Vol 15, No 5 (2019)
Review paper
Published online: 2019-09-05

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Characteristics of in vitro model systems for ovarian cancer studies

Patrycja Tudrej1, Katarzyna Aleksandra Kujawa1, Alexander Jorge Cortez1, Katarzyna Marta Lisowska1
Oncol Clin Pract 2019;15(5):246-259.


Nowadays, targeted therapy plays a growing role in oncological treatment. In ovarian cancer, particularly promising results are achieved with poly (ADP-ribose) polymerase (PARP) inhibitors. Recent clinical trials have shown that PARP inhibitors can result in significantly longer progression-free survival. These results encourage the search for other targeted therapies and bring hope that ovarian cancer can soon become a manageable chronic disease. The main problem in ovarian cancer research is the heterogeneity of this disease. Recent studies have shown that different histological types of ovarian cancer can originate from distinct tissues. According to the recent knowledge, “ovarian cancer” is an artificial term for distinct invasive malignancies localised within the pelvis. Genetic and immunophenotype analyses have shown that high-grade serous ovarian cancer, the most frequent histological type and the one with the worst prognosis, originates mainly from fallopian tube epithelium, while endometrioid and clear-cell cancers originate from the endometrium. For these reasons, in basic and preclinical studies on ovarian cancer, one has to carefully choose a well-defined model system, corresponding to the histological type of interest. In this article, we discuss ovarian cancer cell lines most frequently used in in vitro studies. Our aim is to indicate the advantages and disadvantages of different models, encompassing primary and established cell cultures, two- and three-dimensional models, etc. In particular, we would like to alert researchers to the fact that the most popular cell lines SKOV3 and A2780 do not represent a suitable model for studies on high-grade serous ovarian cancer.

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  1. Cortez AJ, Tudrej P, Kujawa KA, et al. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol. 2018; 81(1): 17–38.
  2. Lee JY, Kim S, Kim YT, et al. Changes in ovarian cancer survival during the 20 years before the era of targeted therapy. BMC Cancer. 2018; 18: 1–8.
  3. Dubeau L. The cell of origin of ovarian epithelial tumors and the ovarian surface epithelium dogma: does the emperor have no clothes? Gynecol Oncol. 1999; 72(3): 437–442.
  4. Dubeau L. The cell of origin of ovarian epithelial tumours. Lancet Oncol. 2008; 9(12): 1191–1197.
  5. Kujawa KA, Lisowska KM. Ovarian cancer — from biology to clinic. Postepy Hig Med Dosw (Online). 2015; 69: 1275–1290.
  6. Cobb LP, Gaillard S, Wang Y, et al. Adenocarcinoma of Mullerian origin: review of pathogenesis, molecular biology, and emerging treatment paradigms. Gynecol Oncol Res Pract. 2015; 2: 1–16.
  7. Shih IM, Kurman R. Ovarian tumorigenesis — A proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004; 164(5): 1511–1518.
  8. Creative Bioarray: Immortalized human fallopian tube secretory epithelial cells (FT33-shp53-R24C). Available online: https://www.creative-bioarray.com/immortalized-human-fallopian-tube-secretory-epithelial-cells-ft33-shp53-r24c-cat-csc-i9204l-item-2114.htm (accessed on 2019-03-14).
  9. Life Line Cell Technology: Fallopian tube epithelial cells. Available online: https://www.lifelinecelltech.com/shop/tissue-type/reproductive-tissue/fallopian-tube-epithelial-cells-fc-0081/ (accessed on 2019-03-13).
  10. ScienCell Research Laboratories: Human Ovarian Surface Epithelial Cells. Available online: https://www.sciencellonline.com/human-ovarian-surface-epithelial-cells.html (accessed on 2019-03-14).
  11. Applied Biological Materials: Human Primary Ovarian Surface Epithelial Cells. Available online: https://www.abmgood.com/Human-Primary-Ovarian-Surface-Epithelial-Cells-T4198.html (accessed on 2019-03-14).
  12. Sasaki R, Narisawa-Saito M, Yugawa T, et al. Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes. Carcinogenesis. 2009; 30(3): 423–431.
  13. Gjyshi A, Dash S, Cen L, et al. Early transcriptional response of human ovarian and fallopian tube surface epithelial cells to norepinephrine. Sci Rep. 2018; 8: 1–11.
  14. Auersperg N, Pan J, Grove BD, et al. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999; 96(11): 6249–6254.
  15. Li NF, Broad S, Lu YJ, et al. Human ovarian surface epithelial cells immortalized with hTERT maintain functional pRb and p53 expression. Cell Prolif. 2007; 40(5): 780–794.
  16. Lawrenson K, Benjamin E, Turmaine M, et al. In vitro three-dimensional modelling of human ovarian surface epithelial cells. Cell Prolif. 2009; 42(3): 385–393.
  17. Lee YL, Lee KF, Xu JS, et al. Establishment and characterization of an immortalized human oviductal cell line. Mol Reprod Dev. 2001; 59(4): 400–409.
  18. Kuhn ET. Rimondi E, Secchiero P. Current preclinical models of ovarian cancer. J Carcinog Mutagen. 2015; 6(2): 1–9.
  19. Tudrej P, Olbryt M, Zembala-Nożyńska E, et al. Establishment and characterization of the novel high-grade serous ovarian cancer cell line OVPA8. Int J Mol Sci. 2018; 19(7): 1–26.
  20. Ince TA, Sousa AD, Jones MA, et al. Characterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours. Nat Commun. 2015; 6: 1–14.
  21. National Cancer Institute: Cell lines in the in vitro Screen. Available online: https://dtp.cancer.gov/discovery_development/nci-60/cell_list.htm (accessed on 15.03.2019).
  22. Ellison G, Klinowska T, Westwood RFR, et al. Further evidence to support the melanocytic origin of MDA-MB-435. Mol Pathol. 2002; 55(5): 294–299.
  23. Rae JM, Creighton CJ, Meck JM, et al. MDA-MB-435 cells are derived from M14 melanoma cells — a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res Treat. 2007; 104(1): 13–19.
  24. Chambers AF. MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res. 2009; 69(13): 5292–5293.
  25. Roschke AV, Tonon G, Gehlhaus KS, et al. Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res. 2003; 63(24): 8634–8647.
  26. Gartler SM. Apparent Hela cell contamination of human heteroploid cell lines. Nature. 1968; 217(5130): 750–751.
  27. Fogh J, Wright WC, Loveless JD. Absence of Hela cell contamination in 169 cell lines derived from human tumors. J Natl Cancer Inst. 1977; 58(2): 209–214.
  28. Anglesio MS, Wiegand KC, Melnyk N, et al. Type-specific cell line models for type-specific ovarian cancer research. PLoS One. 2013; 8(9): e72162.
  29. Domcke S, Sinha R, Levine DA, et al. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013; 4: 1–10.
  30. Beaufort CM, Helmijr JCA, Piskorz AM, et al. Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PLoS One. 2014; 9(9): 1–16.
  31. Fogh J, Trempe G. New human tumor cell lines. Human Tumor Cells in Vitro. 1975: 115–159.
  32. Hamilton TC, Young RC, Ozols RF. Experimental-model systems of ovarian-cancer — applications to the design and evaluation of new treatment approaches. Semin Oncol. 1984; 11(3): 285–298. .
  33. Shaw TJ, Senterman MK, Dawson K, et al. Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer. Mol Ther. 2004; 10(6): 1032–1042.
  34. Lee JM, Mhawech-Fauceglia P, Lee N, et al. A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro. Lab Invest. 2013; 93(5): 528–542.
  35. Lau DHM, Lewis AD, Ehsan MN, et al. Multifactorial mechanisms associated with broad cross-resistance of ovarian-carcinoma cells selected by cyanomorpholino doxorubicin. Cancer Res. 1991; 51(19): 5181–5187. .
  36. Wilson AP. Characterization of a cell line derived from the ascites of a patient with papillary serous cystadenocarcinoma of the ovary. J Natl Cancer Inst. 1984; 72(3): 513–521.
  37. Ikediobi ON, Davies H, Bignell G, et al. Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol Cancer Ther. 2006; 5(11): 2606–2612.
  38. Elias KM, Emori MM, Papp E, et al. Beyond genomics: critical evaluation of cell line utility for ovarian cancer research. Gynecol Oncol. 2015; 139(1): 97–103.
  39. Hew KE, Miller PC, El-Ashry D, et al. MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in er-positive high-grade serous ovarian cancer. Clin Cancer Res. 2016; 22(4): 935–947.
  40. Witt AE, Lee CW, Lee TI, et al. Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer. Oncogene. 2017; 36(12): 1707–1720.
  41. Landini I, Lapucci A, Pratesi A, et al. Selection and characterization of a human ovarian cancer cell line resistant to auranofin. Oncotarget. 2017; 8(56): 96062–96078.
  42. Behrens BC, Hamilton TC, Masuda H, et al. Characterization of a cis-diamminedichloroplatinum(Ii)-resistant human ovarian-cancer cell-line and its use in evaluation of platinum analogs. Cancer Res. 1987; 47(2): 414–418. .
  43. Masuda H, Ozols RF, Lai GM, et al. Increased DNA-repair as a mechanism of acquired-resistance to cis-diamminedichloroplatinum(Ii) in human ovarian-cancer cell-lines. Cancer Res. 1988; 48(20): 5713–5716. .
  44. Januchowski R, Zawierucha P, Ruciński M, et al. Drug transporter expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line. Biomed Pharmacother. 2014; 68(4): 447–453.
  45. Sak K. In vitro cytotoxic activity of flavonoids on human ovarian cancer cell lines. Cancer Science & Research: Open Access. 2015; 2(1): 1–13.
  46. Sun Si, Zhao S, Yang Q, et al. Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation. Cancer Sci. 2018; 109(6): 1853–1864.
  47. ECACC General Cancer Collection: A2780ADR. Available online: https://www.phe-culturecollections.org.uk/products/celllines/generalcell/detail.jsp?refId=93112520&collection=ecacc_gc (accessed on 2019-03-15).
  48. Han X, DU F, Jiang Li, et al. A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties. Oncol Lett. 2013; 6(5): 1295–1298.
  49. Resistant Cancer Cell Line Collection. Available online: http://www.wass-michaelislab.org/drug.php?drug=cisplatin (accessed on 2019-03-15).
  50. Jazaeri AA, Shibata E, Park J, et al. Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924. Mol Cancer Ther. 2013; 12(10): 1958–1967.
  51. Ho CM, Lee FK, Huang SH, et al. Everolimus following 5-aza-2-deoxycytidine is a promising therapy in paclitaxel-resistant clear cell carcinoma of the ovary. Am J Cancer Res. 2018; 8(1): 56–69. .
  52. Perego P, Giarola M, Righetti SC, et al. Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res. 1996; 56(3): 556–562. .
  53. Stewart JJ, White JT, Yan X, et al. Proteins associated with csplatin resistance in ovarian cancer cells identified by quantitative proteomic technology and integrated with mRNA expression levels. Mol Cell Proteomics. 2006; 5(3): 433–443.
  54. Stordal B, Hamon M, McEneaney V, et al. Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein. PLoS One. 2012; 7(7): 1–13.
  55. Benedetti V, Perego P, Beretta GL, et al. Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds. Mol Cancer Ther. 2008; 7(3): 679–687.
  56. Maliepaard M, van Gastelen MA, de Jong LA, et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999; 59(18): 4559–4563.
  57. Judson PL, Al Sawah E, Marchion DC, et al. Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity. Int J Gynecol Cancer. 2012; 22(6): 960–967.
  58. Redmond A, Moran E, Clynes M. Multiple drug resistance in the human ovarian carcinoma cell line OAW42-A. Eur J Cancer. 1993; 29A(8): 1078–1081.
  59. Sherman-Baust CA, Becker KG, Wood Iii WH, et al. Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin. J Ovarian Res. 2011; 4(1): 1–11.
  60. Liu Y, Han S, Li Y, et al. MicroRNA-20a contributes to cisplatin-resistance and migration of OVCAR3 ovarian cancer cell line. Oncol Lett. 2017; 14(2): 1780–1786.
  61. Macleod K, Mullen P, Sewell J, et al. Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res. 2005; 65(15): 6789–6800.
  62. Yu DH, Wolf JK, Scanlon M, et al. Enhanced C-Erbb-2/Neu expression in human ovarian-cancer cells correlates with more severe malignancy that can be suppressed by E1a. Cancer Res. 1993; 53(4): 891–898. .
  63. Yan XD, Li M, Yuan Y, et al. Biological comparison of ovarian cancer resistant cell lines to cisplatin and taxol by two different administrations. Oncol Rep. 2007; 17(5): 1163–1169. .
  64. Kubota N, Nishio K, Takeda Y, et al. Characterization of an etoposide-resistant human ovarian cancer cell line. Cancer Chemoth Pharm. 1994; 34(3): 183–190.
  65. Li L, Luan YZ, Wang GD, et al. Development and characterization of five cell models for chemoresistance studies of human ovarian carcinoma. Int J Mol Med. 2004; 14(2): 257–264. .
  66. Lee C. Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells. Mol Med Rep. 2015; 12(1): 1485–1492.
  67. Bradley G, Naik M, Ling V. P-glycoprotein expression in multidrug-resistant human ovarian-carcinoma cell-lines. Cancer Res. 1989; 49(10): 2790–2796. .
  68. Leung CS, Yeung TL, Yip KP, et al. Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance. J Clin Invest. 2018; 128(2): 589–606.
  69. Dasari S, Fang Y, Mitra AK. Cancer associated fibroblasts: naughty neighbors that drive ovarian cancer progression. Cancers (Basel). 2018; 10(11): 1–18.
  70. Januchowski R, Zawierucha P, Ruciński M, et al. Microarray-based detection and expression analysis of extracellular matrix proteins in drug‑resistant ovarian cancer cell lines. Oncol Rep. 2014; 32(5): 1981–1990.
  71. Wu YH, Chang TH, Huang YF, et al. COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization. Oncotarget. 2015; 6(27): 23748–23763.
  72. Cornelison R, Llaneza DC, Landen CN. Emerging therapeutics to overcome chemoresistance in epithelial ovarian cancer: a mini-review. Int J Mol Sci. 2017; 18(10): 1–20.
  73. Roy L, Cowden Dahl KD. Can stemness and chemoresistance be therapeutically targeted via signaling pathways in ovarian cancer? Cancers (Basel). 2018; 10(8): 1–23.
  74. Suh D, Kim MK, Kim H, et al. Epigenetic therapies as a promising strategy for overcoming chemoresistance in epithelial ovarian cancer. Journal of Cancer Prevention. 2013; 18(3): 227–234.
  75. Smith HJ, Straughn JM, Buchsbaum DJ, et al. Epigenetic therapy for the treatment of epithelial ovarian cancer: A clinical review. Gynecol Oncol Rep. 2017; 20: 81–86.
  76. Moufarrij S, Dandapani M, Arthofer E, et al. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics. 2019; 11(1): 7.
  77. Lisowska KM, Olbryt M, Student S, et al. Unsupervised analysis reveals two molecular subgroups of serous ovarian cancer with distinct gene expression profiles and survival. J Cancer Res Clin Oncol. 2016; 142(6): 1239–1252.
  78. Lisowska KM, Olbryt M, Dudaladava V, et al. Gene expression analysis in ovarian cancer — faults and hints from DNA microarray study. Front Oncol. 2014; 4: 1–11.
  79. Konecny GE, Winterhoff B, Wang C. Gene-expression signatures in ovarian cancer: Promise and challenges for patient stratification. Gynecol Oncol. 2016; 141(2): 379–385.
  80. Lupia M, Cavallaro U. Ovarian cancer stem cells: still an elusive entity? Mol Cancer. 2017; 16(1): 64.
  81. Klemba A, Purzycka-Olewiecka JK, Wcisło G, et al. Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance. Contemp Oncol (Pozn). 2018; 22(1A): 48–55.
  82. Ottevanger PB. Ovarian cancer stem cells more questions than answers. Semin Cancer Biol. 2017; 44: 67–71.
  83. Luo X, Dong Z, Chen Y, et al. Enrichment of ovarian cancer stem-like cells is associated with epithelial to mesenchymal transition through an miRNA-activated AKT pathway. Cell Prolif. 2013; 46(4): 436–446.
  84. Nowicka A, Marini FC, Solley TN, et al. Human omental-derived adipose stem cells increase ovarian cancer proliferation, migration, and chemoresistance. PLoS One. 2013; 8(12): e81859.
  85. Coffman LG, Pearson AT, Frisbie LG, et al. Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma. Stem Cells. 2019; 37(2): 257–269.
  86. Coffman LG, Choi YJ, McLean K, et al. Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop. Oncotarget. 2016; 7(6): 6916–6932.
  87. Klopp AH, Gupta A, Spaeth E, et al. Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2011; 29(1): 11–19.
  88. Bernardo AD, Thorsteinsdóttir S, Mummery CL. Advantages of the avian model for human ovarian cancer. Mol Clin Oncol. 2015; 3(6): 1191–1198.
  89. Kitel R, Czarnecka J, Rusin A. Three-dimensional cell cultures. Applications in basic science and biotechnology. Postepy Bochemii. 2013; 59(3): 305–314. .
  90. Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell. 2007; 130(4): 601–610.
  91. Heredia-Soto V, Redondo A, Berjón A, et al. High-throughput 3-dimensional culture of epithelial ovarian cancer cells as preclinical model of disease. Oncotarget. 2018; 9(31): 21893–21903.
  92. Barbolina MV, Adley BP, Ariztia EV, et al. Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression. J Biol Chem. 2007; 282(7): 4924–4931.
  93. Barbolina MV, Moss NM, Westfall SD, et al. Microenvironmental regulation of ovarian cancer metastasis. Cancer Treat Res. 2009; 149: 319–334.
  94. Loessner D, Rizzi SC, Stok KS, et al. A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread. Biomaterials. 2013; 34(30): 7389–7400.
  95. Muranen T, Selfors LM, Worster DT, et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell. 2012; 21(2): 227–239.
  96. White EA, Kenny HA, Lengyel E. Three-dimensional modeling of ovarian cancer. Adv Drug Deliv Rev. 2014; 79-80: 184–192.
  97. Nieman KM, Kenny HA, Penicka CV, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011; 17(11): 1498–1503.
  98. Zhang Y, Coletta AM, Allen PK, et al. Perirenal adiposity is associated with lower progression-free survival from ovarian cancer. Int J Gynecol Cancer. 2018; 28(2): 285–292.
  99. Lawrenson K, Notaridou M, Lee N, et al. In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. BMC Cell Biol. 2013; 14: 43.