Chemotherapy Induces Adaptive Drug Resistance and Metastatic Potentials Via Phenotypic CXCR4-expressing Cell State Transition in Ovarian Cancer

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Feb 15

PMID 28196146

Citations 32

Authors

Hyun Hee Lee

Vanessa Bellat

Benedict Law

Affiliations

Soon will be listed here.

Abstract

Ovarian cancer (OVC) patients who receive chemotherapy often acquire drug resistance within one year. This can lead to tumor reoccurrence and metastasis, the major causes of mortality. We report a transient increase of a small distinctive CXCR4High/CD24Low cancer stem cell population (CXCR4High) in A2780 and SKOV-3 OVC cell lines in response to cisplatin, doxorubicin, and paclitaxel, treatments. The withdrawal of the drug challenges reversed this cell-state transition. CXCR4High exhibits dormancy in drug resistance and mesenchymal-like invasion, migration, colonization, and tumor formation properties. The removal of this cell population from a doxorubicin-resistant A2780 lineage (A2780/ADR) recovered the sensitivity to drug treatments. A cytotoxic peptide (CXCR4-KLA) that can selectively target cell-surface CXCR4 receptor was further synthesized to investigate the therapeutic merits of targeting CXCR4High. This peptide was more potent than the conventional CXCR4 antagonists (AMD3100 and CTCE-9908) in eradicating the cancer stem cells. When used together with cytotoxic agents such as doxorubicin and cisplatin, the combined drug-peptide regimens exhibited a synergistic cell-killing effect on A2780, A2780/ADR, and SKOV-3. Our data suggested that chemotherapy could establish drug-resistant and tumor-initiating properties of OVC via reversible CXCR4 cell state transition. Therapeutic strategies designed to eradicate rather than antagonize CXCR4High might offer a far-reaching potential as supportive chemotherapy.

Citing Articles

STAU1-mediated CNBP mRNA degradation by LINC00665 alters stem cell characteristics in ovarian cancer.

Liu X, Chen Y, Li Y, Bai J, Zeng Z, Wang M Biol Direct. 2024; 19(1):59.

PMID: 39080743 PMC: 11288052. DOI: 10.1186/s13062-024-00506-w.

The Potential of Epigallocatechin Gallate in Targeting Cancer Stem Cells: A Comprehensive Review.

Chaudhuri R, Samanta A, Saha P, Ghosh S, Sinha D Curr Med Chem. 2024; 31(32):5255-5280.

PMID: 38243984 DOI: 10.2174/0109298673281666231227053726.

CRISPR/Cas9-mediated silencing of CD44: unveiling the role of hyaluronic acid-mediated interactions in cancer drug resistance.

Xu Z Naunyn Schmiedebergs Arch Pharmacol. 2023; 397(5):2849-2876.

PMID: 37991544 DOI: 10.1007/s00210-023-02840-8.

Targeting CXCR4 abrogates resistance to trastuzumab by blocking cell cycle progression and synergizes with docetaxel in breast cancer treatment.

Liu S, Xie S, Liu W, Gagea M, Hanker A, Nguyen N Breast Cancer Res. 2023; 25(1):62.

PMID: 37280713 PMC: 10245436. DOI: 10.1186/s13058-023-01665-w.

Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance.

Nairuz T, Mahmud Z, Manik R, Kabir Y Stem Cell Rev Rep. 2023; 19(6):1577-1595.

PMID: 37129728 DOI: 10.1007/s12015-023-10529-x.

References

Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N . Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood. 2005; 106(5):1824-30. DOI: 10.1182/blood-2004-12-4918. View

Jankowski K, Kucia M, Wysoczynski M, Reca R, Zhao D, Trzyna E . Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res. 2003; 63(22):7926-35. View

Ferrandina G, Bonanno G, Pierelli L, Perillo A, Procoli A, Mariotti A . Expression of CD133-1 and CD133-2 in ovarian cancer. Int J Gynecol Cancer. 2007; 18(3):506-14. DOI: 10.1111/j.1525-1438.2007.01056.x. View

Hsu E, Chen N, Westbrook A, Wang F, Zhang R, Taylor R . CXCR4 and CXCL12 down-regulation: a novel mechanism for the chemoprotection of 3,3'-diindolylmethane for breast and ovarian cancers. Cancer Lett. 2008; 265(1):113-23. DOI: 10.1016/j.canlet.2008.02.033. View

Takenaga M, Tamamura H, Hiramatsu K, Nakamura N, Yamaguchi Y, Kitagawa A . A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma. Biochem Biophys Res Commun. 2004; 320(1):226-32. DOI: 10.1016/j.bbrc.2004.05.155. View

Righi E, Kashiwagi S, Yuan J, Santosuosso M, Leblanc P, Ingraham R . CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res. 2011; 71(16):5522-5534. PMC: 3959864. DOI: 10.1158/0008-5472.CAN-10-3143. View

Zhang S, Balch C, Chan M, Lai H, Matei D, Schilder J . Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008; 68(11):4311-20. PMC: 2553722. DOI: 10.1158/0008-5472.CAN-08-0364. View

Li J, Jiang K, Qiu X, Li M, Hao Q, Wei L . Overexpression of CXCR4 is significantly associated with cisplatin-based chemotherapy resistance and can be a prognostic factor in epithelial ovarian cancer. BMB Rep. 2013; 47(1):33-8. PMC: 4163846. DOI: 10.5483/bmbrep.2014.47.1.069. View

Xue B, Wu W, Huang K, Xie T, Xu X, Zhang H . Stromal cell-derived factor-1 (SDF-1) enhances cells invasion by αvβ6 integrin-mediated signaling in ovarian cancer. Mol Cell Biochem. 2013; 380(1-2):177-84. DOI: 10.1007/s11010-013-1671-1. View

10.

Hall J, Korach K . Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol Endocrinol. 2003; 17(5):792-803. DOI: 10.1210/me.2002-0438. View

11.

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. Int J Cancer. 2007; 122(1):91-9. DOI: 10.1002/ijc.23083. View

12.

Chou T . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006; 58(3):621-81. DOI: 10.1124/pr.58.3.10. View

13.

Ma W, Feng S, Yao X, Yuan Z, Liu L, Xie Y . Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells. Sci Rep. 2015; 5:18789. PMC: 4686932. DOI: 10.1038/srep18789. View

14.

Elisseeva E, Slupsky C, Crump M, Clark-Lewis I, Sykes B . NMR studies of active N-terminal peptides of stromal cell-derived factor-1. Structural basis for receptor binding. J Biol Chem. 2000; 275(35):26799-805. DOI: 10.1074/jbc.M003386200. View

15.

Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W . SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett. 2012; 322(2):169-76. PMC: 3408048. DOI: 10.1016/j.canlet.2012.02.035. View

16.

Rhodes L, Short S, Neel N, Salvo V, Zhu Y, Elliott S . Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Res. 2010; 71(2):603-13. PMC: 3140407. DOI: 10.1158/0008-5472.CAN-10-3185. View

17.

Goldman A, Majumder B, Dhawan A, Ravi S, Goldman D, Kohandel M . Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition. Nat Commun. 2015; 6:6139. PMC: 4339891. DOI: 10.1038/ncomms7139. View

18.

Forster R, Kremmer E, Schubel A, Breitfeld D, Kleinschmidt A, Nerl C . Intracellular and surface expression of the HIV-1 coreceptor CXCR4/fusin on various leukocyte subsets: rapid internalization and recycling upon activation. J Immunol. 1998; 160(3):1522-31. View

19.

Gao Y, Foster R, Yang X, Feng Y, Shen J, Mankin H . Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer. Oncotarget. 2015; 6(11):9313-26. PMC: 4496219. DOI: 10.18632/oncotarget.3220. View

20.

Huang K, Kiefer C, Kamal A . Novel role for NFAT3 in ERK-mediated regulation of CXCR4. PLoS One. 2014; 9(12):e115249. PMC: 4267837. DOI: 10.1371/journal.pone.0115249. View