BOSTON – Activation of specific genes in the bronchial epithelium occurs at very early stages of lung cancer tumorigenesis. Such changes in the genomic signature of the bronchial airways may serve as biomarker for lung cancer risk, US researchers report.

A better understanding of the molecular pathways of human lung cancer may not only aid early detection and improve prognosis but may help to identify suitable chemopreventive agents. In a recent study published in the journal Science Translational Medicine, US researchers sought to identify early events leading to lung tumorigenesis by describing pathways that are deregulated in the bronchial airway of smokers with – or at risk for – lung cancer.

Although smoking is the main cause of lung cancer, it is not known which smokers are at highest risk of cancer development. This study provides new insight into signalling pathways that are affected early in the process of tumorigenesis, indicating that, even before any cytological changes occur, there is activation of one such pathway, the so-called phosphoinositide 3-kinase (PI3K) pathway, in smokers who develop lung cancer.

Phosphoinositide 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking – processes which in turn are involved in cancer.

The researchers found that genes regulating the PI3K pathway – the genes involved in lung cancer oncogenesis- are activated to higher levels in the airways of smokers with lung cancer than in the airways of smokers without lung cancer.

“Although the PI3K pathway is known to play a role in some cases of lung cancer, its activation in cytologically normal airway epithelium of smokers with lung cancer suggests that this pathway is altered early in lung cancer development,” write Dr Adam M. Gustafson of the Boston University Medical Center, Boston, USA, and colleagues.

The researchers had observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before the actual tumorigenesis.
The big question asked by the researchers is whether a reduction in PI3K pathway activity in at-risk individuals would have any therapeutic potential.

In favour of this assumption would be the finding that, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol.

Myo-inositol, a candidate lung cancer chemopreventive agent that reduces dysplastic lesions in the airways, has been shown to inhibit the PI3K pathway in vitro. It is an oral agent that is also well-tolerated, the researchers emphasise.

Gene expression profiling on bronchial airway brushings – a relatively noninvasive procedure – seems a promising approach: “These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalised approaches to chemoprevention and therapy.”

Reference: Gustafson AM et al. Sci Transl Med 2010; 2: 26ra25.