Adenocarcinoma of the lung is a type of non-small cell lung cancer that accounts for over 30% of all lung cancer cases. The prognosis for patients diagnosed with this condition is generally poor (although less so than for some other types of lung cancer), with about 17% surviving five years after diagnosis. Furthermore, the molecular mechanisms of lung adenocarcinoma development are still poorly understood.

A group of researchers led by Tyler Jacks at Massachusetts Institute of Technology, Cambridge, MA, USA has now used a mouse model of this disease to elucidate some of these mechanisms, and has identified a transcription factor known as Nkx2-1 (or, the NK2-related homeobox transcription factor) as a suppressor of metastasis in this tumour type.

These experiments used a strain of transgenic mice that had been engineered to develop lung adenocarcinomas with defined genetic modifications only after the administration of a lentivirus vector. Following lentivirus injection, these mice each developed between 5 and 20 lung tumours, some of which became malignant and metastasised, and lived for a further 8-14 months. Cell lines were derived from both metastatic and non-metastatic primary tumours and from metastases.

Jacks and his co-workers derived gene expression profiles from all these cell lines and found that the expression profile of non-metastatic tumour cells was significantly different from those of metastatic tumour cells and of metastases. Similar patterns were observed in gene expression datasets from human patients with this condition, and these were seen to correlate with patient prognosis, indicating that molecular mechanisms of lung adenocarcinoma progression were conserved between mice and humans.

The gene for the homeobox transcription factor Nkx2-1 was one of those significantly over-expressed in non-metastatic compared to metastatic cells. Interestingly, this gene had previously been identified as a lung adenocarcinoma oncogene.

The group then explored the mechanism of action of this protein further, first identifying that Nkx2-1 was down-regulated principally in high-grade, poorly differentiated tumours in their mouse model. It was also down-regulated in poorly differentiated areas of metastatic primary tumours compared to more differentiated areas of the same tumours. This, and associated human data, suggested that Nkx2-1 was either a functional regulator or a marker of adenocarcinoma progression.

Furthermore, knockdown of Nkx2-1 in non-metastatic cells using short hairpin RNA initiated metastasis in vivo, although not in cell culture. Further comparison of the gene expression profiles focused the researchers on one gene regulated by Nkx2-1, the embryonically restricted chromatin regulator Hmga2.

This gene is expressed in embryonic and adult stem cells and in many tumour types and controls gene expression globally through its regulation of the structure of chromatin. Hmga2 was found to be down-regulated in those non-metastatic tumours in which Nkx2-1 was up-regulated, and vice versa. The contrasting phenotypes NKX2-1+ / HMGA2- (well differentiated, non-malignant) and NKX2-1- / HMGA2+ (poorly differentiated, malignant) could also be observed in human lung adenocarcinoma cells, and, similarly, NKX2-1 expression could be correlated with good outcomes for patients and HMGA2 expression with poor ones.

The human gene NKX2-1 has previously been classified as an oncogene in lung adenocarcinoma because of its amplification in some tumours. These results imply that down-regulation of its expression is associated with a poorly differentiated, metastatic tumour phenotype and thus that it can also act as a tumour suppressor gene. Jacks and his co-workers concluded by suggesting that the function of this gene in a particular tumour will be context dependent, and by describing it as a dual-function lineage factor.

Article: Winslow, M.M., Dayton, T.L., Verhaak, R.G.W. and 13 others (2011). Suppression of lung adenocarcinoma progression by Nkx2-1. Nature, published online ahead of print 6 April 2011. doi:10.1038/nature09881