Publikationsserver der Universitätsbibliothek Marburg

Titel:Untersuchung des Einflusses von CA125 auf Chemoresistenz, Sphäroidbildung und Tumorstammzellmarkerexpression in Ovarialkarzinomzellen
Autor:Kull, Eva
Weitere Beteiligte: Wagner, U. (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0295
DOI: https://doi.org/10.17192/z2017.0295
URN: urn:nbn:de:hebis:04-z2017-02957
DDC: Medizin, Gesundheit
Titel(trans.):Influence of CA125 on chemosensitivity, sphere formation and cancer stem cell markers in ovarian cancer cells
Publikationsdatum:2017-05-03
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Sphäroide, Tumostammzellmarker, CD117, CD133, CD24, CD22, Chemoresistenz, ALDH, CA125, MUC16, Ovarialkarzinom, Ovarian Cancer

Zusammenfassung:
Einfluss von CA125 auf Chemoresistenz, Sphäroidbildung und Tumorstammzellmarkerexpression in Ovarialkarzinomzellen Das tumorassoziierte Antigen CA125 wird häufig zur Verlaufskontrolle von Patientinnen mit Ovarialkarzinom angewendet, da es in Ovarialkarzinomzellen zumeist überexprimiert wird. Dabei ist die physiologische Funktion des Muzins bis heute weitgehend unbekannt. Ziel dieser Arbeit ist es daher, zu untersuchen, welchen Einfluss der Knockdown von CA125 in Ovarialkarzinomzellen auf die Chemosensibilität der Zellen, die Fähigkeit zu Sphäroidbildung sowie auf die Expression von Tumorstammzellmarkern besitzt. Zu diesem Zweck wurden zwei Subklone der Zelllinie OAW42 verwendet, deren CA125-Expression mittels stabiler Transfektion signifikant gehemmt wird. In dieser Arbeit konnte gezeigt werden, dass die adhärenten Zellen der Zelllinie OAWH8+ durch den CA125 Knockdown eine signifikant höhere Carboplatinresistenz besitzen, wohingegen die Paclitaxelresistenz durch die CA125 Expression unbeeinflusst bleibt. In der Zelllinie OAWB8- hingegen bewirkte der CA125 Knockdown einen gegenteiligen Effekt bezüglich der Carboplatinresistenz, so dass der CA125 Knockdown hier zu einer Erhöhung der Carboplatinsensibilität führte. Gegenüber Paclitaxel hatte CA125 wiederum keinen markanten Einfluss. Weiterhin wurde der Einfluss des CA125 Knockdowns auf die Expression von Tumorstammzellmarkern untersucht, wobei sich bei den Versuchen dieser Arbeit kein Zusammenhang nachweisen lässt. Zudem verstärkte die CA125 Expression die homotypische Interaktion der OAWB8- Zellen, sodass CA125+ Zellen eine stärkere Sphäroidbildung zeigten als die CA125- Knockdownklone. Für die Zelllinie OAWB8- zeigte hingegen nur der CA125- OAWB8- Knockdownklon die Fähigkeit zur Sphäroidbildung. Zusammenfassend konnte für beide Zelllinien beobachtet werden, dass die Zellen in Sphäroidkultur eine deutlichere Resistenz gegenüber Carboplatin und Paclitaxel aufwiesen, als die adhärenten Kontrollzellen. Besonders in der Sekundärtherapie des Ovarialkarzinoms sind Chemoresistenzen weit verbreitet. Dabei scheint CA125 eine zentrale Rolle für das Überleben von Ovarialkarzinomzellen einzunehmen. Mit welchem Mechanismus und über welche Signalmoleküle CA125 die Chemoresistenz beeinflusst, sollte daher weiter erforscht werden, um langfristig einen neuen Therapieansatz für eine kurative Therapie des Ovarialkarzinoms zu etablieren. Generell bedarf es zur Entwicklung weiterer Therapieoptionen einer umfangreichen Erforschung der physiologischen Funktion von CA125. Des Weiteren bleibt die Detektion optimaler Tumorstammzellmarker für Ovarialkarzinomzellen zu eruieren, um Tumorstammzellen effektiv identifizieren zu können. Dabei sollte in Zukunft insbesondere der Frage nachgegangen werden, ob sich im Verlauf einer Ovarialkarzinomerkrankung auch in vivo eine Veränderung der CA125 Expression sowie der Tumorstammzellanteile beobachten lässt. Hierfür würde sich besonders die Entnahme von Sphäroidzellen im Aszites von Ovarialkarzinompatientinnen nach Erstdiagnose sowie gegebenenfalls bei Auftreten eines Rezidivs eignen.

Summary:
Influence of CA125 on chemosensitivity, sphere formation and cancer stem cell markers in ovarian cancer cells Since the tumor associated antigen CA125 is commonly highly expressed in ovarian cancer cells, it is frequently used to monitor patients with ovarian cancer. To this day, the physiological role of this mucin is largely unknown. Therefore it is the aim of the present study to investigate the impact of CA125 gene silencing in ovarian cancer cells on its chemosensitivity, its ability to form spheres as well as on the expression of tumor stem cell markers. For this purpose, two subclones of the OAW42 cell line were used whose CA125 expression is significantly inhibited by means of stable transfection. In the present research study it was shown that adherent cells of the OAWH8+ cell line displayed a significantly higher carboplatin resistance, whereas paclitaxel resistance was unaffected by CA125 expression. In contrast, the OAWB8- cell line showed a divergent effect on carboplatin resistance. Here, CA125 gene silencing caused an increase of carboplatin sensitivity whereas it did not show any distinctive influence on paclitaxel. Furthermore the influence of CA125 gene silencing on the expression of cancer stem cell markers was investigated, but during the present studies no prove of any correlation could be found. Moreover CA125 expression increased the interaction between OAWB8- cells so that CA125+ cells showed an enhanced sphere formation compared to CA125- clones. With regard to the OAWB8- cell line, only the CA125- clone showed the ability to form spheres. In summary, for both cell lines it was observed that sphere forming cells showed an enhanced and significant resistance to carboplatin and paclitaxel compared to adherent cells. Especially in second line treatment of ovarian cancer chemoresistance is widespread. Moreover it seems that CA125 plays a central role in the survival of ovarian cancer cells. To establish new therapeutic approaches for curative therapy of ovarian cancer it should be further explored what mechanism and via which signaling pathways CA125 affects chemoresistance. Generally, extensive research on the physiological function of CA125 is necessary to develop new therapeutic options. In order to effectively identify tumor stem cells it furthermore remains to elicit ideal tumor stem cell markers. In the future, attention should particularly be focused on the question whether there is a change in CA125 expression in vivo and tumor stem cell properties in process of ovarian cancer. For this purpose, the withdrawal of sphere cells in ascites of ovarian cancer patients at initial diagnosis and in case of recidivation could be one methodic option.

Bibliographie / References

  1. Yin, B. W. T., Dnistrian, A., & Lloyd, K. O. (2002). Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. International Journal of Cancer. Journal International Du Cancer, 98(5), 737-40. doi:10.1002/ijc.10250
  2. Kryczek, I., Liu, S., Roh, M., Vatan, L., Szeliga, W., Wei, S., … Zou, W. (2012). Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. International Journal of Cancer. Journal International Du Cancer, 130(1), 29-39. doi:10.1002/ijc.25967
  3. Markman, M. (2001). Second-line therapy for potentially platinum-sensitive recurrent ovarian cancer: what is optimal treatment? Gynecologic Oncology, 81(1), 1-2. doi:10.1006/gyno.2001.6162
  4. Covens, A., Carey, M., Bryson, P., Verma, S., Fung Kee Fung, M., & Johnston, M. (2002). Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecologic Oncology, 85(1), 71-80. doi:10.1006/gyno.2001.6552
  5. Meng, E., Long, B., Sullivan, P., McClellan, S., Finan, M. a, Reed, E., … Rocconi, R. P. (2012). CD44+/CD24- ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clinical & Experimental Metastasis, 29(8), 939-48. doi:10.1007/s10585-012-9482-4
  6. Jonckheere, N., Skrypek, N., & Van Seuningen, I. (2014). Mucins and tumor resistance to chemotherapeutic drugs. Biochimica et Biophysica Acta, 1846(1), 142-51. doi:10.1016/j.bbcan.2014.04.008
  7. Lee, J., Kotliarova, S., Kotliarov, Y., Li, A., Su, Q., Donin, N. M., … Fine, H. A. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serumcultured cell lines. Cancer Cell, 9(5), 391-403. doi:10.1016/j.ccr.2006.03.030
  8. Reinartz, S., Failer, S., Schuell, T., & Wagner, U. (2012). CA125 (MUC16) gene silencing suppresses growth properties of ovarian and breast cancer cells. European Journal of Cancer (Oxford, England : 1990), 48(10), 1558-69. doi:10.1016/j.ejca.2011.07.004
  9. Huber, D., Cimorelli, V., Usel, M., Bouchardy, C., Rapiti, E., & Petignat, P. (2013). European Journal of Obstetrics & Gynecology and Reproductive Biology How many ovarian cancer patients are eligible for fertility-sparing surgery ? European Journal of Obstetrics and Gynecology, 170(1), 270-274. doi:10.1016/j.ejogrb.2013.06.039
  10. Feng, T., Tian, H., Xu, C., Lin, L., Xie, Z., Lam, M. H.-W., … Chen, X. (2014). Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V. doi:10.1016/j.ejpb.2014.09.012
  11. Dasari, S., & Bernard Tchounwou, P. (2014). Cisplatin in cancer therapy: Molecular mechanisms of action. European Journal of Pharmacology, 740C, 364-378. doi:10.1016/j.ejphar.2014.07.025
  12. Kurman, R. J., & Shih, I.-M. (2011). Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm. Human Pathology, 42(7), 918-31. doi:10.1016/j.humpath.2011.03.003
  13. Prat, J. (2014). Staging classification for cancer of the ovary, fallopian tube, and peritoneum. International Journal of Gynaecology and Obstetrics: The Official Organ of the International Federation of Gynaecology and Obstetrics, 124(1), 1- 5. doi:10.1016/j.ijgo.2013.10.001
  14. Shield, K., Ackland, M. L., Ahmed, N., & Rice, G. E. (2009). Multicellular spheroids in ovarian cancer metastases: Biology and pathology. Gynecologic Oncology, 113(1), 143-8. doi:10.1016/j.ygyno.2008.11.032
  15. Harter, P., Muallem, Z. M., Buhrmann, C., Lorenz, D., Kaub, C., Hils, R., … du Bois, A. (2011). Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer. Gynecologic Oncology, 121(3), 615-9. doi:10.1016/j.ygyno.2011.02.014
  16. Thériault, C., Pinard, M., Comamala, M., Migneault, M., Beaudin, J., Matte, I., … Rancourt, C. (2011). MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis. Gynecologic Oncology, 121(3), 434-43. doi:10.1016/j.ygyno.2011.02.020
  17. Vergote, I., du Bois, A., Amant, F., Heitz, F., Leunen, K., & Harter, P. (2013). Neoadjuvant chemotherapy in advanced ovarian cancer: On what do we agree and disagree? Gynecologic Oncology, 128(1), 6-11. doi:10.1016/j.ygyno.2012.09.013
  18. Rustin, G. J. S., van der Burg, M. E. L., Griffin, C. L., Guthrie, D., Lamont, A., Jayson, G. C., … Swart, A. M. (2010). Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet, 376(9747), 1155-63. doi:10.1016/S0140-6736(10)61268-8
  19. Climate, B., Dyck, V., Phylogenies, T. F., & Compare, E. P. (2004). Identification of human brain tumour initiating cells, 432(November). doi:10.1038/nature03031.1.
  20. Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., … Dirks, P. B. (2004). Identification of human brain tumour initiating cells. Nature, 432(7015), 396-401. doi:10.1038/nature03128
  21. Trumpp, A., & Wiestler, O. D. (2008). Mechanisms of Disease: cancer stem cells-- targeting the evil twin. Nature Clinical Practice. Oncology, 5(6), 337-47. doi:10.1038/ncponc1110
  22. Pardal, R., Clarke, M. F., & Morrison, S. J. (2003). Applying the principles of stemcell biology to cancer. Nature Reviews. Cancer, 3(12), 895-902. doi:10.1038/nrc1232
  23. Ponta, H., Sherman, L., & Herrlich, P. A. (2003). CD44: from adhesion molecules to signalling regulators. Nature Reviews. Molecular Cell Biology, 4(1), 33-45. doi:10.1038/nrm1004
  24. Gao, M.-Q., Choi, Y.-P., Kang, S., Youn, J. H., & Cho, N.-H. (2010). CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene, 29(18), 2672-80. doi:10.1038/onc.2010.35
  25. Raina, D., Uchida, Y., Kharbanda, A., Rajabi, H., Panchamoorthy, G., Jin, C., … Kufe, D. (2014). Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene, 33(26), 3422-31. doi:10.1038/onc.2013.308
  26. Meyer, T., & Rustin, G. J. (2000). Role of tumour markers in monitoring epithelial ovarian cancer. British Journal of Cancer, 82(9), 1535-8. doi:10.1054/bjoc.2000.1174
  27. Uesato, S., Yamashita, H., Maeda, R., Hirata, Y., Yamamoto, M., Matsue, S., … Ju-ichi, M. (2014). Synergistic antitumor effect of a combination of paclitaxel and carboplatin with nobiletin from Citrus depressa on non-small-cell lung cancer cell lines. Planta Medica, 80(6), 452-7. doi:10.1055/s-0034-1368321
  28. Yin, B. W., & Lloyd, K. O. (2001). Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. The Journal of Biological Chemistry, 276(29), 27371-5. doi:10.1074/jbc.M103554200
  29. Friedrich, J., Ebner, R., & Kunz-Schughart, L. A. (2007). Experimental anti-tumor therapy in 3-D: spheroids--old hat or new challenge? International Journal of Radiation Biology, 83(11-12), 849-71. doi:10.1080/09553000701727531
  30. Ma, L., Lai, D., Liu, T., Cheng, W., & Guo, L. (2010). Cancer stem-like cells can be isolated with drug selection in human ovarian cancer cell line SKOV3. Acta Biochimica et Biophysica Sinica, 42(9), 593-602. doi:10.1093/abbs/gmq067
  31. Ferrero, J.-M., Weber, B., Geay, J.-F., Lepille, D., Orfeuvre, H., Combe, M., … PujadeLauraine, E. (2007). Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a GINECO phase II trial. Annals of Oncology : Official Journal of the European Society for Medical Oncology / ESMO, 18(2), 263-8. doi:10.1093/annonc/mdl376
  32. Tse, B. W. C., Collins, a, Oehler, M. K., Zippelius, a, & Heinzelmann-Schwarz, V. a. (2014). Antibody-based immunotherapy for ovarian cancer: where are we at? Annals of Oncology : Official Journal of the European Society for Medical Oncology / ESMO, 25(2), 322-31. doi:10.1093/annonc/mdt405
  33. Dixon, S. C., Nagle, C. M., Thrift, A. P., Pharoah, P. D. P., Pearce, C. L., Zheng, W., … Webb, P. M. (2016). Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study. International Journal of Epidemiology, 1-12. doi:10.1093/ije/dyw158
  34. Rustin, G., Quinn, M., Thigpen, T., du Bois, A., Pujade-Lauraine, E., Jakobsen, A., … Vermorken, J. (2004). Re: New Guidelines to Evaluate the Response to Treatment in Solid Tumors (Ovarian Cancer). JNCI Journal of the National Cancer Institute, 96(6), 487-488. doi:10.1093/jnci/djh081
  35. Haridas, D., Ponnusamy, M. P., Chugh, S., Lakshmanan, I., Seshacharyulu, P., & Batra, S. K. (2014). MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 28(10), 4183-99. doi:10.1096/fj.14-257352
  36. Seidman, J. D., Horkayne-Szakaly, I., Haiba, M., Boice, C. R., Kurman, R. J., & Ronnett, B. M. (2004). The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists, 23(1), 41-4. doi:10.1097/01.pgp.0000101080.35393.16
  37. Partridge, E., Kreimer, A. R., Greenlee, R. T., Williams, C., Xu, J., Church, T. R., … Buys, S. S. (2009). Results from four rounds of ovarian cancer screening in a randomized trial. Obstetrics and Gynecology, 113(4), 775-82. doi:10.1097/AOG.0b013e31819cda77
  38. Kurman, R. J., & Shih, I.-M. (2010). The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. The American Journal of Surgical Pathology, 34(3), 433-43. doi:10.1097/PAS.0b013e3181cf3d79
  39. Fujii, T., Shimada, K., Anai, S., Fujimoto, K., & Konishi, N. (2013). ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression. Cancer Science, 104(3), 321-7. doi:10.1111/cas.12089
  40. Shimizu, A., Hirono, S., Tani, M., Kawai, M., Okada, K.-I., Miyazawa, M., … Yamaue, H. (2012). Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma. Cancer Science, 103(4), 739-46. doi:10.1111/j.1349-7006.2012.02214.x
  41. Duffy, M. J., Bonfrer, J. M., Kulpa, J., Rustin, G. J. S., Soletormos, G., Torre, G. C., … Zwirner, M. (2005). CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society, 15(5), 679-91. doi:10.1111/j.1525-1438.2005.00130.x
  42. Kinkel, K., Lu, Y., Mehdizade, A., Pelte, M.-F., & Hricak, H. (2005). Indeterminate ovarian mass at US: incremental value of second imaging test for characterization--meta-analysis and Bayesian analysis. Radiology, 236(1), 85- 94. doi:10.1148/radiol.2361041618
  43. Lalwani, N., Prasad, S. R., Vikram, R., Shanbhogue, A. K., Huettner, P. C., & Fasih, N. (2011). Histologic, molecular, and cytogenetic features of ovarian cancers: implications for diagnosis and treatment. Radiographics : A Review Publication of the Radiological Society of North America, Inc, 31(3), 625-46. doi:10.1148/rg.313105066
  44. Meyer, M. J., Fleming, J. M., Lin, A. F., Hussnain, S. A., Ginsburg, E., & Vonderhaar, B. K. (2010). CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Research, 70(11), 4624-33. doi:10.1158/0008-5472.CAN-09-3619
  45. Smyth, J. F., Gourley, C., Walker, G., MacKean, M. J., Stevenson, A., Williams, A. R. W., … Langdon, S. P. (2007). Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 13(12), 3617-22. doi:10.1158/1078-0432.CCR-06-2878
  46. Tanei, T., Morimoto, K., Shimazu, K., Kim, S. J., Tanji, Y., Taguchi, T., … Noguchi, S. (2009). Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 15(12), 4234-41. doi:10.1158/1078-0432.CCR-08-1479
  47. Kharbanda, A., Rajabi, H., Jin, C., Raina, D., & Kufe, D. (2013). Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer. Molecular Cancer Research : MCR, 11(7), 714-23. doi:10.1158/1541-7786.MCR-12-0668
  48. He, Q.-Z., Luo, X.-Z., Wang, K., Zhou, Q., Ao, H., Yang, Y., … Duan, T. (2014). Isolation and characterization of cancer stem cells from high-grade serous ovarian carcinomas. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 33(1), 173- 84. doi:10.1159/000356660
  49. Shmelkov, S. V, Butler, J. M., Hooper, A. T., Hormigo, A., Kushner, J., Milde, T., … Rafii, S. (2008). CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. The Journal of Clinical Investigation, 118(6), 2111-20. doi:10.1172/JCI34401
  50. L'Espérance, S., Bachvarova, M., Tetu, B., Mes-Masson, A.-M., & Bachvarov, D. (2008). Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids. BMC Genomics, 9, 99. doi:10.1186/1471-2164-9-99
  51. Skates, S. J., Horick, N., Yu, Y., Xu, F.-J., Berchuck, A., Havrilesky, L. J., … Bast, R. C. (2004). Preoperative sensitivity and specificity for early-stage ovarian cancer when combining cancer antigen CA-125II, CA 15-3, CA 72-4, and macrophage colony-stimulating factor using mixtures of multivariate normal distributions. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 22(20), 4059-66. doi:10.1200/JCO.2004.03.091
  52. Hogg, R., & Friedlander, M. (2004). Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 22(7), 1315-27. doi:10.1200/JCO.2004.07.179
  53. Stirling, D., Porteous, M. E., Evans, D. G., Pichert, G., & Steel, M. (2006). Familial ovarian cancer screening. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 24(6), e11. doi:10.1200/JCO.2005.04.3356
  54. Fader, A. N., & Rose, P. G. (2007). Role of surgery in ovarian carcinoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 25(20), 2873-83. doi:10.1200/JCO.2007.11.0932
  55. Ferrandina, G., Ludovisi, M., Lorusso, D., Pignata, S., Breda, E., Savarese, A., … Scambia, G. (2008). Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 26(6), 890-6. doi:10.1200/JCO.2007.13.6606
  56. Kaye, S. B., Lubinski, J., Matulonis, U., Ang, J. E., Gourley, C., Karlan, B. Y., … Kaufman, B. (2012). Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 30(4), 372-9. doi:10.1200/JCO.2011.36.9215
  57. Sabbatini, P., Harter, P., Scambia, G., Sehouli, J., Meier, W., Wimberger, P., … Pfisterer, J. (2013). Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 31(12), 1554-61. doi:10.1200/JCO.2012.46.4057
  58. Rao, B. R., & Slotman, B. J. (1991). Endocrine factors in common epithelial ovarian cancer. Endocrine Reviews, 12(1), 14-26. doi:10.1210/edrv-12-1-14
  59. Kim, Y. J., Sauer, C., Testa, K., Wahl, J. K., Svoboda, R. a, Johnson, K. R., … Knudsen, K. a. (2005). Modulating the strength of cadherin adhesion: evidence for a novel adhesion complex. Journal of Cell Science, 118(Pt 17), 3883-94. doi:10.1242/jcs.02508
  60. Duffy, M. J. (2004). Evidence for the clinical use of tumour markers. Annals of Clinical Biochemistry, 41(Pt 5), 370-7. doi:10.1258/0004563041731529
  61. Sturgeon, C. M., Duffy, M. J., & Walker, G. (2011). The National Institute for Health and Clinical Excellence (NICE) guidelines for early detection of ovarian cancer: the pivotal role of the clinical laboratory. Annals of Clinical Biochemistry, 48(Pt 4), 295-9. doi:10.1258/acb.2011.011117
  62. Lathia, J. D., Gallagher, J., Myers, J. T., Li, M., Vasanji, A., McLendon, R. E., … Rich, J. N. (2011). Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells. PloS One, 6(9), e24807. doi:10.1371/journal.pone.0024807
  63. Latifi, A., Luwor, R. B., Bilandzic, M., Nazaretian, S., Stenvers, K., Pyman, J., … Ahmed, N. (2012). Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors. PloS One, 7(10), e46858. doi:10.1371/journal.pone.0046858
  64. Liu, S., Liu, C., Min, X., Ji, Y., Wang, N., Liu, D., … Li, K. (2013). Prognostic value of cancer stem cell marker aldehyde dehydrogenase in ovarian cancer: a metaanalysis. PloS One, 8(11), e81050. doi:10.1371/journal.pone.0081050
  65. Liao, J., Qian, F., Tchabo, N., Mhawech-Fauceglia, P., Beck, A., Qian, Z., … Odunsi, K. (2014). Ovarian Cancer Spheroid Cells with Stem Cell-Like Properties Contribute to Tumor Generation, Metastasis and Chemotherapy Resistance through Hypoxia-Resistant Metabolism. PloS One, 9(1), e84941. doi:10.1371/journal.pone.0084941
  66. Rao, T. D., Tian, H., Ma, X., Yan, X., Thapi, S., Schultz, N., … Spriggs, D. R. (2015). Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion. PloS One, 10(5), e0126633. doi:10.1371/journal.pone.0126633
  67. Hellstrom, I., & Hellstrom, K. E. (2011). fTwo novel biomarkers, mesothelin and HE4, for diagnosis of ovarian carcinoma. Expert Opinion on Medical Diagnostics, 5(3), 227-240. doi:10.1517/17530059.2011.559459
  68. Constantinou, P. E., Danysh, B. P., Dharmaraj, N., & Carson, D. D. (2011). Transmembrane mucins as novel therapeutic targets. Expert Review of Endocrinology & Metabolism, 6(6), 835-848. doi:10.1586/eem.11.70
  69. Guppy, A. E., & Rustin, G. J. S. (2002). CA125 response: can it replace the traditional response criteria in ovarian cancer? The Oncologist, 7(5), 437-43. doi:10.1634/theoncologist.7-5-437
  70. Shen, Y.-A., Wang, C.-Y., Chuang, H.-Y., Hwang, J. J.-J., Chi, W.-H., Shu, C.-H., … Chen, Y.-J. (2016). CD44 and CD24 coordinate the reprogramming of nasopharyngeal carcinoma cells towards a cancer stem cell phenotype through STAT3 activation. Oncotarget. doi:10.18632/oncotarget.11113
  71. Liu, Q., Cheng, Z., Luo, L., Yang, Y., Zhang, Z., Ma, H., … Li, X. (2016). C-terminus of MUC16 activates Wnt signaling pathway through its interaction with β- catenin to promote tumorigenesis and metastasis. Oncotarget. doi:10.18632/oncotarget.9191
  72. Lam, S. S. N., Ip, C. K. M., Mak, A. S. C., & Wong, A. S. T. (2016). A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression. Oncotarget. doi:10.18632/oncotarget.9345
  73. Munroe, M., & Kolesar, J. (2016). Olaparib for the treatment of BRCA-mutated advanced ovarian cancer. American Journal of Health-System Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists, 73(14), 1037-41. doi:10.2146/ajhp150550
  74. Pavlik, E. J., & van Nagell, J. R. (2013). Early detection of ovarian tumors using ultrasound. Women's Health (London, England), 9(1), 39-55; quiz 56-7. doi:10.2217/whe.12.62
  75. Suh-Burgmann, E., & Kinney, W. (2016). The Value of Ultrasound Monitoring of Adnexal Masses for Early Detection of Ovarian Cancer. Frontiers in Oncology, 6, 25. doi:10.3389/fonc.2016.00025
  76. Fargeas, C. A., Karbanová, J., Jászai, J., & Corbeil, D. (2011). CD133 and membrane microdomains: old facets for future hypotheses. World Journal of Gastroenterology, 17(36), 4149-52. doi:10.3748/wjg.v17.i36.4149
  77. Uchida, Y., Raina, D., Kharbanda, S., & Kufe, D. (2013). Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells. Cancer Biology & Therapy, 14(2), 127-34. doi:10.4161/cbt.22634
  78. Coosemans, A., Vergote, I., & Van Gool, S. W. (2013). Dendritic cell-based immunotherapy in ovarian cancer. Oncoimmunology, 2(12), e27059. doi:10.4161/onci.27059
  79. Wang, Z., Wang, Q., Wang, Q., Wang, Y., & Chen, J. (2016). Prognostic significance of CD24 and CD44 in breast cancer: a meta-analysis. The International Journal of Biological Markers. doi:10.5301/jbm.5000224
  80. Lloyd, K. O., & Yin, B. W. (2001). Synthesis and secretion of the ovarian cancer antigen CA 125 by the human cancer cell line NIH:OVCAR-3. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine, 22(2), 77-82. doi:50600
  81. O'Brien, T. J., Beard, J. B., Underwood, L. J., & Shigemasa, K. (2002). The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine, 23(3), 154-69. doi:64032
  82. Silva, I. a, Bai, S., McLean, K., Yang, K., Griffith, K., Thomas, D., … Buckanovich, R. J. (2011). Aldehyde dehydrogenase in combination with CD133 defines
  83. Rump, A., Morikawa, Y., Tanaka, M., Minami, S., Umesaki, N., Takeuchi, M., & Miyajima, A. (2004). Binding of ovarian cancer antigen CA125/MUC16 to
  84. Goff, B. a, Mandel, L. S., Drescher, C. W., Urban, N., Gough, S., Schurman, K. M., … Andersen, M. R. (2007). Development of an ovarian cancer symptom index:
  85. Kaatsch, P., Spix, C., & Hentschel, S. (2013). Krebs in Deutschland 2009/2010. (9. Auflage., p. 148). Berlin: Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg).
  86. Ledermann, J., Harter, P., Gourley, C., Friedlander, M., Vergote, I., Rustin, G., … Matulonis, U. (2014). Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. The Lancet. Oncology, 15(8), 852-61. doi:10.1016/S1470- 2045(14)70228-1
  87. possibilities for earlier detection. Cancer, 109(2), 221-7.
  88. Fedele, L., Arcaini, L., Vercellini, P., Marchini, M., Baglioni, A., & Bianchi, S. (1989). Serum Ca-125 concentrations in endometriosis. Acta Europaea Fertilitatis,
  89. Moore, R. G., Brown, A. K., Miller, M. C., Skates, S., Allard, W. J., Verch, T., … Bast, R. C. (2008). The use of multiple novel tumor biomarkers for the detection of
  90. Makhija, S., Taylor, D. D., Gibb, R. K., & Gerçel-Taylor, C. (1999). Taxol-induced bcl-2 phosphorylation in ovarian cancer cell monolayer and spheroids. International Journal of Oncology, 14(3), 515-21. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10024685
  91. Vasiliou, V., Bairoch, A., Tipton, K. F., & Nebert, D. W. (1999). Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping. Pharmacogenetics, 9(4), 421-34. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10780262
  92. O'Brien, T. J., Beard, J. B., Underwood, L. J., Dennis, R. A., Santin, A. D., & York, L. (2001). The CA 125 gene: an extracellular superstructure dominated by repeat sequences. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine, 22(6), 348-66. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11786729
  93. Tuxen, M. K., Sölétormos, G., & Dombernowsky, P. (2002). Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up. Scandinavian Journal of Clinical and Laboratory Investigation, 62(3), 177-88. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12088336
  94. Trimbos, J. B., Vergote, I., Bolis, G., Vermorken, J. B., Mangioni, C., Madronal, C., … Pecorelli, S. (2003). Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. Journal of the National Cancer Institute, 95(2), 113-25. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12529344
  95. Wilder, J. L., Pavlik, E., Straughn, J. M., Kirby, T., Higgins, R. V, DePriest, P. D., … Nagell, J. van. (2003). Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: a preliminary investigation. Gynecologic Oncology, 89(2), 233-5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12713985
  96. Parmar, M. K. B., Ledermann, J. A., Colombo, N., du Bois, A., Delaloye, J.-F., Kristensen, G. B., … Tropé, C. (2003). Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet, 361(9375), 2099-106. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12826431
  97. Sutherland, R. M., & Durand, R. E. (1976). Radiation response of multicell spheroids--an in vitro tumour model. Current Topics in Radiation Research Quarterly, 11(1), 87-139. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/128440
  98. Ren, J., Agata, N., Chen, D., Li, Y., Yu, W., Huang, L., … Kufe, D. (2004). Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell, 5(2), 163-75. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14998492
  99. Reinartz, S., Köhler, S., Schlebusch, H., Krista, K., Giffels, P., Renke, K., … Wagner, U. (2004). Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II). Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 10(5), 1580-7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15014007
  100. Soper, J. T., Hunter, V. J., Daly, L., Tanner, M., Creasman, W. T., & Bast, R. C. (1990). Preoperative serum tumor-associated antigen levels in women with pelvic masses. Obstetrics and Gynecology, 75(2), 249-54. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2300353
  101. Paavonen, J., Miettinen, A., Heinonen, P. K., Aaran, R. K., Teisala, K., Aine, R., … Lehtinen, M. (1989). Serum CA 125 in acute pelvic inflammatory disease. British Journal of Obstetrics and Gynaecology, 96(5), 574-9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2604772
  102. Jacobs, I., & Bast, R. C. (1989). The CA 125 tumour-associated antigen: a review of the literature. Human Reproduction (Oxford, England), 4(1), 1-12. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2651469
  103. Haga, Y., Sakamoto, K., Egami, H., Yoshimura, R., Mori, K., & Akagi, M. (1986). Clinical significance of serum CA125 values in patients with cancers of the digestive system. The American Journal of the Medical Sciences, 292(1), 30-4. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3459357
  104. Pittaway, D. E., & Fayez, J. A. (1987). Serum CA-125 antigen levels increase during menses. American Journal of Obstetrics and Gynecology, 156(1), 75-6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3467595
  105. Haga, Y., Sakamoto, K., Egami, H., Yoshimura, R., & Akagi, M. (1986). Evaluation of serum CA125 values in healthy individuals and pregnant women. The American Journal of the Medical Sciences, 292(1), 25-9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3521278
  106. Sutherland, R. M., McCredie, J. A., & Inch, W. R. (1971). Growth of multicell spheroids in tissue culture as a model of nodular carcinomas. Journal of the National Cancer Institute, 46(1), 113-20. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5101993
  107. Kenemans, P., Verstraeten, A. A., van Kamp, G. J., & von Mensdorff-Pouilly, S. (1995). The second generation CA 125 assays. Annals of Medicine, 27(1), 107- 13. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7741988
  108. Jones, R. J., Barber, J. P., Vala, M. S., Collector, M. I., Kaufmann, S. H., Ludeman, S. M., … Hilton, J. (1995). Assessment of aldehyde dehydrogenase in viable cells. Blood, 85(10), 2742-6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7742535
  109. Olive, P. L., & Durand, R. E. (1994). Drug and radiation resistance in spheroids: cell contact and kinetics. Cancer Metastasis Reviews, 13(2), 121-38. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7923546
  110. Lloyd, K. O., Yin, B. W., & Kudryashov, V. (1997). Isolation and characterization of ovarian cancer antigen CA 125 using a new monoclonal antibody (VK-8): identification as a mucin-type molecule. International Journal of Cancer. Journal International Du Cancer, 71(5), 842-50. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9180155
  111. Fendrick, J. L., Konishi, I., Geary, S. M., Parmley, T. H., Quirk, J. G., & O'Brien, T. J. (1997). CA125 phosphorylation is associated with its secretion from the WISH human amnion cell line. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine, 18(5), 278-89. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9276028
  112. Weaver, V. M., Lelièvre, S., Lakins, J. N., Chrenek, M. A., Jones, J. C. R., Giancotti, F., … Bissell, M. J. (2002). beta4 integrin-dependent formation of polarized threedimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell, 2(3), 205-16. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2788997&tool= pmcentrez&rendertype=abstract
  113. Tang, Z., Qian, M., & Ho, M. (2013). The role of mesothelin in tumor progression and targeted therapy. Anti-Cancer Agents in Medicinal Chemistry, 13(2), 276- 80. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3568227&tool= pmcentrez&rendertype=abstract
  114. Giannakouros, P., Comamala, M., Matte, I., Rancourt, C., & Piché, A. (2015). MUC16 mucin (CA125) regulates the formation of multicellular aggregates by altering β-catenin signaling. American Journal of Cancer Research, 5(1), 219-30. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4300699&tool= pmcentrez&rendertype=abstract


* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten