sequence and chromosomal location of the human SOX2 gene. Mamm. Genome. 1994;5(10):640– 642. DOI: 10.1007/BF00411460.

22. Peng S., Maihle N.J., Huang Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene. 2010;29(14):2153–2159. DOI: 10.1038/onc.2009.500.

23. Baba T., Convery P.A., Matsumura N., Whitaker R.S., Kondoh E., Perry T. et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene. 2009;28(2):209–218. DOI: 10.1038/onc.2008.374.

24. Curley M.D., Therrien V.A., Cummings C.L., Sergent P.A., Koulouris C.R., Friel A.M. et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009;27(12):2875–2883. DOI: 10.1002/stem.236.

25. Silva I.A., Bai S., McLean K., Yang K., Griffith K., Thomas D. et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011;71(11):3991–4001. DOI: 10.1158/0008-5472.CAN-10-3175.

26. Wei X., Dombkowski D., Meirelles K., Pieretti-Vanmarcke R., Szotek P.P., Chang H.L. et al. Mullerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics. Proc. Natl. Acad. Sci. U S A. 2010;107(44):18874–18879. DOI: 10.1073/pnas.1012667107.

27. Jiang H., Lin X., Liu Y., Gong W., Ma X., Yu Y. et al. Transformation of epithelial ovarian cancer stemlike cells into mesenchymal lineage via EMT results in cellular heterogeneity and supports tumor engraftment. Mol. Med. 2012;18(1):1197– 1208. DOI: 10.2119/molmed.2012.00075.

28. Motohara T., Masuko S., Ishimoto T., Yae T., Onishi N., Muraguchi T. et al. Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells. Carcinogenesis. 2011;32(11):1597–1606. DOI: 10.1093/carcin/bgr183.

29. Gao M.Q., Choi Y.P., Kang S., Youn J.H., Cho N.H. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 2010;29(18):2672– 2680. DOI: 10.1038/onc.2010.35.

30. Кайгородова Е.В., Федулова Н.В., Очиров М.О., Дьяков Д.А., Молчанов С.В., Часовских Н.Ю. Различные популяции опухолевых клеток в асцитической жидкости больных раком яичников. Бюллетень сибирской медицины. 2020;19(1):50–58. DOI: 10.20538/1682-0363-2020-1-50-58.

31. Кайгородова Е.В., Очиров М.О., Молчанов С.В., Рогачев Р.Р., Дьяков Д.Д., Чернышова А.Л. и др. Различные популяции EpСam-положительных клеток в асцитической жидкости у больных раком яичников: связь со степенью канцероматоза. Бюллетень сибирской медицины. 2021;20(2):44–53. DOI: 10.20538/1682-0363-2021-2-44-53.

32. Wang Z., Yang L., Huang Z., Li X., Xiao J., Qu Y. et al. Identification of prognosis biomarkers for high-grade serous ovarian cancer based on stemness. Front. Genet. 2022;13:861954. DOI: 10.3389/fgene.2022.861954.

33. Bai S., Ingram P., Chen Y.C., Deng N., Pearson A., Niknafs Y.S. et al. EGFL6 regulates the asymmetric division, maintenance, and metastasis of ALDH+ ovarian cancer cells. Cancer Res. 2016;76(21):6396–6409. DOI: 10.1158/0008-5472.CAN-16-0225.

34. Wang K., Wang Y., Wang Y., Liu S., Wang C., Zhang S. et al. EIF5A2 enhances stemness of epithelial ovarian cancer cells via a E2F1/KLF4 axis. Stem Cell Res. Ther. 2021;12(1):186. DOI: 10.1186/s13287-021-02256-2.

35. Giordano M., Decio A., Battistini C., Baronio M., Bianchi F., Villa A. et al. L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling. J. Exp. Clin. Cancer Res. 2021;40(1):319. DOI: 10.1186/s13046-021-02117-z.

36. Zhang Y., Wang Y., Zhao G., Tanner E.J., Adli M., Matei D. FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway. J. Clin. Invest. 2022;132(10):151591. DOI: 10.1172/JCI151591.

37. Schwitalla S., Fingerle A.A., Cammareri P., Nebelsiek T., Göktuna S.I., Ziegler P.K. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-celllike properties. Cell. 2013;152(1-2):25–38. DOI: 10.1016/j.cell.2012.12.012.

38. Raghavan S., Mehta P., Xie Y., Lei Y.L., Mehta G. Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments. J. Immunother. Cancer. 2019;7(1):190. DOI: 10.1186/s40425-019-0666-1.

39. Zhang S., Balch C., Chan M.W., Lai H.C., Matei D., Schilder J.M. et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008;68(11):4311–4320. DOI: 10.1158/0008-5472.CAN-08-0364.

40. Lau W., Peng W.C., Gros P., Clevers H. The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 2014;28(4):305–316. DOI: 10.1101/gad.235473.113.

41. Генинг С.О., Абакумова Т.В., Антонеева И.И., Ризванов А.А., Генинг Т.П., Гуфурбаева Д.У. Стволово-подобные опухолевые клетки и провоспалительные цитокины в асцитической жидкости пациенток с раком яичников. Клиническая лабораторная диагностика. 2021;66(5):297– 303. DOI: 10.51620/0869-2084-2021-66-5-297-303.

42. Meirelles K., Benedict L.A., Dombkowski D., Pepin D., Preffer F.I., Teixeira J. et al. Human ovarian cancer stem/ progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(7):2358–2363. DOI: 10.1073/pnas.1120733109.

43. Bourguignon L.Y., Peyrollier K., Xia W., Gilad E. Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat- 3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. The Journal of Biological Chemistry. 2008;283(25):17635–17651. DOI: 10.1074/jbc.M800109200.

44. Xia M., Overman M.J., Rashid A., Chatterjee D., Wang H., Katz M.H. et al. Expression and clinical significance of epidermal growth factor receptor and insulin-like growth factor receptor 1 in patients with ampullary adenocarcinoma. Human Pathology. 2015;46(9):1315–1322. DOI: 10.1016/j.humpath.2015.05.012.

45. Garson K., Vanderhyden B.C. Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm. Reproduction. 2015;149(2):59–70. DOI: 10.1530/REP-14-0234.

46. Jäger M., Schoberth A., Ruf P., Hess J., Hennig M., Schmalfeldt B. et al. Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Cancer Res. 2012;72(1):24–32. DOI: 10.1158/0008-5472.CAN-11-2235.

47. Akhter M.Z., Sharawat S.K., Kumar V., Kochat V., Equbal Z., Ramakrishnan M. et al. Aggressive serous epithelial ovarian cancer is potentially propagated by EpCAM+CD45+ phenotype. Oncogene. 2018;37(16):2089–2103. DOI: 10.1038/s41388-017-0106-y.

48. Wicha M.S., Liu S., Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883–1890. DOI: 10.1158/0008-5472.CAN-05-3153.

49. Кайгородова Е.В., Ковалев О.В., Чернышова А.Л., Вторушин С.В., Шпилёва О.В. Гетерогенность EpCAM-положительных клеток в асцитической жидкости low-grade серозной карциномы яичников: клинический случай. Опухоли женской репродуктивной системы. 2021;17(4):90– 95. DOI: 10.17650/1994 4098 2021 17 4 90 95.

50. Козик А.В., Кайгородова Е.В., Грищенко М.Ю., Вторушин С.В., Чернышова А.Л. EPCAM+CD45+ клетки в асцитической жидкости больных новообразованиями яичников: связь с уровнями онкомаркеров и степенью злокачественности. Сибирский онкологический журнал. 2022;21(5):44– 51. DOI: 10.21294/1814-4861-2022-21-5-44-51.

51. Kaigorodova E.V., Kozik A.V., Zavaruev I.S. Grishchenko M.Y. Hybrid/atypical forms of circulating tumor cells: current state of the art. Biochemistry Moscow. 2022;87(4):380– 390. DOI: 10.1134/S0006297922040071.

52. Izar B., Tirosh I., Stover E.H., Wakiro I., Cuoco M.S., Alter I. et al. A single-cell landscape of high-grade serous ovarian cancer. Nature Medicine. 2020;26(8):1271–1279. DOI: 10.1038/s41591-020-0926-0.

53. Wu X., Liu X., Koul S., Lee C.Y., Zhang Z., Halmos B. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014;5(20):9546–9563. DOI: 10.18632/oncotarget.2542.

54. Shield K., Ackland M.L., Ahmed N., Rice G.E. Multicellular spheroids in ovarian cancer metastases: Biology and pathology. Gynecologic Oncology. 2009;113(1):143–148. DOI: 10.1016/j.ygyno.2008.11.032.

55. Bapat S.A., Mali A.M., Koppikar C.B., Kurrey N.K. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 2005;65(8):3025– 3029. DOI: 10.1158/0008-5472.CAN-04-3931.

56. Shield K., Ackland M.L., Ahmed N., Rice G.E. Multicellular spheroids in ovarian cancer metastases: biology and pathology. Gynecol. Oncol. 2009;113(1):143–148. DOI: 10.1016/j.ygyno.2008.11.032.

57. Liu X., Taftaf R., Kawaguchi M., Chang Y.F., Chen W., Entenberg D. et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov. 2019;9(1):96–113. DOI: 10.1158/2159-8290.CD-18-0065.

58. Xu S., Yang Y., Dong L., Qiu W., Yang L., Wang X. et al. Construction and characteristics of an E-cadherin-related three-dimensional suspension growth model of ovarian cancer. Scientific Reports. 2014;4:5646. DOI: 10.1038/srep05646.

59. Sodek K.L., Ringuette M.J., Brown T.J. Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype. International Journal of Cancer. 2009;124(9):2060–2070. DOI: 10.1002/ijc.24188.

60. Kenny H.A., Chiang C.Y., White E.A., Schryver E.M., Habis M., Romero I.L. et al. Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. The Journal of Clinical Investigation. 2014;124(10):4614–4628. DOI: 10.1172/JCI74778.

61. Iwanicki M.P., Chen H.Y., Iavarone C., Zervantonakis I.K., Muranen T., Novak M. et al. Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition. JCI Insight. 2016;1(10):e86829. DOI: 10.1172/jci.insight.86829.

62. Lengyel E. Ovarian cancer development and metastasis. Am. J. Pathol. 2010;177(3):1053–1064. DOI: 10.2353/ajpath.2010.100105.

63. Elloul S., Elstrand M.B., Nesland J.M., Tropé C.G., Kvalheim G., Goldberg I. et al. Snail, slug, and smad-interacting protein 1 as novel parameters of disease aggressive ness in metastatic ovarian and breast carcinoma. Cancer. 2005;103(8):1631–1643. DOI: 10.1002/cncr.20946.

64. Veatch A.L., Carson L.F., Ramakrishnan S. Differential expression of the cell-cell adhesion molecule E-cadherin in ascites and solid human ovarian tumor cells. International Journal of Cancer. 1994;58(3):393–399. DOI: 10.1002/ijc.2910580315.

65. Latifi A., Luwor R.B., Bilandzic M., Nazaretian S., Stenvers K., Pyman J. et al. Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors. PloS One. 2012;7(10):e46858. DOI: 10.1371/journal.pone.0046858.

66. Fritz J.L., Collins O., Saxena P., Buensuceso A., Ramos Valdes Y., Francis K.E. et al. A novel role for NUAK1 in promoting ovarian cancer metastasis through regulation of fibronectin production in spheroids. Cancers. 2020;12(5):1250. DOI: 10.3390/cancers12051250.

67. Ojasalu K., Brehm C., Hartung K., Nischak M., Finkernagel F., Rexin P. et al. Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion. Molecular Oncology. 2020;14(9):2142–2162. DOI: 10.1002/1878-0261.12749.

68. Reinartz S., Lieber S., Pesek J., Brandt D.T., Asafova A., Finkernagel F. et al. Cell type-selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment. Molecular Oncology. 2019;13(2):185–201. DOI: 10.1002/1878-0261.12396.

69. Kipps E., Tan D.S., Kaye S.B. Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research. Nature reviews. Cancer. 2013;13(4):273–282. DOI: 10.1038/nrc3432.

70. Rakina M., Kazakova A., Villert A., Kolomiets L., Larionova I. Spheroid formation and peritoneal metastasis in ovarian cancer: the role of stromal and immune components. International Journal of Molecular Sciences. 2022;23(11):6215. DOI: 10.3390/ijms23116215.

71. Dick J.E., Bhatia M., Gan O., Kapp U., Wang J.C. Assay of human stem cells by repopulation of NOD/SCID mice. Stem Cells. 1997;15Suppl.1:199–203;discussion 204–197. DOI: 10.1002/stem.5530150826.

72. Wang L., Mezencev R., Bowen N.J., Matyunina L.V., McDonald J.F. Isolation and characterization of stem-like cells from a human ovarian cancer cell line. Molecular and Cellular Biochemistry. 2012;363(1-2):257–268. DOI: 10.1007/s11010-011-1178-6.

73. De Thé H. Differentiation therapy revisited. Nat. Rev. Cancer. 2018;18(2):117–127 DOI: 10.1038/nrc.2017.103.

74. Nayak S., Mahenthiran A., Yang Y., McClendon M., Mania-Farnell B., James C.D. et al. Bone morphogenetic protein 4 targeting glioma stem-like cells for malignant glioma treatment: latest advances and implications for clinical application. Cancers (Basel). 2020;12(2):516. DOI: 10.3390/cancers12020516.

75. Arima Y., Nobusue H., Saya H. Targeting of cancer stem cells by differentiation therapy. Cancer Sci. 2020;111(8):2689– 2695. DOI: 10.1111/cas.14504.

76. Correa R.J., Peart T., Valdes Y.R., DiMattia G.E., Shepherd T.G. Modulation of AKT activity is associated with reversible dormancy in ascites-derived epithelial ovarian cancer spheroids. Carcinogenesis. 2012;33(1):49–58. DOI: 10.1093/carcin/bgr241.

77. Hua H., Zhang H., Chen J., Wang J., Liu J., Jiang Y. Targeting Akt in cancer for precision therapy. Journal of Hematology & Oncology. 2021;4(1):128. DOI: 10.1186/s13045-021-01137-8.

78. Emami K.H., Nguyen C., Ma H., Kim D.H., Jeong K.W., Eguchi M. et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(34):12682–12687. DOI: 10.1073/pnas.0404875101.

79. Rafehi S., Ramos Valdes Y., Bertrand M., McGee J., Préfontaine M., Sugimoto A. et al. TGFβ signaling regulates epithelial-mesenchymal plasticity in ovarian cancer ascites-derived spheroids. Endocrine-Related Cancer. 2016;23(3):147–159. DOI: 10.1530/ERC-15-0383.

80. Jäger M., Schoberth A., Ruf P., Hess J., Hennig M., Schmalfeldt B. et al. Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Cancer Research. 2012;72(1):24–32. DOI: 10.1158/0008-5472.CAN11-2235.