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Hedgehog Signaling and Cancer Treatment Resistance

  • Yu-Jen ChenEmail author
  • Hui-Fen Liao
  • Clifford Chao
Chapter
  • 459 Downloads

Abstract

Cancer treatment modalities, including radiotherapy (RT), chemotherapy, and chemoradiotherapy (CRT) are considered effective for many types of cancers through their cytotoxic effects, including DNA damage. However, the development of resistance to these cancer treatment modalities remains a limitation to be overcome. Growing evidence from preclinical and translational research suggests that hedgehog (HH) signaling, one of cancer stem cell (CSC) signaling pathways, may affect the treatment outcome of cancer. This chapter briefly introduces the correlation between CSC and treatment resistance. The possible role of HH signaling in cancer treatment resistance is addressed from four aspects, including the induction of tumor regrowth and CSCs, anti-apoptosis and cell cycle regulation, modulation of DNA damage repair, and stimulation of multiple drug resistant transporter system. It concludes that HH signaling pathway could be regarded a target for the development of novel therapeutics against cancer as well as CSCs. Several pharmacological agents with HH blockade activity are currently undergoing clinical investigations.

Keywords

Epidermal Growth Factor Receptor Chronic Myeloid Leukemia Cancer Stem Cell Tumor Regrowth Basal Cell Nevus Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087PubMedCrossRefGoogle Scholar
  2. 2.
    Adolphe C et al (2004) An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 131:5009–5019PubMedCrossRefGoogle Scholar
  3. 3.
    Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432:324–331PubMedCrossRefGoogle Scholar
  4. 4.
    Sims-Mourtada J et al (2006) Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res 12:6565–6572PubMedCrossRefGoogle Scholar
  5. 5.
    Berman DM et al (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851PubMedCrossRefGoogle Scholar
  6. 6.
    Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Therond PP (2003) Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Biol 5:907–913PubMedCrossRefGoogle Scholar
  7. 7.
    Yoon JW et al (2002) Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277:5548–5555PubMedCrossRefGoogle Scholar
  8. 8.
    Thayer SP et al (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856PubMedCrossRefGoogle Scholar
  9. 9.
    Watkins DN et al (2003) Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422:313–317PubMedCrossRefGoogle Scholar
  10. 10.
    Yilmaz OH et al (2006) PTEN dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475–482PubMedCrossRefGoogle Scholar
  11. 11.
    Chufal KS et al (2010) Exploring new potentials and generating hypothesis for management of locally advanced head neck cancer: analysis of pooled data from two phase II trials. J Cancer Res Ther 6:185–193PubMedCrossRefGoogle Scholar
  12. 12.
    Durand RE, Aquino-Parsons C (2004) Predicting response to treatment in human cancers of the uterine cervix: sequential biopsies during external beam radiotherapy. Int J Radiat Oncol Biol Phys 58:555–560PubMedCrossRefGoogle Scholar
  13. 13.
    Stinchcombe TE, Bogart J, Wigle DA, Govindan R (2010) Annual review of advances in lung cancer clinical research: a report for the year 2009. J Thorac Oncol 5:935–939PubMedCrossRefGoogle Scholar
  14. 14.
    Yi Y et al (2010) Predictors of sensitivity to chemoradiotherapy of esophageal squamous cell carcinoma. Tumour Biol 31:333–340PubMedCrossRefGoogle Scholar
  15. 15.
    Wilkowski R et al (2009) Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer – a multi-centre randomised phase II stud. Br J Cancer 101:1853–1859PubMedCrossRefGoogle Scholar
  16. 16.
    Dikken JL et al (2010) Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence patterns in gastric cancer. J Clin Oncol 28:2430–2436PubMedCrossRefGoogle Scholar
  17. 17.
    Lin JZ et al (2010) Phase II study of pre-operative radiotherapy with capecitabine and oxaliplatin for rectal cancer and carcinoembryonic antigen as a predictor of pathological tumour response. J Int Med Res 38:645–654PubMedGoogle Scholar
  18. 18.
    Mimeault M, Hauke R, Batra SK (2008) Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin Pharmacol Ther 83:673–691PubMedCrossRefGoogle Scholar
  19. 19.
    McClendon AK, Dean JL, Ertel A, Knudsen ES (2010) Differential impact of tumor suppressor pathways on DNA damage response and therapy-induced transformation in a mouse primary cell model. PLoS One 5:e8558PubMedCrossRefGoogle Scholar
  20. 20.
    Provencio M, Sánchez A, Garrido P, Valcárcel F (2010) New molecular targeted therapies integrated with radiation therapy in lung cancer. Clin Lung Cancer 11:91–97PubMedCrossRefGoogle Scholar
  21. 21.
    Nakano T, Ohno T, Ishikawa H, Suzuki Y, Takahashi T (2010) Current advancement in radiation therapy for uterine cervical cancer. J Radiat Res 51:1–8PubMedCrossRefGoogle Scholar
  22. 22.
    Goldie JH, Coldman AJ (1984) The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res 44:3643–3653PubMedGoogle Scholar
  23. 23.
    Silva AS, Gatenby RA (2010) A theoretical quantitative model for evolution of cancer chemotherapy resistance. Biol Direct 5:25–42PubMedCrossRefGoogle Scholar
  24. 24.
    Nakano T, Oka K (1993) Differential values of Ki-67 index and mitotic index of proliferating cell population: an assessment of cell cycle and prognosis in radiation therapy for cervical cancer. Cancer 72:2401–2408PubMedCrossRefGoogle Scholar
  25. 25.
    Hambardzumyan D, Squatrito M, Carbajal E, Holland EC (2008) Glioma formation, cancer stem cells, and Akt signaling. Stem Cell Rev 4:203–210PubMedCrossRefGoogle Scholar
  26. 26.
    Eyler CE et al (2008) Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 26:3027–3036PubMedCrossRefGoogle Scholar
  27. 27.
    Westhoff M-A et al (2009) The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene 28:3586–3596PubMedCrossRefGoogle Scholar
  28. 28.
    Kao GD, Jiang Z, Fernandes AM, Gupta AK, Maity A (2007) Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 282:21206–21212PubMedCrossRefGoogle Scholar
  29. 29.
    Frosina G (2010) The bright and the dark sides of DNA repair in stem cells. J Biomed Biotechnol 2010:845396PubMedCrossRefGoogle Scholar
  30. 30.
    Urtasun RC et al (1986) Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia. Int J Radiat Oncol Biol Phys 12:1263–1267PubMedCrossRefGoogle Scholar
  31. 31.
    Nordsmark M, Overgaard M, Overgaard J (1996) Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41:31–39PubMedGoogle Scholar
  32. 32.
    Kawamura H et al (2009) Ceramide induces myogenic differentiation and apoptosis in Drosophila Schneider cells. J Radiat Res 50:161–169PubMedCrossRefGoogle Scholar
  33. 33.
    Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9:517–531PubMedCrossRefGoogle Scholar
  34. 34.
    Eke I et al (2010) PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1α. J Clin Invest 120:2516–2527PubMedCrossRefGoogle Scholar
  35. 35.
    Baumann M, Krause M, Hill R (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–554PubMedCrossRefGoogle Scholar
  36. 36.
    Crook T et al (1992) Clonal p53 mutation in primary cervical cancer: association with human papilloma virus-negative tumors. Lancet 339:1070–1073PubMedCrossRefGoogle Scholar
  37. 37.
    Kubo A, Corley DA (2004) Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 99:582–588PubMedCrossRefGoogle Scholar
  38. 38.
    Cui D, Xu Q, Wang K, Che X (2010) Gli-1 is a potential target for alleviating multidrug resistance of gliomas. J Neurol Sci 288:156–166PubMedCrossRefGoogle Scholar
  39. 39.
    Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15:2177–2196PubMedCrossRefGoogle Scholar
  40. 40.
    Leonard JM, Ye H, Wetmore C, Karnitz LM (2008) Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability. J Cell Biol 183:385–391PubMedCrossRefGoogle Scholar
  41. 41.
    Cho RW, Clarke MF (2008) Recent advances in cancer stem cells. Curr Opin Genet Dev 18:48–53PubMedCrossRefGoogle Scholar
  42. 42.
    McDonald JW et al (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:1410–1412PubMedCrossRefGoogle Scholar
  43. 43.
    Pajonk F, Vlashi E, Mcbride WH (2010) Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited. Stem Cells 28:639–648PubMedCrossRefGoogle Scholar
  44. 44.
    Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signaling regulators. Nat Rev Mol Cell Biol 4:33–45PubMedCrossRefGoogle Scholar
  45. 45.
    Jin L et al (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12:1167–1174PubMedCrossRefGoogle Scholar
  46. 46.
    Li C et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037PubMedCrossRefGoogle Scholar
  47. 47.
    O’Brien CA et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110PubMedCrossRefGoogle Scholar
  48. 48.
    Ricci-Vitiani L et al (2007) Identification and expansion of human colon-cancerinitiating cells. Nature 445:111–115PubMedCrossRefGoogle Scholar
  49. 49.
    Singh SK et al (2004) Identification of human brain tumor initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  50. 50.
    Karhadkar SS et al (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–712PubMedCrossRefGoogle Scholar
  51. 51.
    Zhao C et al (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458:776–779PubMedCrossRefGoogle Scholar
  52. 52.
    Chen YJ, Wang YF, Chao KSC (2009) Cancer stem cells and sonic hedgehog signaling in head and neck cancer: potential targets for overcoming chemoradiation resistance. J Clin Oncol Soc 25:81–88Google Scholar
  53. 53.
    Jeong J et al (2004) Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 18:937–951PubMedCrossRefGoogle Scholar
  54. 54.
    Sacedon R et al (2005) Sonic hedgehog is produced by follicular dendritic cells and protects germinal center B cells from apoptosis. J Immunol 174:1456–1461PubMedGoogle Scholar
  55. 55.
    Kurita S et al (2010) GLI3-dependent repression of DR4 mediates hedgehog antagonism of TRAIL-induced apoptosis. Oncogene 29(34):4848–4858PubMedCrossRefGoogle Scholar
  56. 56.
    Hegde GV et al (2008) Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol Cancer Res 6:1928–1936PubMedCrossRefGoogle Scholar
  57. 57.
    Athar M et al (2004) Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res 64:7545–7552PubMedCrossRefGoogle Scholar
  58. 58.
    Bigelow RL et al (2004) Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through GLI-1. J Biol Chem 279:1197–1205PubMedCrossRefGoogle Scholar
  59. 59.
    Wyman C, Kanaar R (2006) DNA double-strand break repair: all’s well that ends well. Annu Rev Genet 40:363–383PubMedCrossRefGoogle Scholar
  60. 60.
    Frapparta PO et al (2009) Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc Natl Acad Sci USA 106:1880–1885CrossRefGoogle Scholar
  61. 61.
    Keeney S, Chang GJ, Linn S (1993) Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E. J Biol Chem 268:21293–21300PubMedGoogle Scholar
  62. 62.
    Sun NK, Sun CL, Lin CH, Pai1 LM, Chao CC (2010) Damaged DNA-binding protein 2 (DDB2) protects against UV irradiation in human cells and Drosophila. J Biomed Sci 17:27–40Google Scholar
  63. 63.
    Wang SC et al (2006) Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 8:1359–1368PubMedCrossRefGoogle Scholar
  64. 64.
    Dittmann K et al (2005) Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 280:31182–31189PubMedCrossRefGoogle Scholar
  65. 65.
    Hsu SC, Miller SA, Wang Y, Hung MC (2009) Nuclear EGFR is required for cisplatin resistance and DNA repair. Am J Transl Res 1:249–258PubMedGoogle Scholar
  66. 66.
    Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33:9–23PubMedCrossRefGoogle Scholar
  67. 67.
    Stubbert LJ, Smith JM, McKay BC (2010) Decreased transcription-coupled nucleotide excision repair capacity is associated with increased p53- and MLH1-independent apoptosis in response to cisplatin. BMC Cancer 10:207–216PubMedCrossRefGoogle Scholar
  68. 68.
    Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22:7265–7279PubMedCrossRefGoogle Scholar
  69. 69.
    Bhana S, Lloyd DR (2008) The role of p53 in DNA damage-mediated cytotoxicity overrides its ability to regulate nucleotide excision repair in human fibroblasts. Mutagenesis 23:43–50PubMedCrossRefGoogle Scholar
  70. 70.
    Dellovade T, Romer JT, Curran T, Rubin LL (2006) The hedgehog pathway and neurological disorders. Annu Rev Neurosci 29:539–563PubMedCrossRefGoogle Scholar
  71. 71.
    Couvé-Privat S et al (2002) Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. Cancer Res 62:7186–7189PubMedGoogle Scholar
  72. 72.
    Hambardzumyan D et al (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22:436–448PubMedCrossRefGoogle Scholar
  73. 73.
    Shafaee Z, Schmidt H, Du W, Posner M, Weichselbaum R (2006) Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells. Cancer Chemother Pharmacol 58:765–770PubMedCrossRefGoogle Scholar
  74. 74.
    Chen YJ, Sims-Mourtada1 J, Izzo J, Chao KS (2007) Targeting the hedgehog pathway to mitigate treatment resistance. Cell Cycle 6:1826–1830Google Scholar
  75. 75.
    Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427PubMedCrossRefGoogle Scholar
  76. 76.
    Widmer N, Colombo S, Buclin T, Decosterd LA (2003) Functional consequence of MDR1 expression on imatinib intracellular concentrations. Blood 102:1142PubMedCrossRefGoogle Scholar
  77. 77.
    Gao L et al (2006) STI571 combined with vincristine greatly suppressed the tumor formation of multidrug-resistant K562 cells in a human-nude mice xenograft model. Chin Med J 119:911–918PubMedGoogle Scholar
  78. 78.
    Sims-Mourtada J, Izzo JG, Ajani J, Chao KS (2007) Sonic hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26:5674–5679PubMedCrossRefGoogle Scholar
  79. 79.
    Tas S, Avci O (2004) Rapid clearance of psoriatic skin lesions induced by topical cyclopamine. A preliminary proof of concept study. Dermatology 209:126–131PubMedCrossRefGoogle Scholar
  80. 80.
    Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol Biosyst 6:44–54PubMedCrossRefGoogle Scholar
  81. 81.
    Kim J, Lee JJ, Kim J, Gardner D, Beachy PA (2010) Arsenic antagonizes the hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci USA 107(30):13432–13437PubMedCrossRefGoogle Scholar
  82. 82.
    Yang L, Xie G, Fan Q, Xie J (2010) Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 29:469–481PubMedCrossRefGoogle Scholar
  83. 83.
    Williams JA et al (2003) Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinomalike lesions. Proc Natl Acad Sci USA 100:4616–4621PubMedCrossRefGoogle Scholar
  84. 84.
    De Smaele E, Ferretti E, Gulino A (2010) Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs 11:707–718PubMedGoogle Scholar
  85. 85.
    Doggrell SA (2010) The hedgehog pathway inhibitor GDC-0449 shows potential in skin and other cancers. Expert Opin Investig Drugs 19:451–454PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.School of MedicineNational Yang Ming UniversityTaipeiTaiwan
  2. 2.Department of Radiation OncologyMackay Memorial HospitalTaipeiTaiwan
  3. 3.Institute of PharmacologyTaipei Medical UniversityTaipeiTaiwan

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