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Studies on the Chromosomal Heterogeneity Derived from Tetraploid Tumor Cells and the Influence of the Heterogeneity on the Drug Efficacy

梅田, 正 筑波大学 DOI:10.15068/0002000835

2021.08.02

概要

Chromosomal instability is one of the most prominent features of tumor cells, and it causes aneuploidy and heterogeneity. Heterogeneity contributes to drug resistance in tumors. In chapter 1, I focused on the tetraploidy as an intermediate of aneuploidy. Although a number of studies have shown the importance of tetraploidy in cancer development, how tetraploid cells transform into aneuploid cells is poorly understood. Here, I show that spindle polarity (e.g., bipolarity or multipolarity) in tetraploid cells depends on the level of functional phospho-Eg5, a mitotic kinesin, localised at the spindles. Tetraploid cells with high levels of functional Eg5 give rise to a heterogeneous aneuploid population via multipolar division. This process is suppressed by inhibition of Eg5 or expression of a non-phosphorylatable Eg5 mutant, as well as by changing the balance between opposing forces required for centrosome separation. Furthermore, Eg5 expression levels correlate with ploidy status in gastric cancer specimens. In chapter 2, to speculate the influence of heterogeneity on acquired drug resistance, I assessed the treatment-induced changes to a treatment targeted molecule (human epidermal growth factor receptor 2: HER2) using highly heterogeneous gastric cancer specimens. I analysed 6 paired pre- and post-treatment samples, and found that in 5 cases, HER2 overexpressed tumor cells were lost after treatment, and that includes both anti-HER2 treatment and cytotoxic chemotherapy. The loss of HER2 expressed cells could cause the resistance to subsequent anti-HER2 therapies. Collectively, highly Eg5 expressed tetraploid cancer cells can accelerate the generation of aneuploidy and heterogeneity. Heterogeneous tumors can acquire resistance to targeted therapies by inducing the loss of target molecules, such as HER2.

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参考文献

1. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144(5): p. 646-74.

2. Cancer Genome Atlas Research, N., Comprehensive molecular characterization of gastric adenocarcinoma. Nature, 2014. 513(7517): p. 202-9.

3. Storchova, Z. and D. Pellman, From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol, 2004. 5(1): p. 45-54.

4. Storchova, Z. and C. Kuffer, The consequences of tetraploidy and aneuploidy. J Cell Sci, 2008. 121(Pt 23): p. 3859-66.

5. Fisher, R., L. Pusztai, and C. Swanton, Cancer heterogeneity: implications for targeted therapeutics. British Journal Of Cancer, 2013. 108: p. 479.

6. Heng, H.H., et al., Chromosomal instability (CIN): what it is and why it is crucial to cancer evolution. Cancer Metastasis Rev, 2013. 32(3-4): p. 325-40.

7. Alsina, M., I. Gullo, and F. Carneiro, Intratumoral heterogeneity in gastric cancer: a new challenge to face. Ann Oncol, 2017. 28(5): p. 912-913.

8. Lee, H.E., et al., Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur J Cancer, 2013. 49(6): p. 1448-57.

9. Yang, J., et al., Intratumoral heterogeneity determines discordant results of diagnostic tests for human epidermal growth factor receptor (HER) 2 in gastric cancer specimens. Cell Biochem Biophys, 2012. 62(1): p. 221-8.

10. Duelli, D.M., et al., A primate virus generates transformed human cells by fusion.The Journal of Cell Biology, 2005. 171(3): p. 493-503.

11. Brito, D.A. and C.L. Rieder, Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol, 2006. 16(12): p. 1194-200.

12. Shi, Q. and R.W. King, Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature, 2005. 437(7061): p. 1038-42.

13. Daniels, M.J., et al., Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science, 2004. 306(5697): p. 876-9.

14. Fujiwara, T., et al., Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature, 2005. 437(7061): p. 1043-7.

15. Galipeau, P.C., et al., 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. Proc Natl Acad Sci U S A, 1996. 93(14): p. 7081-4.

16. Olaharski, A.J., et al., Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis, 2006. 27(2): p. 337-43.

17. Arteaga, C.L., et al., Treatment of HER2-positive breast cancer: current status and future perspectives. Nature Reviews Clinical Oncology, 2012. 9(1): p. 16-32.

18. Bang, Y.J., et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro- oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010. 376(9742): p. 687-97.

19. Satoh, T., et al., Lapatinib plus paclitaxel versus paclitaxel alone in the second- line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol, 2014. 32(19): p. 2039-49.

20. Thuss-Patience, P.C., et al., Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol, 2017. 18(5): p. 640-653.

21. Verma, S., et al., Trastuzumab emtansine for HER2-positive advanced breast cancer. New England Journal of Medicine, 2012. 367(19): p. 1783-1791.

22. Holland, A.J. and D.W. Cleveland, Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep, 2012. 13(6): p. 501-14.

23. King, R.W., When 2+2=5: the origins and fates of aneuploid and tetraploid cells.Biochim Biophys Acta, 2008. 1786(1): p. 4-14.

24. Ganem, N.J., Z. Storchova, and D. Pellman, Tetraploidy, aneuploidy and cancer.Curr Opin Genet Dev, 2007. 17(2): p. 157-62.

25. Sturgill, E.G., et al., Kinesin-5 inhibitor resistance is driven by kinesin-12. J Cell Biol, 2016. 213(2): p. 213-27.

26. Weil, D., et al., Targeting the kinesin Eg5 to monitor siRNA transfection in mammalian cells. Biotechniques, 2002. 33(6): p. 1244-8.

27. Naito, Y., et al., CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites. Bioinformatics, 2015. 31(7): p. 1120-3.

28. Cong, L., et al., Multiplex genome engineering using CRISPR/Cas systems.Science, 2013. 339(6121): p. 819-23.

29. He, J., et al., PTEN regulates EG5 to control spindle architecture and chromosome congression during mitosis. Nat Commun, 2016. 7: p. 12355.

30. Iimori, M., et al., Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability. Nat Commun, 2016. 7: p. 11117.

31. Saijo, T., et al., Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy. Lung Cancer, 2006. 54(2): p. 217-25.

32. Otsu, H., et al., Gastric Cancer Patients with High PLK1 Expression and DNA Aneuploidy Correlate with Poor Prognosis. Oncology, 2016. 91(1): p. 31-40.

33. Ando, K., et al., High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer. Cancer Sci, 2010. 101(3): p. 639- 45.

34. Furuya, T., et al., Relationship between chromosomal instability and intratumoral regional DNA ploidy heterogeneity in primary gastric cancers. Clin Cancer Res, 2000. 6(7): p. 2815-20.

35. Hiddemann, W., et al., Convention on nomenclature for DNA cytometry. Committee on Nomenclature, Society for Analytical Cytology. Cancer Genet Cytogenet, 1984. 13(2): p. 181-3.

36. Schneider, C.A., W.S. Rasband, and K.W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis. Nat Methods, 2012. 9(7): p. 671-5.

37. Tsuda, Y., et al., Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent-induced mitotic arrest. Sci Rep, 2017. 7(1): p. 16762.

38. Hauf, S., et al., The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol, 2003. 161(2): p. 281-94.

39. Rath, O. and F. Kozielski, Kinesins and cancer. Nat Rev Cancer, 2012. 12(8): p. 527-39.

40. Kapoor, T.M., et al., Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol, 2000. 150(5): p. 975-88.

41. Sawin, K.E., et al., Mitotic spindle organization by a plus-end-directed microtubule motor. Nature, 1992. 359(6395): p. 540-3.

42. Mayer, T.U., et al., Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science, 1999. 286(5441): p. 971-4.

43. Vitale, I., et al., Multipolar mitosis of tetraploid cells: inhibition by p53 and dependency on Mos. EMBO J, 2010. 29(7): p. 1272-84.

44. Roschke, A.V., et al., Stable Karyotypes in Epithelial Cancer Cell Lines Despite High Rates of Ongoing Structural and Numerical Chromosomal Instability. Neoplasia (New York, N.Y.), 2002. 4(1): p. 19-31.

45. Landry, J.J., et al., The genomic and transcriptomic landscape of a HeLa cell line.G3 (Bethesda), 2013. 3(8): p. 1213-24.

46. Macville, M., et al., Comprehensive and definitive molecular cytogenetic characterization of HeLa cells by spectral karyotyping. Cancer Res, 1999. 59(1):p. 141-50.

47. Castedo, M., et al., Apoptosis regulation in tetraploid cancer cells. EMBO J, 2006.25(11): p. 2584-95.

48. Thompson, S.L. and D.A. Compton, Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol, 2010. 188(3): p. 369-81.

49. Blangy, A., et al., Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell, 1995. 83(7): p. 1159-69.

50. Cahu, J., et al., Phosphorylation by Cdk1 Increases the Binding of Eg5 to Microtubules In Vitro and in Xenopus Egg Extract Spindles. PLoS ONE, 2008. 3(12): p. e3936.

51. Chee, M.K. and S.B. Haase, B-cyclin/CDKs regulate mitotic spindle assembly by phosphorylating kinesins-5 in budding yeast. PLoS Genet, 2010. 6(5): p. e1000935.

52. Sawin, K.E. and T.J. Mitchison, Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle. Proc Natl Acad Sci U S A, 1995. 92(10): p. 4289-93.

53. Avunie-Masala, R., et al., Phospho-regulation of kinesin-5 during anaphase spindle elongation. J Cell Sci, 2011. 124(Pt 6): p. 873-8.

54. Tanenbaum, M.E., et al., Kif15 cooperates with eg5 to promote bipolar spindle assembly. Curr Biol, 2009. 19(20): p. 1703-11.

55. She, Z.-Y. and W.-X. Yang, Molecular mechanisms of kinesin-14 motors in spindle assembly and chromosome segregation. Journal of Cell Science, 2017. 130(13):p. 2097-2110.

56. Mountain, V., et al., The kinesin-related protein, HSET, opposes the activity of Eg5 and cross-links microtubules in the mammalian mitotic spindle. J Cell Biol, 1999. 147(2): p. 351-66.

57. Norris, S.R., et al., Microtubule minus-end aster organization is driven by processive HSET-tubulin clusters. Nat Commun, 2018. 9(1): p. 2659.

58. Kim, N. and K. Song, KIFC1 is essential for bipolar spindle formation and genomic stability in the primary human fibroblast IMR-90 cell. Cell Struct Funct, 2013. 38(1): p. 21-30.

59. Jin, Q., et al., High Eg5 expression predicts poor prognosis in breast cancer.Oncotarget, 2017. 8(37): p. 62208-62216.

60. Liu, C., et al., Eg5 Overexpression Is Predictive of Poor Prognosis in Hepatocellular Carcinoma Patients. Dis Markers, 2017. 2017: p. 2176460.

61. Tao, W., et al., Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell, 2005. 8(1): p. 49-59.

62. Kapitein, L.C., et al., The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature, 2005. 435(7038): p. 114-8.

63. Chen, Y. and W.O. Hancock, Kinesin-5 is a microtubule polymerase. Nat Commun, 2015. 6: p. 8160.

64. Sercin, O., et al., Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nat Cell Biol, 2016. 18(1): p. 100-10.

65. Ganem, N.J., S.A. Godinho, and D. Pellman, A mechanism linking extra centrosomes to chromosomal instability. Nature, 2009. 460(7252): p. 278-82.

66. van Ree, J.H., et al., Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes. Nat Cell Biol, 2016. 18(7): p. 814-21.

67. Rapley, J., et al., The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation. J Cell Sci, 2008. 121(Pt 23):p. 3912-21.

68. Liu, Y., et al., Protein Phosphatase 2A (PP2A) Regulates EG5 to Control Mitotic Progression. Sci Rep, 2017. 7(1): p. 1630.

69. Abarbanel, J., et al., Cytogenetic studies in patients with gastric cancer. World J Surg, 1991. 15(6): p. 778-82.

70. Tsushima, K., et al., Correlation of DNA ploidy, histopathology, stage and clinical outcome in gastric carcinoma. Surg Oncol, 1992. 1(1): p. 17-25.

71. Daigo, K., et al., Characterization of KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer. 2017.

72. Kato, T., et al., Personalized siRNA-Nanoparticle Systemic Therapy using Metastatic Lymph Node Specimens Obtained with EBUS-TBNA in Lung Cancer. Molecular Cancer Research, 2018. 16(1): p. 47.

73. Cutsem, E.V., et al., Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Journal of Clinical Oncology, 2009. 27(18S): p. LBA4509-LBA4509.

74. Gravalos, C. and A. Jimeno, HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol, 2008. 19(9): p. 1523-9.

75. He, C., et al., Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer. World J Gastroenterol, 2013. 19(14): p. 2171-8.

76. Kim, K.C., et al., Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol, 2011. 18(10): p. 2833-40.

77. Otsu, H., et al., Correlation of HER2 expression with clinicopathological characteristics and prognosis in resectable gastric cancer. Anticancer Res, 2015. 35(4): p. 2441-6.

78. Guarneri, V., et al., Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients. Ann Oncol, 2013. 24(12): p. 2990-4.

79. Mittendorf, E.A., et al., Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res, 2009. 15(23): p. 7381-8.

80. Ishimine, Y., et al., Loss of HER2 Positivity after Trastuzumab in HER2-Positive Gastric Cancer: Is Change in HER2 Status Significantly Frequent? Case Reports in Gastrointestinal Medicine, 2015. 2015: p. 132030.

81. Pietrantonio, F., et al., HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research. Int J Cancer, 2016. 139(12): p. 2859-2864.

82. Seo, S., et al., Loss of HER2 positivity after anti-HER2 chemotherapy in HER2- positive gastric cancer patients: Results of GASTric cancer HER2 reassessment study 3 (GASTHER3). Journal of Clinical Oncology, 2017. 35(4_suppl): p. 27-27.

83. Baselga, J., et al., Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res, 1998. 58(13): p. 2825-31.

84. Fujimoto-Ouchi, K., et al., Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol, 2007. 59(6): p. 795-805.

85. Kwak, E.L., et al., Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer. Cancer Discov, 2015. 5(12): p. 1271-81.

86. Fuse, N., et al., Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients. Gastric Cancer, 2016. 19(1): p. 183- 91.

87. Nagatsuma, A.K., et al., Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer, 2015.18(2): p. 227-38.

88. Abrahao-Machado, L.F. and C. Scapulatempo-Neto, HER2 testing in gastric cancer: An update. World J Gastroenterol, 2016. 22(19): p. 4619-25.

89. Hofmann, M., et al., Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology, 2008. 52(7): p. 797-805.

90. Ruschoff, J., et al., HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch, 2010. 457(3): p. 299-307.

91. Hanna, W.M., et al., HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity. Mod Pathol, 2014. 27(1):p. 4-18.

92. Varella-Garcia, M., et al., EGFR fluorescence in situ hybridisation assay: guidelines for application to non-small-cell lung cancer. J Clin Pathol, 2009. 62(11): p. 970-7.

93. Verma, S., et al., Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med, 2012. 367(19): p. 1783-91.

94. Yamashita-Kashima, Y., et al., Importance of formalin fixing conditions for HER2 testing in gastric cancer: immunohistochemical staining and fluorescence in situ hybridization. Gastric Cancer, 2014. 17(4): p. 638-647.

95. Chi, F., et al., HER2 induces cell proliferation and invasion of non-small-cell lung cancer by upregulating COX-2 expression via MEK/ERK signaling pathway. Onco Targets Ther, 2016. 9: p. 2709-16.

96. Eladdadi, A. and D. Isaacson, A mathematical model for the effects of HER2 overexpression on cell proliferation in breast cancer. Bull Math Biol, 2008. 70(6):p. 1707-29.

97. Baselga, J., et al., HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications. Oncology (Williston Park), 1997. 11(3 Suppl 2):p. 43-8.

98. Muss, H.B., et al., c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med, 1994. 330(18): p. 1260-6.

99. Jia, Y.-X., et al., The coexpression and prognostic significance of c-MET, fibroblast growth factor receptor 2, and human epidermal growth factor receptor 2 in resected gastric cancer: a retrospective study. OncoTargets and therapy, 2016. 9: p. 5919-5929.

100. Stahl, P., et al., Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer. BMC Gastroenterol, 2015. 15: p. 7.

101. Gullo, I., et al., Minimum biopsy set for HER2 evaluation in gastric and gastro- esophageal junction cancer. Endoscopy International Open, 2015. 3(2): p. E165- E170.

102. Huang, S.C., et al., HER2 testing in paired biopsy and excision specimens of gastric cancer: the reliability of the scoring system and the clinicopathological factors relevant to discordance. Gastric Cancer, 2016. 19(1): p. 176-82.

103. Purcell, J.W., et al., Activity of the Kinesin Spindle Protein Inhibitor Ispinesib (SB-715992) in Models of Breast Cancer. Clinical Cancer Research, 2010. 16(2):p. 566.

104. Komlodi-Pasztor, E., D.L. Sackett, and A.T. Fojo, Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin Cancer Res, 2012. 18(1): p. 51-63.

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