Notch signaling and Tp53/RB1 pathway in pulmonary neuroendocrine tumorigenesis

Small cell lung cancer (SCLC) is a unique histological type of lung cancers, characterized by high grade malignant biological behavior and neuroendocrine differentiation. SCLC is subdivided into pure and combined types, and in the latter type, non-small cell lung cancer (NSCLC) features co-exist alongside with SCLC features. It has been reported that double mutations in Tp53 and RB1 are essential in small cell carcinogenesis, and that neuroendocrine differentiation is regulated by proneural transcription factors, such as Achaete-scute homolog 1 (ASCL1) and its signaling regulator; Notch signaling pathway. According to a recent article reported by Meder et al., secondary SCLC is derived from NSCLC, with loss of Notch activity, accompanying with increased ASCL1 activity, and with further additional genetic changes in Tp53 and RB1. They analyzed combined type SCLC cases, from the view point of the Notch-ASCL1-p53-RB axis, and it was the first to address comprehensively the molecular mechanisms of small cell carcinogenesis, regarding these four molecules. It is thus an urgent issue to clarify the molecular mechanisms of small cell carcinogenesis, progression, metastasis and acquisition of resistance to chemo-radiotherapy, for proper identification of a novel therapeutic target. But, in this perspective, we discussed the molecular mechanisms of small cell carcinogenesis, from the point of neuroendocrine differentiation in SCLC.