Transcriptional deregulation underlying the pathogenesis of small cell lung cancer

Abstract

The discovery of recurrent alterations in genes encoding transcription regulators and chromatin modifiers is one of the most important recent developments in the study of the small cell lung cancer (SCLC) genome. With advances in models and analytical methods, the field of SCLC biology has seen remarkable progress in understanding the deregulated transcription networks linked to the tumor development and malignant progression. This review will discuss recent discoveries on the roles of RB and P53 family of tumor suppressors and MYC family of oncogenes in tumor initiation and development. It will also describe the roles of lineage-specific factors in neuroendocrine (NE) cell differentiation and homeostasis and the roles of epigenetic alterations driven by changes in NFIB and chromatin modifiers in malignant progression and chemoresistance. These recent findings have led to a model of transcriptional network in which multiple pathways converge on regulatory regions of crucial genes linked to tumor development. Validation of this model and characterization of target genes will provide critical insights into the biology of SCLC and novel strategies for tumor intervention.

Keywords: chromatin modifier; genetically engineered mouse model (GEMM); small cell lung cancer (SCLC); transcription factor.

Figure 1

Proposed models of major genetic events and their roles in SCLC development and progression. (A) A model of SCLC development in the Rb/p53 conditional-mutant mice. Pulmonary neuroendocrine cells are likely cells-of-origin. Validated or potential tumor suppressors and oncogenic drivers are indicated in blue and red, respectively; (B) preSC-based model. Images of preSCs, L-Myc-transformed preSCs, and SCLC cells. The L-Myc-preSCs behave similar to SCLC, forming tumor in nude mice (arrow); (C) a model of interactions among chromatin modifiers on histone H3 lysine 4 and 27. preSC, precancerous neuroendocrine cells; Me, methylation; Ac, acetylation.