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Open Access 01-06-2011 | NON-THEMATIC REVIEW

DNA repair: the culprit for tumor-initiating cell survival?

Authors: Lesley A. Mathews, Stephanie M. Cabarcas, William L. Farrar

Published in: Cancer and Metastasis Reviews | Issue 2/2011

Abstract

The existence of “tumor-initiating cells” (TICs) has been a topic of heated debate for the last few years within the field of cancer biology. Their continuous characterization in a variety of solid tumors has led to an abundance of evidence supporting their existence. TICs are believed to be responsible for resistance against conventional treatment regimes of chemotherapy and radiation, ultimately leading to metastasis and patient demise. This review summarizes DNA repair mechanism(s) and their role in the maintenance and regulation of stem cells. There is evidence supporting the hypothesis that TICs, similar to embryonic stem (ES) cells and hematopoietic stem cells (HSCs), display an increase in their ability to survive genotoxic stress and injury. Mechanistically, the ability of ES cells, HSCs and TICs to survive under stressful conditions can be attributed to an increase in the efficiency at which these cells undergo DNA repair. Furthermore, the data presented in this review summarize the results found by our lab and others demonstrating that TICs have an increase in their genomic stability, which can allow for TIC survival under conditions such as anticancer treatments, while the bulk population of tumor cells dies. We believe that these data will greatly impact the development and design of future therapies being engineered to target and eradicate this highly aggressive cancer cell population.

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Dick, J. E. (2008). Stem cell concepts renew cancer research. Blood, 112(13), 4793–4807.PubMedCrossRef

O’Brien, C. A., Kreso, A., & Jamieson, C. H. (2010). Cancer stem cells and self-renewal. Clinical Cancer Research, 16(12), 3113–3120.PubMedCrossRef

Sengupta, A., & Cancelas, J. A. (2010). Cancer stem cells: A stride towards cancer cure? Journal of Cellular Physiology, 225(1), 7–14.PubMedCrossRef

Reiman, J. M., Knutson, K. L., & Radisky, D. C. (2010). Immune promotion of epithelial–mesenchymal transition and generation of breast cancer stem cells. Cancer Research, 70(8), 3005–3008.PubMedCrossRef

Raimondi, C., Gianni, W., Cortesi, E., et al. (2010). Cancer stem cells and epithelial–mesenchymal transition: Revisiting minimal residual disease. Current Cancer Drug Targets, 10(5), 496–508.PubMedCrossRef

Bhattacharyya, S., & Khanduja, K. L. (2010). New hope in the horizon: Cancer stem cells. Acta Biochimica et Biophysica Sinica (Shanghai), 42(4), 237–242.CrossRef

Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., et al. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 3983–3988.PubMedCrossRef

Graziano, A., d’Aquino, R., Tirino, V., et al. (2008). The stem cell hypothesis in head and neck cancer. Journal of Cellular Biochemistry, 103(2), 408–412.PubMedCrossRef

Cariati, M., & Purushotham, A. D. (2008). Stem cells and breast cancer. Histopathology, 52(1), 99–107.PubMedCrossRef

10.

Kasper, S. (2008). Exploring the origins of the normal prostate and prostate cancer stem cell. Stem Cell Reviews, 4(3), 193–201.PubMedCrossRef

11.

Takaishi, S., Okumura, T., & Wang, T. C. (2008). Gastric cancer stem cells. Journal of Clinical Oncology, 26(17), 2876–2882.PubMedCrossRef

12.

Lee, C. J., Dosch, J., & Simeone, D. M. (2008). Pancreatic cancer stem cells. Journal of Clinical Oncology, 26(17), 2806–2812.PubMedCrossRef

13.

Lapidot, T., Sirard, C., Vormoor, J., et al. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 367(6464), 645–648.PubMedCrossRef

14.

Miki, J., & Rhim, J. S. (2008). Prostate cell cultures as in vitro models for the study of normal stem cells and cancer stem cells. Prostate Cancer and Prostatic Diseases, 11(1), 32–39.PubMedCrossRef

15.

Dontu, G., Abdallah, W. M., Foley, J. M., et al. (2003). In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes & Development, 17(10), 1253–1270.CrossRef

16.

Hurt, E. M., Kawasaki, B. T., Klarmann, G. J., et al. (2008). CD44⁺CD24(−) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. British Journal of Cancer, 98(4), 756–765.PubMedCrossRef

17.

Gaviraghi, M., Tunici, P., Valensin, S., et al. (2010). Pancreatic cancer spheres are more than just aggregates of stem marker positive cells. Bioscience Reports, 31, 45–55.PubMedCrossRef

18.

Gou, S., Liu, T., Wang, C., et al. (2007). Establishment of clonal colony-forming assay for propagation of pancreatic cancer cells with stem cell properties. Pancreas, 34(4), 429–435.PubMedCrossRef

19.

Duhagon, M. A., Hurt, E. M., Sotelo-Silveira, J. R., et al. (2010). Genomic profiling of tumor initiating prostatospheres. BMC Genomics, 11, 324.PubMedCrossRef

20.

Sherry, M. M., Reeves, A., Wu, J. K., et al. (2009). STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells, 27(10), 2383–2392.PubMedCrossRef

21.

Sansone, P., Storci, G., Tavolari, S., et al. (2007). IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. Journal of Clinical Investigation, 117(12), 3988–4002.PubMedCrossRef

22.

Klarmann, G. J., Hurt, E. M., Matthews, L. A., et al. (2009). Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clinical & Experimental Metastasis, 26(5), 433–436.CrossRef

23.

Yu, S. C., & Bian, X. W. (2009). Enrichment of cancer stem cells based on heterogeneity of invasiveness. Stem Cell Reviews, 5(1), 66–71.PubMedCrossRef

24.

Moss, R. A., & Lee, C. (2010). Current and emerging therapies for the treatment of pancreatic cancer. OncoTargets and Therapy, 3, 111–127.PubMedCrossRef

25.

Ischenko, I., Seeliger, H., Jauch, K. W., et al. (2009). Metastatic activity and chemotherapy resistance in human pancreatic cancer—Influence of cancer stem cells. Surgery, 146(3), 430–434.PubMedCrossRef

26.

Shah, A. N., Summy, J. M., Zhang, J., et al. (2007). Development and characterization of gemcitabine-resistant pancreatic tumor cells. Annals of Surgical Oncology, 14(12), 3629–3637.PubMedCrossRef

27.

Thompson, L. H. (2005). Unraveling the Fanconi anemia–DNA repair connection. Nature Genetics, 37(9), 921–922.PubMedCrossRef

28.

Thompson, L. H., Hinz, J. M., Yamada, N. A., et al. (2005). How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery. Environmental and Molecular Mutagenesis, 45(2–3), 128–142.PubMedCrossRef

29.

Ralhan, R., Kaur, J., Kreienberg, R., et al. (2007). Links between DNA double strand break repair and breast cancer: Accumulating evidence from both familial and nonfamilial cases. Cancer Letters, 248(1), 1–17.PubMedCrossRef

30.

Tichy, E. D., & Stambrook, P. J. (2008). DNA repair in murine embryonic stem cells and differentiated cells. Experimental Cell Research, 314(9), 1929–1936.PubMedCrossRef

31.

Sengupta, S., & Harris, C. C. (2005). p53: Traffic cop at the crossroads of DNA repair and recombination. Nature Reviews. Molecular Cell Biology, 6(1), 44–55.PubMedCrossRef

32.

Kinsella, T. J. (2009). Coordination of DNA mismatch repair and base excision repair processing of chemotherapy and radiation damage for targeting resistant cancers. Clinical Cancer Research, 15(6), 1853–1859.PubMedCrossRef

33.

Vaish, M. (2007). Mismatch repair deficiencies transforming stem cells into cancer stem cells and therapeutic implications. Molecular Cancer, 6, 26.PubMedCrossRef

34.

Dalhus, B., Laerdahl, J. K., Backe, P. H., et al. (2009). DNA base repair—Recognition and initiation of catalysis. FEMS Microbiology Reviews, 33(6), 1044–1078.PubMedCrossRef

35.

Munroe, R. J., Bergstrom, R. A., Zheng, Q. Y., et al. (2000). Mouse mutants from chemically mutagenized embryonic stem cells. Nature Genetics, 24(3), 318–321.PubMedCrossRef

36.

Thomas, J. W., LaMantia, C., & Magnuson, T. (1998). X-ray-induced mutations in mouse embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 95(3), 1114–1119.PubMedCrossRef

37.

Savatier, P., Lapillonne, H., Jirmanova, L., et al. (2002). Analysis of the cell cycle in mouse embryonic stem cells. Methods Mol Biol, 185, 27–33.PubMed

38.

Baumann, P., Benson, F. E., & West, S. C. (1996). Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell, 87(4), 757–766.PubMedCrossRef

39.

Adams, B. R., Golding, S. E., Rao, R. R., et al. (2010). Dynamic dependence on ATR and ATM for double-strand break repair in human embryonic stem cells and neural descendants. PLoS ONE, 5(4), e10001.PubMedCrossRef

40.

Adams, B. R., Hawkins, A. J., Povirk, L. F., et al. (2010). ATM-independent, high-fidelity nonhomologous end joining predominates in human embryonic stem cells. Aging (Albany NY), 2(9), 582–596.

41.

Harfouche, G., & Martin, M. T. (2010). Response of normal stem cells to ionizing radiation: A balance between homeostasis and genomic stability. Mutation Research, 704(1–3), 167–174.PubMed

42.

Roos, W. P., Christmann, M., Fraser, St, et al. (2007). Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O(6)-methylguanine due to high E2F1 regulated mismatch repair. Cell Death and Differentiation, 14(8), 1422–1432.PubMedCrossRef

43.

Van Sloun, P. P., Jansen, J. G., Weeda, G., et al. (1999). The role of nucleotide excision repair in protecting embryonic stem cells from genotoxic effects of UV-induced DNA damage. Nucleic Acids Research, 27(16), 3276–3282.PubMedCrossRef

44.

Nouspikel, T. (2007). DNA repair in differentiated cells: Some new answers to old questions. Neuroscience, 145(4), 1213–1221.PubMedCrossRef

45.

Mohrin, M., Bourke, E., Alexander, D., et al. (2010). Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell, 7(2), 174–185.PubMedCrossRef

46.

Sotiropoulou, P. A., Candi, A., Mascré, G., et al. (2010). Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat Cell Biol, 12(6), 572–82.PubMedCrossRef

47.

Harfouche, G., Vaigot, P., Rachidi, W., et al. (2010). Fibroblast growth factor type 2 signaling is critical for DNA repair in human keratinocyte stem cells. Stem Cells, 28(9), 1639–1648.PubMedCrossRef

48.

Frosina, G. (2010). The bright and the dark sides of DNA repair in stem cells. Journal of Biomedicine and Biotechnology, 2010, 845396.PubMedCrossRef

49.

Frosina, G. (2009). DNA repair and resistance of gliomas to chemotherapy and radiotherapy. Molecular Cancer Research, 7(7), 989–999.PubMedCrossRef

50.

Bao, S., Wu, Q., McLendon, R. E., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(7120), 756–760.PubMedCrossRef

51.

Ropolo, M., Daga, A., Griffero, F., et al. (2009). Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. Molecular Cancer Research, 7(3), 383–392.PubMedCrossRef

52.

Bao, S., Wu, Q., Sathornsumetee, S., et al. (2006). Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Research, 66(16), 7843–7848.PubMedCrossRef

53.

McCord, A. M., Jamal, M., Williams, E. S., et al. (2009). CD133⁺ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clinical Cancer Research, 15(16), 5145–5153.PubMedCrossRef

54.

Dirks, P. B. (2006). Cancer: Stem cells and brain tumours. Nature, 444(7120), 687–688.PubMedCrossRef

55.

Frosina, G. (2009). DNA repair in normal and cancer stem cells, with special reference to the central nervous system. Current Medicinal Chemistry, 16(7), 854–866.PubMedCrossRef

56.

Zabludoff, S. D., Deng, C., Grondine, M. R., et al. (2008). AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Molecular Cancer Therapeutics, 7(9), 2955–2966.PubMedCrossRef

57.

Facchino, S., Abdouh, M., Chatoo, W., et al. (2010). BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. The Journal of Neuroscience, 30(30), 10096–10111.PubMedCrossRef

58.

Crea, F., M.A. Duhagon Serrat, E.M. Hurt, et al. (2010). BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer. doi:10.1002/ijc.25522

59.

Zhuang, W., B. Li, L. Long, et al. (2011). Knockdown of the DNA-dependent protein kinase catalytic subunit radiosensitizes glioma-initiating cells by inducing autophagy. Brain Res, 1371, 7–15.

60.

Gaspar, N., Marshall, L., Perryman, L., et al. (2010). MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature. Cancer Research, 70(22), 9243–9252.PubMedCrossRef

61.

Sciuscio, D., A.C. Diserens, K. van Dommelen, et al. (2011). Extent and Patterns of MGMT Promoter Methylation in Glioblastoma and Respective Derived Spheres. Clin Cancer Res, 17(2), 255–266.

62.

Yuki, K., Natsume, A., Yokoyama, H., et al. (2009). Induction of oligodendrogenesis in glioblastoma-initiating cells by IFN-mediated activation of STAT3 signaling. Cancer Letters, 284(1), 71–79.PubMedCrossRef

63.

Kato, T. N., Natsume, A., Toda, H., et al. (2010). Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells. Gene Therapy, 17(11), 1363–1371.PubMedCrossRef

64.

Korkaya, H., Paulson, A., Charafe-Jauffret, E., et al. (2009). Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biology, 7(6), e1000121.PubMedCrossRef

65.

Suva, M. L., Riggi, N., Janiszewska, M., et al. (2009). EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Research, 69(24), 9211–9218.PubMedCrossRef

66.

Yu, J., Yu, J., Rhodes, D. R., et al. (2007). A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Research, 67(22), 10657–10663.PubMedCrossRef

67.

Sarasin, A., & Dessen, P. (2010). DNA repair pathways and human metastatic malignant melanoma. Current Molecular Medicine, 10(4), 413–418.PubMedCrossRef

68.

Kauffmann, A., Rosselli, F., Lazar, V., et al. (2008). High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene, 27(5), 565–573.PubMedCrossRef

69.

Sarasin, A., & Kauffmann, A. (2008). Overexpression of DNA repair genes is associated with metastasis: A new hypothesis. Mutation Research, 659(1–2), 49–55.PubMed

70.

Karimi-Busheri, F., Rasouli-Nia, A., Mackey, J. R., et al. (2010). Senescence evasion by MCF-7 human breast tumor-initiating cells. Breast Cancer Research, 12(3), R31.PubMedCrossRef

71.

Woodward, W. A., & Bristow, R. G. (2009). Radiosensitivity of cancer-initiating cells and normal stem cells (or what the Heisenberg uncertainly principle has to do with biology). Seminars in Radiation Oncology, 19(2), 87–95.PubMedCrossRef

72.

Zhang, M., Atkinson, R. L., & Rosen, J. M. (2010). Selective targeting of radiation-resistant tumor-initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 107(8), 3522–3527.PubMedCrossRef

73.

Zhang, M., Behbod, F., Atkinson, R. L., et al. (2008). Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Research, 68(12), 4674–4682.PubMedCrossRef

74.

Parsels, L.A., M.A. Morgan, D.M. Tanska, et al. (2009). Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells. Mol Cancer Ther, 8(1), 45–54.PubMedCrossRef

75.

Glinsky, G. V. (2006). Genomic models of metastatic cancer: Functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated Polycomb Group (PcG) protein chromatin silencing pathway. Cell Cycle, 5(11), 1208–1216.PubMedCrossRef

76.

Harada, T., Chelala, C., Bahkta, V., et al. (2008). Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene, 27(13), 1951–1960.PubMedCrossRef

77.

Magee, J. A., Araki, T., Patil, S., et al. (2001). Expression profiling reveals hepsin overexpression in prostate cancer. Cancer Research, 61(15), 5692–5696.PubMed

78.

Vanaja, D. K., Cheville, J. C., Iturria, S. J., et al. (2003). Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Research, 63(14), 3877–3882.PubMed

79.

Lapointe, J., Li, C., Higgins, J. P., et al. (2004). Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 101(3), 811–816.PubMedCrossRef

80.

LaTulippe, E., Satagopan, J., Smith, A., et al. (2002). Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Research, 62(15), 4499–4506.PubMed

81.

Varambally, S., Yu, J., Laxman, B., et al. (2005). Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell, 8(5), 393–406.PubMedCrossRef

82.

Pyeon, D., Newton, M. A., Lambert, P. F., et al. (2007). Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers. Cancer Research, 67(10), 4605–4619.PubMedCrossRef

83.

Schlingemann, J., Habtemichael, N., Ittrich, C., et al. (2005). Patient-based cross-platform comparison of oligonucleotide microarray expression profiles. Lab Invest, 85(8), 1024–1039.PubMedCrossRef

84.

Albino, D., Scaruffi, P., Moretti, S., et al. (2008). Identification of low intratumoral gene expression heterogeneity in neuroblastic tumors by genome-wide expression analysis and game theory. Cancer, 113(6), 1412–1422.PubMedCrossRef

85.

Yusenko, M. V., Kuiper, R. P., Boethe, T., et al. (2009). High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas. BMC Cancer, 9, 152.PubMedCrossRef

86.

Sanchez-Carbayo, M., Socci, N. D., Lozano, J., et al. (2006). Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. Journal of Clinical Oncology, 24(5), 778–789.PubMedCrossRef

Title: DNA repair: the culprit for tumor-initiating cell survival?
Authors: Lesley A. Mathews
Stephanie M. Cabarcas
William L. Farrar
Publication date: 01-06-2011
Publisher: Springer US
Published in: Cancer and Metastasis Reviews / Issue 2/2011
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-011-9277-0

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