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Heterogeneity of Small Cell Lung Cancer Stem Cells

  • D. Prabavathy
  • Niveditha Ramadoss
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1139)

Abstract

Small cell lung cancer, a subtype of lung cancer is an extremely malignant disease due to its metastases and recurrence. Patients with SCLC develop resistance to chemotherapy and the disease relapses. This relapse and resistance are attributed to the heterogeneity of SCLC. Various factors such as recurrent mutations in key regulatory genes such as TP53, RB1, and myc, epigenetic changes, and cancer stem cells contribute to the observed heterogeneity. Cancer stem cell models predict neuroendocrine origin of SCLC. Though an unambiguous established CSC marker has not been assigned, markers CD133, CD44 have been found associated with SCLC. Genetically engineered mouse models (GEMMs) allow the validation of driver mutations and are necessary for design of targeted therapy. This chapter outlines the factors contributing to SCLC heterogeneity, detection methods, and the current therapy trials.

Keywords

SCLC Neuroendocrine markers CD133 CD44 Side population cells Intratumor heterogeneity TP53 RB1 Clonal evolution CSC model Lysine demethylase 1 Notch pathway Genetically engineered mouse model 

References

  1. Adamo A et al (2011) LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol 13(6):652–659CrossRefGoogle Scholar
  2. Arcaro A (2015) Targeted therapies for small cell lung cancer: where do we stand? Crit Rev Oncol Hematol 95(2):154–164CrossRefGoogle Scholar
  3. Borromeo MD et al (2016) ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep 16(5):1259–1272CrossRefGoogle Scholar
  4. Carter L et al (2017) Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med 23(1):114–119CrossRefGoogle Scholar
  5. Carvajal LA, Manfredi JJ (2013) Another fork in the road—life or death decisions by the tumour suppressor p53. EMBO Rep 14(5):414–421CrossRefGoogle Scholar
  6. Chappell J, Dalton S (2013) Roles for MYC in the establishment and maintenance of pluripotency. Cold Spring Harb Perspect Med 3:a014381CrossRefGoogle Scholar
  7. Christensen CL et al (2014) Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26(6):909–922CrossRefGoogle Scholar
  8. Codony-Servat J et al (2016) Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res 5(1):16–25PubMedPubMedCentralGoogle Scholar
  9. Coe BP et al (2013) Genomic deregulation of the E2F/ Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer. PLoS One 8(8):e71670CrossRefGoogle Scholar
  10. Daniel VC et al (2009) A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res 69(8):3364–3373CrossRefGoogle Scholar
  11. Dean M (2009) ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia 14(1):3–9CrossRefGoogle Scholar
  12. Dick JE (2008a) Stem cell concepts renew cancer research. Blood 112(13):4793–4807CrossRefGoogle Scholar
  13. Dick JE (2008b) Stem cell concepts renew cancer research. Blood 112(13):4793–4807CrossRefGoogle Scholar
  14. Dong N et al (2017) Role of epigenetics in lung cancer heterogeneity and clinical implication. Semin Cell Dev Biol 64:18–25CrossRefGoogle Scholar
  15. Eramo A et al (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15(3):504–514CrossRefGoogle Scholar
  16. Gaponova AV et al (2016) A novel HSP90 inhibitor-drug conjugate to SN38 is highly effective in small cell lung cancer (SCLC). Clin Cancer Res 22(20):5120–5129CrossRefGoogle Scholar
  17. Gazdar AF (2018) Morphologic and other forms of heterogeneity in small cell lung cancer: what can we learn from them? J Thorac Oncol 13(2):148–150CrossRefGoogle Scholar
  18. George J et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524(7563):47–53CrossRefGoogle Scholar
  19. Govindan R et al (2006) Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24(28):4539–4544CrossRefGoogle Scholar
  20. Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481(7381):306–313CrossRefGoogle Scholar
  21. Gutova M et al (2007) Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS One 2(2):243CrossRefGoogle Scholar
  22. Hassan KA (2018) Small cell lung cancer heterogeneity: elevated a notch above the rest! J Thorac Dis 10(2):554–556CrossRefGoogle Scholar
  23. Jackman DM, Johnson BE (2005) Small-cell lung cancer. Lancet 366(9494):1385–1396CrossRefGoogle Scholar
  24. Jiang F et al (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7(3):330–338CrossRefGoogle Scholar
  25. Koch LK et al (2008) Stem cell marker expression in small cell lung carcinoma and developing lung tissue. Hum Pathol 39(11):1597–1605CrossRefGoogle Scholar
  26. Krystal G et al (1988) Multiple mechanisms for transcriptional regulation of the myc gene family in small-cell lung cancer. Mol Cel Biol 8(8):3373–3381CrossRefGoogle Scholar
  27. Kubo T et al (2013) Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy. Cancer Sci 104(1):78–84CrossRefGoogle Scholar
  28. Leelatian N et al (2017) Single cell analysis of human tissues and solid tumors with mass cytometry. Cytometry B Clin Cytom 92(1):68–78CrossRefGoogle Scholar
  29. Lim JS et al (2017) Intratumoral heterogeneity generated by notch signaling promotes small cell lung cancer. Nature 545(7654):360–364CrossRefGoogle Scholar
  30. Lv T et al (2012) Over-expression of LSD1 promotes proliferation, migration and invasion in non small cell lung cancer. PLoS One 7(4):e35065CrossRefGoogle Scholar
  31. Marignol L (2017) Notch signalling: the true driver of small cell lung cancer? Transl Cancer Res 6(S7):S1191–S1196CrossRefGoogle Scholar
  32. Medema JP (2013) Cancer stem cells: the challenges ahead. Nat Cell Biol 15(4):338–344CrossRefGoogle Scholar
  33. Mohammad HP, Kruger RG (2016) Antitumor activity of LSD1 inhibitors in lung cancer. Mol Cell Oncol 3(2):e1117700CrossRefGoogle Scholar
  34. Nakatsugawa M et al (2011) SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity. Lab Investig 91(12):1796–1804CrossRefGoogle Scholar
  35. Notta F et al (2011) Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells. Nature 469(7330):362–367CrossRefGoogle Scholar
  36. Osada H et al (2008) Roles of achaete-scute homologue 1 in DKK1 and E cadherin repression and neuroendocrine differentiation in lung cancer. Cancer Res 68(6):1647–1655CrossRefGoogle Scholar
  37. Osborne JK et al (2013) NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM. Proc Natl Acad Sci U S A 110(16):6524–6529CrossRefGoogle Scholar
  38. Paumier A, Péchoux CL (2010) Radiotherapy in small-cell lung cancer: where should it go? Lung Cancer 69(2):133–140CrossRefGoogle Scholar
  39. Peifer M et al (2012) Integrative genome analyses identify key somatic driver mutations of small cell lung cancer. Nat Genet 44(10):1104–1110CrossRefGoogle Scholar
  40. Pietanza MC et al (2016) A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer. Lung Cancer 99:23–30CrossRefGoogle Scholar
  41. Polley E et al (2016) Small cell lung cancer screen of oncology drugs, investigational agents, and gene and microRNA expression. J Natl Cancer Inst 108(10):djw122CrossRefGoogle Scholar
  42. Rodriguez E, Lilenbaum RC (2010) Small cell lung cancer: past, present and future. Curr Oncol Rep 12(5):327–334CrossRefGoogle Scholar
  43. Ross JS et al (2014) Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer. J Clin Pathol 67(9):772–776CrossRefGoogle Scholar
  44. Rudin CM et al (2008) Novel systemic therapies for small cell lung cancer. J Natl Compr Cancer Netw 6(3):315–322CrossRefGoogle Scholar
  45. Sarvi S et al (2014) CD133+ cancer stem-like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist. Cancer Res 74(5):1554–1565CrossRefGoogle Scholar
  46. Semenova EA et al (2015) Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev 29(14):1447–1462CrossRefGoogle Scholar
  47. Shackleton M et al (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829CrossRefGoogle Scholar
  48. Shibata T et al (2009) Oncogenic mutation of PIK3CA in small cell lung carcinoma: a potential therapeutic target pathway for chemotherapy-resistant lung cancer. Cancer Lett 283(2):203–211CrossRefGoogle Scholar
  49. Shivapurkar N et al (1999) Deletions of chromosome 4 at multiple sites are frequent in malignant mesothelioma and small cell lung carcinoma. Clin Cancer Res 5(1):17–23PubMedGoogle Scholar
  50. Shue YT et al (2018) Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models. Transl Lung Cancer Res 7(1):21–31CrossRefGoogle Scholar
  51. Singh AK et al (2015) Tumor heterogeneity and cancer stem cell paradigm: updates in concept, controversies and clinical relevance. Int J Cancer 136(9):1991–2000CrossRefGoogle Scholar
  52. Snitow ME et al (2015) Ezh2 represses the basal cell lineage during lung endoderm development. Development 142(1):108–117CrossRefGoogle Scholar
  53. Stewart CA, Byers LA (2015) Altering the course of small cell lung cancer: targeting cancer stem cells via LSD1 inhibition. Cancer Cell 28(1):4–6CrossRefGoogle Scholar
  54. Sutherland KD, Berns A (2010) Cell of origin of lung cancer. Mol Oncol 4(5):397–403CrossRefGoogle Scholar
  55. Szczepny A et al (2017) The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer. Oncogene 36(39):5544CrossRefGoogle Scholar
  56. Takahashi T et al (1989) p53: a frequent target for genetic abnormalities in lung cancer. Science 246(4929):491–494CrossRefGoogle Scholar
  57. Takebe N et al (2015) Targeting notch, hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12(8):445–464CrossRefGoogle Scholar
  58. Toyooka S et al (2003) The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 21(3):229–239CrossRefGoogle Scholar
  59. Umemura S et al (2014) Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis. J Thorac Oncol 9(9):1324–1331CrossRefGoogle Scholar
  60. Wang B et al (2010) Biologic characteristics of the side population of human small cell lung cancer cell line H446. Chin J Cancer 29(3):254–260CrossRefGoogle Scholar
  61. Wang P et al (2013) Identification and characterization of cells with cancer stem cell properties in human primary lung cancer cell lines. PLoS One 8(3):57020CrossRefGoogle Scholar
  62. Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81(3):323–330CrossRefGoogle Scholar
  63. Wilbertz T et al (2011) SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Mod Pathol 24(7):944–953CrossRefGoogle Scholar
  64. Wistuba II et al (2000a) Molecular changes in the bronchial epithelium of patients with small cell lung cancer. Clin Cancer Res 6(7):2604–2610PubMedPubMedCentralGoogle Scholar
  65. Wistuba II et al (2000b) High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 60(7):1949–1960PubMedGoogle Scholar
  66. Yu L et al (2018) Promiximab-duocarmycin, a new CD56 antibody-drug conjugates, is highly efficacious in small cell lung cancer xenograft models. Oncotarget 9(4):5197–5207CrossRefGoogle Scholar
  67. Zhou S et al (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stemcells and is a molecular determinant of the side-population phenotype. Nat Med 7(9):1028–1034CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • D. Prabavathy
    • 1
  • Niveditha Ramadoss
    • 2
  1. 1.Department of Biotechnology, School of Bio and Chemical EngineeringSathyabama Institute of Science and TechnologyChennaiIndia
  2. 2.Department of BiologyCalifornia State University NorthridgeNorthridgeUSA

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