Advertisement

Human Cell

, Volume 30, Issue 1, pp 1–10 | Cite as

Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1

  • Takaaki Ito
  • Shinji Kudoh
  • Takaya Ichimura
  • Kosuke Fujino
  • Wael Ahmed Maher Abdo Hassan
  • Naoko Udaka
Review Article

Abstract

Small cell lung cancer (SCLC) is one of the most malignant neoplasms in common human cancers. The tumor is composed of small immature-looking cells with a round or fusiform shape, which possesses weak adhesion features among them, suggesting that SCLC shows the morphological characteristics of epithelial to mesenchymal transition (EMT). SCLC is characterized by high metastatic and recurrent rates, sensitivity to the initial chemotherapy, and easy acquirement of chemoresistance afterwards. These characters may be related to the EMT phenotype of SCLC. Notch signaling is an important signaling pathway, and could have roles in regulating neuroendocrine differentiation, proliferation, cell adhesion, EMT, and chemoresistance. Notch1 is usually absent in SCLC in vivo, but could appear after chemotherapy. Notch1 can enhance cell adhesion by induction of E-cadherin in SCLC, which indicates mesenchymal to epithelial transition. On the other hand, achaete-scute complex homologue 1 (ASCL1), negatively regulated by Notch signaling, is a lineage-specific gene of SCLC, and functions to promote neuroendocrine differentiation as well as EMT. ASCL1-transfected adenocarcinoma cell lines induced neuroendocrine phenotypes and lost epithelial cell features. SCLC is characterized by neuroendocrine differentiation and EMT-like features, which could be produced by inactive Notch signaling and ASCL1 expression. In addition, chemical and radiation treatments can activate Notch signaling, which suppress neuroendocrine differentiation and induces chemoradioresistance, accompanied by secession from EMT. Thus, the status of Notch signaling and ASCL1 expression may determine the cell behaviors of SCLC partly through modifying EMT phenotypes.

Keywords

Small cell lung cancer Epithelial-mesenchymal transition (EMT) Notch signaling Achaete-scute complex homologue 1 (ASCL1) Neuroendocrine 

Notes

Acknowledgements

The authors appreciate Dr. Artavanis-Tsakonas, Dr. Kopan, and Dr. Morimoto for their generous gift of Notch1 vectors. The authors appreciate Dr. S. Okada for giving us immunodeficient mice for xenotransplantation experiments. Ms. M. Kagayama and Ms. T. Maeda helped us by making excellent histological samples and Western blotting. The study was in part supported by a Grant-in-Aid for Scientific Research (C; Nos. 22590865, 23220010, 25460439) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and in part from Smoking Research Foundation.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

All studies using human pathological samples followed the guidelines of the Ethics Committee of Kumamoto University. All animal experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee of Kumamoto University.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cnacer J Clin. 2016;66:7–30.CrossRefGoogle Scholar
  2. 2.
    Rodriguez E, Lilenbaum RC. Small cell lung cancer: past, present, and future. Curr Oncol Rep. 2010;12:327–34.CrossRefPubMedGoogle Scholar
  3. 3.
    Bunn PA Jr, Minna JD, Augustyn A, et al. Small cell lung cancer: can recent advances in biology and molecular biology be translated into improved outocome. J Thorac Oncol. 2016;11:453–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Pietanza MC, Byers LA, Minna JD, Rudin CM. Small cell lung cancer: will recent progress lead to improved outcomes? Clin Cancer Res. 2015;21:2244–55.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature Genet. 2012;44:1104–10.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ruden CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature Genet. 2012;44:1111–6.CrossRefGoogle Scholar
  7. 7.
    George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L. Rational targeting of Notch signaling in cancer. Oncogene. 2008;27:5124–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Roy M, Pear WP, Aster J. The multifaced role of Notch in cancer. Curr Opin Genet Dev. 2007;17:52–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Wael HA, Yoshida R, Kudoh S, Hasegawa K, Kita-Niimori K, Ito T. Notch1 signaling controls cell proliferation, apoptosis and differentiation in lung carcinoma. Lung Cancer. 2014;85:131–40.CrossRefPubMedGoogle Scholar
  11. 11.
    Sriurangpong V, Borges M, Ravi R, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61:3200–5.Google Scholar
  12. 12.
    Hassan WA, Yoshida R, Kudoh S, Hasegawa K, Kita-Niimori K, Ito T. Notch1 controls cell invasion and metastasis in small cell lung carcinoma cell lines. Lung Cancer. 2014;86:304–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Hassan WA, Yoshida R, Kudoh S, Hasegawa K, Kita-Niimori K, Ito T. Notch1 controls cell chemo-resistance in small cell lung carcinoma cells. Thorac Cancer. 2016;7:123–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Ito T, Udaka N, Yazawa T, et al. Basic helix-loop-helix factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium. Development. 2000;127:3913–21.PubMedGoogle Scholar
  15. 15.
    Morimoto M, Nishinakamura R, Saga Y, et al. Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development. 2012;139:4365–73.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Noguchi M, Sumiyama K, Morimoto M. Directed migration of pulmonary neuroendocrinecells toward airway branches organizes the stereotypic location of neuroepithelial bodies. Cell Rep. 2015;13:2679–86.CrossRefPubMedGoogle Scholar
  17. 17.
    Fujino K, Motooka Y, Hassan WA, et al. INSM1 is a crucial regulator of neuroendocrine differentiation in lung cancer. Am J Pathol. 2015;185:3164–77.CrossRefPubMedGoogle Scholar
  18. 18.
    Ball DW. Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer. Cancer Lett. 2004;204:159–69.CrossRefPubMedGoogle Scholar
  19. 19.
    Meder L, König K, Ozretić L, et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer. 2016;138:927–38.CrossRefPubMedGoogle Scholar
  20. 20.
    McDowell EM, Hess FG, Trump BF. Epidermoid metaplasia, carcinoma in situ, and carcinomas of the lung. In: Trump BF, Jones RT, editors. Dignositic electron microscopy. New York: Wiley; 1980. p. 37–96.Google Scholar
  21. 21.
    Gould VE, Warren WH, Memoli VA. Neuroendocrine neoplasms of the lung. Light microscopic, immunohistochemical, and ultrastructural specturum. In: Becker KL, Gazdar AF, editors. The endocrine lung in health and disease. Philadelphia: Saunders; 1984. pp. 406–45.Google Scholar
  22. 22.
    Hammar SP. Diagnostic pathology; Neoplasia. In: Schraufnagel DE, editor. Electron microscopy of the lung. New York: Marcel Dekker; 1990. pp. 345–428.Google Scholar
  23. 23.
    Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer. 2002;2:442–54.CrossRefPubMedGoogle Scholar
  24. 24.
    Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMedGoogle Scholar
  25. 25.
    Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27:2192–206.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Timmerman LA1, Grego-Bessa J, Raya A, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004; 18:99–115.Google Scholar
  28. 28.
    Zavadil J, Cermak L, Soto-Nieves N, Böttinger EP. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 2004; 23:1155–65.Google Scholar
  29. 29.
    Chang AC, Fu Y, Garside VC, Niessen K, et al. Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell. 2011;21:288–300.CrossRefPubMedGoogle Scholar
  30. 30.
    Sahlgren C1, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA. 2008; 105:6392–7.Google Scholar
  31. 31.
    Wang Z, Li Y, Kong D, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69:2400–7.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014; 7(344):re8. doi: 10.1126/scisignal.2005189.
  33. 33.
    Wang Z, Li Y, Banerjee S, Sarkar FH. Emerging role of Notch in stem cells and cancer. Cancer Lett. 2009;279:8–12.CrossRefPubMedGoogle Scholar
  34. 34.
    Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011; 307:26–36.Google Scholar
  35. 35.
    Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 2013; 6:1249–59.Google Scholar
  36. 36.
    Fender AW, Nutter JM, Fitzgerald TL, Bertrand FE2, Sigounas G. Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer. J Cell Biochem. 2015; 116:2517–27.Google Scholar
  37. 37.
    Yuan X, Wu H, Han N, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7:87. doi: 10.1186/s13045-014-0087-z.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Deskin B, Lasky J, Zhuang Y, Shan B. Requirement of HDAC6 for activation of Notch1 by TGF-β1. Sci Rep. 2016; 6:31086. doi: 10.1038/srep31086.
  39. 39.
    Capaccione KM1, Hong X, Morgan KM, et al. Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma. Oncotarget. 2014; 5:3636–50.Google Scholar
  40. 40.
    Kang J, Kim E, Kim W, et al. Rhamnetin and cirsiliol induce radiosensitization and inhibition of epithelial-mesenchymal transition (EMT) by miR-34a-mediated suppression of Notch-1 expression in non-small cell lung cancer cell lines. J Biol Chem. 2013; 288:27343–57.Google Scholar
  41. 41.
    Kim AK, Kim EY, Cho EN, et al. Notch1 destabilizes the adherens junction complex through upregulation of the Snail family of E-cadherin repressors in non-small cell lung cancer. Oncol Rep. 2013;30:1423–9.PubMedGoogle Scholar
  42. 42.
    Hassan WA, Yoshida R, Kudoh S, Motooka Y, Ito T. Evaluation of role of Notch3 signaling pathway in human lung cancer cells. J Cancer Res Clin Oncol. 2016;142:981–93.CrossRefPubMedGoogle Scholar
  43. 43.
    Ito T, Hassan WA, Matsuo A. Notch signaling and Tp53/RB1 pathway in pulmonary neuroendocrine tumorigenesis. Transl Cancer Res. 2016;5:213–9.CrossRefGoogle Scholar
  44. 44.
    Brambilla E, Beasley MB, Austin JHM, et al. Neuroendocrine tumours. Small cell carcinoma. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, editors. WHO classification of tumours of the lung, pleura, thyus and heart. Lyon. IARC; 2015. pp. 63–8.Google Scholar
  45. 45.
    Barnard WG. The nature of the “oat-celled sarcoma” of the mediastinum. J Pathol. 1926;29:241–4.CrossRefGoogle Scholar
  46. 46.
    Gazdar AF. Pathology of endocrine tumors of the lung. In: Becker KL, Gazdar AF, editors. The endocrine lung in health and disease. Philadelphia: Saunders; 1984. p. 364–72.Google Scholar
  47. 47.
    Muller KM, Menne. Small cell carcinoma of the lung: pathological anatomy. In: Seeber S, editor. Small cell lung cancer. Berlin: Springer; 1985. pp. 11–24.Google Scholar
  48. 48.
    Böhm M, Totzeck B, Birchmeier W, Wieland I. Differences of E-cadherin expression levels and patterns in primary and metastatic human lung cancer. Clin Exp Metastasis. 1994;12:55–62.CrossRefPubMedGoogle Scholar
  49. 49.
    Tokman MG, Porter RA, Williams CL. Regulation of cadherin-mediated adhesion by the small GTP-binding protein Rho in small cell lung carcinoma cells. Cancer Res. 1997; 57:1785–93.Google Scholar
  50. 50.
    Nitadori J, Ishii G, Tsuta K, et al. Immunohistochemical differential diagnosis between large cell neuroendocrine carcinoma and small cell carcinoma by tissue microarray analysis with a large antibody panel. Am J Clin Pathol. 2006; 125:682–92.Google Scholar
  51. 51.
    Osada H, Tomida S, Yatabe Y, et al. Roles of achaete-scute homologue 1 in DDK and E-cadherin in repression and neuroendocrine differentiation in lung cancer. Cancer Res. 2008;68:1647–55.CrossRefPubMedGoogle Scholar
  52. 52.
    Galván JA, Astudillo A, Vallina A, Crespo G, Folgueras MV. González MV1. Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors. BMC Cancer. 2014;14:855. doi: 10.1186/1471-2407-14-855.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Zynger DL, Dimov ND, Ho LC, Laskin WB, Yeldandi AV. Differential expression of neural-cadherin in pulmonary epithelial tumours. Histopathology. 2008; 52:348–54.Google Scholar
  54. 54.
    Li Xiao-Xia, Li Rui-Jian, Zhao Lu-Jun, Liu Ning-Bo, Wang Ping. Expression of molecular factors correlated with metastasis in small cell lung cancer and their significance. Int J Clin Exp Pathol. 2015;8:14676–84.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Pelosi G, Scarpa A, Veronesi G, et al. A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear beta-catenin immunoreactivity, independent of EGFR and HER-2 gene amplification or expression. Virchows Arch. 2005;447:969–77.CrossRefPubMedGoogle Scholar
  56. 56.
    Hahn N, Heiden M, Seitz R, Salge-Bartels U. Inducible expression of tissue factor in small-cell lung cancer: impact on morphology and matrix metalloproteinase secretion. J Cnacer Res Clin Oncol. 2012;138:695–703.CrossRefGoogle Scholar
  57. 57.
    Li Z, Guo Y, Jiang H, et al. Differential regulation of MMPs by E2F1, Sp1 and NF-kappa B controls the small cell lung cancer invasive phenotype. BMC Cancer. 2014;14:276. doi: 10.1186/1471-2407-14-276.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Galván JA, González MV, Crespo G, Folgueras MV, Astudillo A. Snail nuclear expression parallels higher malignancy potential in neuroendocrine lung tumors. Lung Cancer. 2010;69:289–95.CrossRefPubMedGoogle Scholar
  59. 59.
    Popper HH. Progression and metastasis of lung cancer. Cancer Metastasis Rev. 2016;35:75–91.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Heidemann F, Schildt A, Schmid K, et al. Selectins mediate small cell lung cancer systemic metastasis. PLoS One. 2014; 9:e92327. doi: 10.1371/journal.pone.0092327.
  61. 61.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Krohn A, Ahrens T, Yalcin A, et al. Tumor cell heterogeneity and small cell lung cancer (SCLC): phenotypical and functional differences associated with epithelial-mesenchymal transition (EMT) and DNA methylation changes. PLoS One. 2014;9:e100249. doi: 10.1371/journal.pone.0100249.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Huang C, Huang M, Chen W, et al. N-acetylglucosaminotransferease V modulates radiosinsitivity and migration of small cell lung cancer through epithelial-mesenchymal transition. FEBS J. 2015;282:4295–306.CrossRefPubMedGoogle Scholar
  64. 64.
    Jahchan NS, Lim JS, Bola B, et al. Identification and targeting of long-term tumor-propagating cells in small cell lung cancer. Cell Rep. 2016;16:644–56.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.CrossRefPubMedGoogle Scholar
  66. 66.
    Kopan R, Ilagan M. The cannonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2008;137:216–33.CrossRefGoogle Scholar
  67. 67.
    Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 2011;11:338–51.CrossRefPubMedGoogle Scholar
  68. 68.
    Gray GE, Mann RS, Mitsiadis E, et al. Human ligands of the notch receptor. Am J Pathol. 1999;154:785–94.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Kao HY, Ordentlich P, Koyano-Nakagawa N, et al. A histone deacetylase corepressor complex regulates the notch signal transduction pathway. Genes Dev. 1998;12:2269–77.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kovall RA. More complicated than it looks: assembly of notch pathway transcription complexes. Oncogene. 2008;27:5099–109.CrossRefPubMedGoogle Scholar
  71. 71.
    Larsen JE, Nathan V, Osborne JK, et al. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest. 2016;126:3219–35.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Zhang T, Guo L, Creighton CJ, et al. A genetic cell context-dependent role for ZEB1 in lung cancer. Nat Commun. 2016;7:12231. doi: 10.1038/ncomms12231.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Chen QY, Jiao DM, Wang J, et al. miR-206 regulates cisplatin resistance and EMT in human lung adenocarcinoma cells partly by targeting MET. Oncotarget. 2016;7:24510–26.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Gazdar AF, Carbone DP. The biology and molecular genetics of lung cancer. Austin: R. G. Landes; 1994.Google Scholar
  75. 75.
    Mirski SE, Gerlach JH, Cole SP. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 1987;47:2594–8.PubMedGoogle Scholar
  76. 76.
    Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, Joyner AL. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell. 1993;75:463–76.CrossRefPubMedGoogle Scholar
  77. 77.
    Borges M, Linnoila RI, van de Velde, et al. An Achaete-Scute homologue essential for neuroendocrine differentiation in the lung. Nature. 1997; 386:852–5.Google Scholar
  78. 78.
    Ito T. Differentiation and proliferation of pulmonary neuroendocrine cells. Prog Histochem Cytochem. 1999;34:245–324.CrossRefGoogle Scholar
  79. 79.
    Linnoila RI, Zhao B, DeMayo JL. Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res. 2000;60:4005–9.PubMedGoogle Scholar
  80. 80.
    Sriurangpong V, Borges M, Ravi R, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61:3200–5.Google Scholar
  81. 81.
    Ito T, Udaka N, Okudela K, Yazawa T, Kitamura H. Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma. Endocr Pathol. 2003;14:133–9.CrossRefPubMedGoogle Scholar
  82. 82.
    Osada H, Tatematsu Y, Yatabe Y, Horio Y, Takahashi T. ASH1 gene is a specific therpeutic target for lung cancer with neuroendocrine features. Cancer Res. 2005;65:10680–5.CrossRefPubMedGoogle Scholar
  83. 83.
    Jiang T, Collins BJ, Jin N, et al. Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res. 2009;69:845–54.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Demelash A, Rudrabhatla P, Pant HC, et al. Achaete-scute homologue-1 (ASH1) stimulates migration of lung cancer cells through Cdk5/p35 pathway. Mol Biol Cell. 2012;23:2856–66.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Li Y, Linnoila RI. Multidirectional differentiation of Achaete-scute homologue-1-defined progenitors in lung development and injury repair. Am J Respir Cell Mol Biol. 2012;47:768–75.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Augustyn A, Borromeo M, Wang T, et al. ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancer. Pro Natl Acad USA. 2014;111:14788–93.CrossRefGoogle Scholar
  87. 87.
    Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEURID reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep. 2016;16:1–14.CrossRefGoogle Scholar
  88. 88.
    Kuo CK, Krasnow MA. Formation of a neurosensory organ by epithelial cells slithering. Cell. 2015;163:394–405.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japan Human Cell Society and Springer Japan 2016

Authors and Affiliations

  1. 1.Department of Pathology and Experimental MedicineKumamoto University Graduate School of Medical SciencesKumamotoJapan
  2. 2.Department of PathologySaitama Medical University Faculty of MedicineSaitamaJapan
  3. 3.Department of Thoracic SurgeryKumamoto University Graduate School of Medical SciencesKumamotoJapan
  4. 4.Department of Pathology, Faculty of MedicineSuez Canal UniversityIsmailiaEgypt
  5. 5.Department of Diagnostic PathologyYokohama City University HospitalYokohamaJapan

Personalised recommendations