Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin

Abstract

Lung cancer is the most common cause of cancer deaths worldwide. The two broad histological subtypes of lung cancer are small-cell lung cancer (SCLC), which is the cause of 15% of cases, and non-small-cell lung cancer (NSCLC), which accounts for 85% of cases and includes adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. Although NSCLC and SCLC are commonly thought to be different diseases owing to their distinct biology and genomic abnormalities, the idea that these malignant disorders might share common cells of origin has been gaining support. This idea has been supported by the unexpected findings that a subset of NSCLCs with mutated EGFR return as SCLC when resistance to EGFR tyrosine kinase inhibitors develops. Additionally, other case reports have described the coexistence of NSCLC and SCLC, further challenging the commonly accepted view of their distinct lineages. Here, we summarise the published clinical observations and biology underlying tumours with combined SCLC and NSCLC histology and cancers that transform from adenocarcinoma to SCLC. We also discuss pre-clinical studies pointing to common potential cells of origin, and speculate how the distinct paths of differentiation are determined by the genomics of each disease.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Alveolar type II cells could be a common precursor that can give rise to both adenocarcinoma and small-cell lung cancer (SCLC)

Diagram depicts the cells of origin of adenocarcinoma and SCLC. Neuroendocrine cells and possibly alveolar type II cells can give rise to SCLC (left and centre), whereas clara cells and alveolar type II cells can give rise to adenocarcinoma (right and centre).

Figure 2. Hypothetical model depicting the molecular events that lead to transformation from adenocarcinoma to small-cell lung cancer (SCLC)

Alveolar type II cells have the potential to form both adenocarcinoma and SCLC depending on the mutational status of key oncogenes and tumour suppressors. Transformation from adenocarcinoma to SCLC involves the loss of RB1 and loss of EGFR protein expression.