title: 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.
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.
authors: Department of Pathology and Experimental Medicine, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. takaito@kumamoto-u.ac.jp.
authors: Takaaki
authors: http://orcid.org/0000-0001-5528-3464
authors: T
authors: Ito
authors: Department of Pathology and Experimental Medicine, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Shinji
authors: S
authors: Kudoh
authors: Department of Pathology, Saitama Medical University Faculty of Medicine, Saitama, Japan.
authors: Takaya
authors: T
authors: Ichimura
authors: Department of Thoracic Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors: Kosuke
authors: K
authors: Fujino
authors: Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
authors: Wael Ahmed Maher Abdo
authors: WA
authors: Hassan
authors: Department of Diagnostic Pathology, Yokohama City University Hospital, Yokohama, Japan.
authors: Naoko
authors: N
authors: Udaka
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051881:Receptor, Notch1 / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051881:Receptor, Notch1; C065500:ASCL1 protein, human; C497761:NOTCH1 protein, human
keywords: Achaete-scute complex homologue 1 (ASCL1); Epithelial-mesenchymal transition (EMT); Neuroendocrine; Notch signaling; Small cell lung cancer