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


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.


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



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.


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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

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