How to win the ovarian cancer stem cell battle: destroying the roots

Abstract

Ovarian cancer has the highest mortality rate among gynecologic malignancies. The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer. The initial treatment is usually effective, but many patients with ovarian cancer experience recurrence, and treatment options for recurrent disease remain challenging. Cancer stem cells (CSCs) are suggested to play an essential role in cancer recurrence after initial chemotherapy. Furthermore, they are of great interest as CSCs may also be involved in chemotherapy susceptibility. Thus, understanding the characteristics and mechanisms by which CSCs display resistance to therapeutic agents is important to design effective cancer treatments. In this review, we describe and discuss current therapeutic regimens for ovarian cancer, as well as the various CSC markers, association between CSCs and disease progression, correlation of CSCs with poor prognosis, enrichment of CSCs in tumor tissues following repeated chemotherapy cycles, activation of major signaling pathways following chemotherapy, and potential inhibitors that suppress these signaling cascades. In addition, clinical trials evaluating novel targeted therapies to overcome chemotherapy resistance will be reviewed. The combination of traditional chemotherapy and CSC-targeted therapy could be an effective and promising anticancer treatment for ovarian cancer. Understanding the biological properties of CSCs and the mechanism of chemotherapy resistance are critical to design and develop new therapeutic strategies to overcome CSC-associated chemotherapy resistance.

Keywords

Ovarian cancer / platinum resistance / cancer stem cell / chemotherapy / targeted therapy

References

[1] Colombo N,du Bois A.ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†..Ann Oncol2019;30:672-705

[2] Torre LA,DeSantis CE,Samimi G.Ovarian cancer statistics, 2018..CA Cancer J Clin2018;68:284-96 PMCID:PMC6621554

[3] Kaku T,Kawano Y.Histological classification of ovarian cancer..Med Electron Microsc2003;36:9-17

[4] Shih IM.Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis..Am J Pathol2004;164:1511-8 PMCID:PMC1615664

[5] Alsop K,Meldrum C.BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group..J Clin Oncol2012;30:2654-63 PMCID:PMC3413277

[6] Jayson GC,Kitchener HC.Ovarian cancer..Lancet2014;384:1376-88

[7] Seidman JD,Cosin JA,Kurman RJ.Survival rates for international federation of gynecology and obstetrics stage III ovarian carcinoma by cell type: a study of 262 unselected patients with uniform pathologic review..Int J Gynecol Cancer2012;22:367-71

[8] du Bois A,Pujade-Lauraine E,Ray-Coquard I.Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials..Cancer2009;115:1234-44

[9] Marth C,Zeimet AG.Front-line therapy of advanced epithelial ovarian cancer: standard treatment..Ann Oncol.2017;28 Suppl 8:viii36-9

[10] Muggia F.Platinum compounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer..Gynecol Oncol2009;112:275-81

[11] Rubin SC,Armstrong KA,Hoskins WJ.Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings..Obstet Gynecol1999;93:21-4

[12] Ushijima K.Treatment for recurrent ovarian cancer-at first relapse..J Oncol2010;2010:497429 PMCID:PMC2801501

[13] Takahashi A,Matsuura M.Comparison of secondary cytoreductive surgery plus chemotherapy with chemotherapy alone for recurrent epithelial ovarian, tubal, or peritoneal carcinoma: a propensity score-matched analysis of 112 consecutive patients..Medicine (Baltimore)2017;96:e8006 PMCID:PMC5604650

[14] Burger RA,Bookman MA.Incorporation of bevacizumab in the primary treatment of ovarian cancer..N Engl J Med2011;365:2473-83

[15] Moore K,Scambia G.Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer..N Engl J Med2018;379:2495-505

[16] Perren TJ,Pfisterer J.A phase 3 trial of bevacizumab in ovarian cancer..N Engl J Med2011;365:2484-96

[17] Jiang X,Li W,Zhang Z.PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms..J Cell Mol Med2019;23:2303-13 PMCID:PMC6433712

[18] Kim A,Naka T.Therapeutic strategies in epithelial ovarian cancer..J Exp Clin Cancer Res2012;31:14 PMCID:PMC3309949

[19] Au KK,Francis JA,Koti M.Current state of biomarkers in ovarian cancer prognosis..Future Oncol2015;11:3187-95

[20] Hanker LC,Burchardi N.The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy..Ann Oncol2012;23:2605-12

[21] Chen W,Haiech J,Zeniou M.Cancer stem cell quiescence and plasticity as major challenges in cancer therapy..Stem Cells Int2016;2016:1740936 PMCID:PMC4932171

[22] Takeishi S.To wake up cancer stem cells, or to let them sleep, that is the question..Cancer Sci2016;107:875-81 PMCID:PMC4946711

[23] Gao Y,Yang X.Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer..Oncotarget2015;6:9313-26 PMCID:PMC4496219

[24] Lapidot T,Vormoor J.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice..Nature1994;367:645-8

[25] Al-Hajj M,Benito-Hernandez A,Clarke MF.Prospective identification of tumorigenic breast cancer cells..Proc Natl Acad Sci U S A2003;100:3983-8 PMCID:PMC153034

[26] Singh SK,Terasaki M.Identification of a cancer stem cell in human brain tumors..Cancer Res2003;63:5821-8

[27] Bapat SA,Koppikar CB.Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer..Cancer Res2005;65:3025-9

[28] Zhang S,Chan MW.Identification and characterization of ovarian cancer-initiating cells from primary human tumors..Cancer Res2008;68:4311-20 PMCID:PMC2553722

[29] Curley MD,Cummings CL.CD133 expression defines a tumor initiating cell population in primary human ovarian cancer..Stem Cells2009;27:2875-83

[30] Alvero AB,Holmberg J.Stem-like ovarian cancer cells can serve as tumor vascular progenitors..Stem Cells2009;27:2405-13 PMCID:PMC2783765

[31] Wei X,Meirelles K.Mullerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics..Proc Natl Acad Sci U S A2010;107:18874-9 PMCID:PMC2973919

[32] Kryczek I,Roh M.Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells..Int J Cancer2012;130:29-39 PMCID:PMC3164893

[33] Meng E,Sullivan P.CD44+/CD24- ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival..Clin Exp Metastasis2012;29:939-48

[34] Cao L,Schilder J,Mohammad KS.Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer..Oncogene2012;31:2521-34

[35] Shah V,Garbuzenko OB,Rodriguez-Rodriguez L.Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug..Clin Cancer Res2013;19:6193-204 PMCID:PMC3846837

[36] Akhter MZ,Kumar V.Aggressive serous epithelial ovarian cancer is potentially propagated by EpCAM..Oncogene2018;37:2089-103

[37] Chefetz I,Holmberg JC.TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence..Cell Cycle2013;12:511-21 PMCID:PMC3587452

[38] Ruan Z,Kuang Y.Isolation and characterization of side population cells from the human ovarian cancer cell line SK-OV-3..Exp Ther Med2015;10:2071-8 PMCID:PMC4665172

[39] Boesch M,Reimer D.The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics..Oncotarget2014;5:7027-39 PMCID:PMC4196181

[40] Alvero AB,Fu HH.Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance..Cell Cycle2009;8:158-66 PMCID:PMC3041590

[41] Tsuneki M.CD44 regulation of endothelial cell proliferation and apoptosis via modulation of CD31 and VE-cadherin expression..J Biol Chem2014;289:5357-70 PMCID:PMC3937614

[42] Silasi DA,Illuzzi J.MyD88 predicts chemoresistance to paclitaxel in epithelial ovarian cancer..Yale J Biol Med2006;79:153-63 PMCID:PMC1994803

[43] Ponta H,Herrlich PA.CD44: from adhesion molecules to signalling regulators..Nat Rev Mol Cell Biol2003;4:33-45

[44] Cioffi M,Camerlingo R.Identification of a distinct population of CD133(+)CXCR4(+) cancer stem cells in ovarian cancer..Sci Rep2015;5:10357 PMCID:PMC4650662

[45] Kusumbe AP,Bapat SA.CD133-expressing stem cells associated with ovarian metastases establish an endothelial hierarchy and contribute to tumor vasculature..Stem Cells2009;27:498-508

[46] Sharrow AC,Collector MI,Simons BW.Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy..Gynecol Oncol2016;142:341-8 PMCID:PMC5843190

[47] Silva IA,McLean K.Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival..Cancer Res2011;71:3991-4001 PMCID:PMC3107359

[48] Liao J,Tchabo N.Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism..PLoS One2014;9:e84941 PMCID:PMC3883678

[49] Kuroda T,Torigoe T.ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis..PLoS One2013;8:e65158 PMCID:PMC3675199

[50] Ishiguro T,Ohata H.Establishment and characterization of an in vitro model of ovarian cancer stem-like cells with an enhanced proliferative capacity..Cancer Res2016;76:150-60

[51] Gao MQ,Kang S,Cho NH.CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells..Oncogene2010;29:2672-80

[52] Luo L,Liang B.Ovarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome..Exp Mol Pathol2011;91:596-602

[53] Wen Y,Huang Z,Wang Z.SOX2 is required to maintain cancer stem cells in ovarian cancer..Cancer Sci2017;108:719-31 PMCID:PMC5406610

[54] Belotte J,Alexis M.Sox2 gene amplification significantly impacts overall survival in serous epithelial ovarian cancer..Reprod Sci2015;22:38-46 PMCID:PMC4275450

[55] Curley MD,Schorge JO,Rueda BR.Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer..Front Biosci (Landmark Ed)2011;16:368-92

[56] Burgos-Ojeda D,Buckanovich RJ.Ovarian cancer stem cell markers: prognostic and therapeutic implications..Cancer Lett2012;322:1-7 PMCID:PMC4431611

[57] Tao Y,Huang R.Clinicopathological and Prognostic Significance of Cancer Stem Cell Markers in Ovarian Cancer Patients: Evidence from 52 Studies..Cell Physiol Biochem2018;46:1716-26

[58] Tayama S,Narantuya D.The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer..Oncotarget2017;8:44312-25 PMCID:PMC5546482

[59] Di J,Zusterzeel PL,Massuger LF.The stem cell markers Oct4A, Nanog and c-Myc are expressed in ascites cells and tumor tissue of ovarian cancer patients..Cell Oncol (Dordr)2013;36:363-74

[60] Peng S,Huang Y.Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer..Oncogene2010;29:2153-9

[61] Baker VV,Dixon D,Shingleton HM.c-myc amplification in ovarian cancer..Gynecol Oncol1990;38:340-2

[62] Vita M.The Myc oncoprotein as a therapeutic target for human cancer..Semin Cancer Biol2006;16:318-30

[63] Cancer Genome Atlas Research NetworkIntegrated genomic analyses of ovarian carcinoma..Nature2011;474:609-15 PMCID:PMC3163504

[64] Reyes-González JM,Mangala LS.Targeting c-MYC in platinum-resistant ovarian cancer..Mol Cancer Ther2015;14:2260-9 PMCID:PMC4596776

[65] Wang Y,Fang F.Epigenetic targeting of ovarian cancer stem cells..Cancer Res2014;74:4922-36 PMCID:PMC4155005

[66] Latifi A,Bilandzic M.Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors..PLoS One2012;7:e46858 PMCID:PMC3466197

[67] Steg AD,Katre AA.Stem cell pathways contribute to clinical chemoresistance in ovarian cancer..Clin Cancer Res2012;18:869-81 PMCID:PMC3271164

[68] Bellio C,Spriggs DR,Growdon WB.The metabolic inhibitor CPI-613 negates treatment enrichment of ovarian cancer stem cells..Cancers (Basel)2019;11:1678 PMCID:PMC6896080

[69] Abubaker K,Luwor R.Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden..Mol Cancer2013;12:24 PMCID:PMC3668985

[70] Zhou N,Yang B,Zhang D.Stem cell characteristics of dormant cells and cisplatin-induced effects on the stemness of epithelial ovarian cancer cells..Mol Med Rep2014;10:2495-504

[71] Bellio C,Foster R.PARP Inhibition induces enrichment of DNA repair-proficient CD133 and CD117 positive ovarian cancer stem cells..Mol Cancer Res2019;17:431-45

[72] Chau WK,Mak AS,Wong AS.c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin-ATP-binding cassette G2 signaling..Oncogene2013;32:2767-81

[73] Fischer MM,Yeung VP.WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death..Sci Adv2017;3:e1700090 PMCID:PMC5479655

[74] Song X,Lu C.Activation of hedgehog signaling and its association with cisplatin resistance in ovarian epithelial tumors..Oncol Lett2018;15:5569-76 PMCID:PMC5840551

[75] Park JT,Tropè CG,Shih IeM.Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin..Am J Pathol2010;177:1087-94 PMCID:PMC2928943

[76] Jung SG,Song JA.Prognostic significance of Notch 3 gene expression in ovarian serous carcinoma..Cancer Sci2010;101:1977-83

[77] Martins FC,Trinh A.Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier..Genome Biol2014;15:526 PMCID:PMC4268857

[78] Russo A,Dean M.PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation..Oncogene2018;37:1976-90 PMCID:PMC6472269

[79] Honig A,Meyer S.PI3K inhibitor D-116883 is effective in in vitro models of ovarian cancer..Anticancer Res2012;32:2035-41

[80] Westfall SD.Inhibition of phosphatidylinositol 3-kinase sensitizes ovarian cancer cells to carboplatin and allows adjunct chemotherapy treatment..Mol Cancer Ther2005;4:1764-71

[81] Carden CP,Thavasu P.The association of PI3 kinase signaling and chemoresistance in advanced ovarian cancer..Mol Cancer Ther2012;11:1609-17 PMCID:PMC4630857

[82] Dobbin ZC.The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer..Int J Mol Sci2013;14:8213-27 PMCID:PMC3645739

[83] Chen R,Silasi DA.Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells..Oncogene2008;27:4712-23 PMCID:PMC3041589

[84] Zou Z,Zhang Q.Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells..Autophagy2012;8:1798-810 PMCID:PMC3541289

[85] Chefetz I,Alvero AB,Mor G.Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFĸB pathway..Cell Cycle2011;10:2206-14 PMCID:PMC3154367

[86] Tallman MS,Schiffer CA.All-trans-retinoic acid in acute promyelocytic leukemia..N Engl J Med1997;337:1021-8

[87] Sporn MB.Role of retinoids in differentiation and carcinogenesis..Cancer Res1983;43:3034-40

[88] Kim D,Ryoo IG.High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling..Cell Death Dis2018;9:896 PMCID:PMC6117306

[89] Whitworth JM,Sellers JC.The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells..Gynecol Oncol2012;125:226-30 PMCID:PMC4049085

[90] Shank JJ,Ghannam J.Metformin targets ovarian cancer stem cells in vitro and in vivo..Gynecol Oncol2012;127:390-7 PMCID:PMC3580263

[91] Del Barco S,Cufí S.Metformin: multi-faceted protection against cancer..Oncotarget2011;2:896-917 PMCID:PMC3282095

[92] Zhang R,Wang H.Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+)CD117(+) ovarian cancer stem cells..Stem Cell Res Ther2015;6:262 PMCID:PMC4697317

[93] Brown JR,Shank JJ.Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer..JCI Insight2020;5:133247 PMCID:PMC7308054

[94] Chung H,Kwon M.The effect of salinomycin on ovarian cancer stem-like cells..Obstet Gynecol Sci2016;59:261-8 PMCID:PMC4958671

[95] Chefetz I,Yang K.A Pan-ALDH1A inhibitor induces necroptosis in ovarian cancer stem-like cells..Cell Rep2019;26:3061-3075.e6 PMCID:PMC7061440

[96] Khan I,Chesnokov M,Chefetz I.A decade of cell death studies: Breathing new life into necroptosis..Pharmacol Ther2020;107717:

[97] Nwani NG,Wang Y.A novel ALDH1A1 inhibitor targets cells with stem cell characteristics in ovarian cancer..Cancers (Basel)2019;11:502 PMCID:PMC6521036

[98] Harrington BS,Caminear MW.Drugs targeting tumor-initiating cells prolong survival in a post-surgery, post-chemotherapy ovarian cancer relapse model..Cancers (Basel)2020;12:1645 PMCID:PMC7352549

[99] Guo F,Kulbe H,Sehouli J.Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation..Biomed Pharmacother2019;118:109371

[100] Wu Y,Wu P,Xu ZP.Increased PD-L1 expression in breast and colon cancer stem cells..Clin Exp Pharmacol Physiol2017;44:602-4

[101] Codd AS,Torigo T.Cancer stem cells as targets for immunotherapy..Immunology2018;153:304-14 PMCID:PMC5795182

[102] Heddleston JM,Lathia JD,Hjelmeland AB.Hypoxia inducible factors in cancer stem cells..Br J Cancer2010;102:789-95 PMCID:PMC2833246

[103] Markowska A,Markowska J.Angiogenesis and cancer stem cells: New perspectives on therapy of ovarian cancer..Eur J Med Chem2017;142:87-94

[104] Ronco C,Demange L.ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells..Medchemcomm2017;8:295-319 PMCID:PMC6072143

[105] Deng J,Feng X.Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression..BMC Cancer2019;19:618 PMCID:PMC6591840

[106] Asiedu MK,Ingle JN,Radisky DC.AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells..Oncogene2014;33:1316-24 PMCID:PMC3994701

[107] Witt AE,Lee TI.Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer..Oncogene2017;36:1707-20 PMCID:PMC5364039

[108] Chesnokov M,Park Y.The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma..bioRxiv2019;772061