Differential disruption of cell cycle pathways in small cell and non-small cell lung cancer

Abstract

Lung cancer is the leading cause of cancer-related mortality in the world, with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) comprising the two major cell types. Although these cell types can be distinguished readily at the histological level, knowledge of their underlying molecular differences is very limited. In this study, we compared 14 SCLC cell lines against 27 NSCLC cell lines using an integrated array comparative genomic hybridisation and gene expression profiling approach to identify subtypespecific disruptions. Using stringent criteria, we have identified 159 of the genes that are responsible for the different biology of these cell types. Sorting of these genes by their biological functions revealed the differential disruption of key components involved in cell cycle pathways. Our novel comparative combined genome and transcriptome analysis not only identified differentially altered genes, but also revealed that certain shared pathways are preferentially disrupted at different steps in these cell types. Small cell lung cancer exhibited increased expression of MRP5, activation of Wnt pathway inhibitors, and upregulation of p38 MAPK activating genes, while NSCLC showed downregulation of CDKN2A, and upregulation of MAPK9 and EGFR. This information suggests that cell cycle upregulation in SCLC and NSCLC occurs through drastically different mechanisms, highlighting the need for differential molecular target selection in the treatment of these cancers.

Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

“…As has been shown recently, there are molecular differences between small cell cancer, large cell cancer, squamous cell cancer, and adenocarcinomas of the lung (33,34). As an example, EGFR mutations are more common in adenocarcinomas than the other histologies of lung cancer (40% versus 3%; ref.…”

A systems biology approach for pathway level analysis

“…Since early articles on the molecular mechanisms perturbed in lung cancers (Slebos and Rodenhuis 1989;Nau et al 1985) until the most recent articles on this topic (Panani and Roussos 2006;Coe et al 2006), there is a consensus that the cell cycle is highly deranged in lung cancers. Moreover, cell cycle genes have started to be considered both as potential prognostic factors and therapeutic targets (Vincenzi et al 2006).…”

The Epithelial Cell and Lung Cancer: The Link between Chronic Obstructive Pulmonary Disease and Lung Cancer

“…In a landmark clinical and molecular study, it was shown that the transcriptome profile of normal bronchial epithelium is distinct from that of the lung parenchyma, that this profile differs again between SCLC and NSCLC, and that there is in each individual an association between cumulative tobacco exposure and gene transcription [52,53]. In addition, the expression of a number of presumed oncogenes and tumour suppressor genes in the airway epithelial cells of smokers did not return to normal for decades after smoking cessation [54], although many others (especially the antioxidant and drug-metabolising genes) did so within 2 years.…”