Intricate modelling

Lung cancer causes most cancer-related deaths worldwide, and of the different lung tumour types, adenocarcinoma is the most common. The involvement of K-ras in lung cancer was confirmed last year (see June 2001 Highlights), when Tyler Jacks' group showed that the somatic activation of a constitutively active K-ras allele ( K-ras ^G12D ) can alone cause cancer. This study is now followed up by two new K-ras^G12D mouse models — one made by Jacks' group and the other by Harold Varmus' group — in which conditional gene-activation systems have been used to switch on this mutant K-ras allele. Importantly, these studies shed much needed light on the events required for lung tumour initiation, maintenance and regression, and are a step towards much better mouse models of cancer that can be used to develop and test new cancer therapies.

The gene-expression switches used by each team allowed them to ask different questions about lung tumour biology. Jacks' team used the Cre/loxP system to activate K-ras^G12D by targeting the endogenous K-ras locus with a 'lox–stop–lox' (LSL) K-ras allele in which loxP sites flank a transcriptional Stop element. When Cre was introduced into the lungs of LSL-K-ras^G12D mice through a nasally delivered adenovirus, their lungs became covered in precancerous lesions within four weeks, and there was evidence that Cre-induced activation of K-ras^G12D was responsible for this highly penetrant and rapid lung tumorigenesis.

However, such severe tumorigenesis is a problem — in last year's study, for example, the mice developed so many tumours that many died before the earlier lesions could progress to malignancy. The Jacks' group tackled this problem by lowering adenoviral-Cre doses to reduce tumour numbers, allowing the mice to survive and progress to later stages of tumorigenesis. Only then could the team solve the long-standing question of which of several early precancerous lesions give rise to adenocarcinomas — they report that it's most probably a lesion called atypical adenomatous hyperplasia, which seems to originate from one particular cell type, the alveolar type II cell. The authors also identified a new cell type, possibly a new lung stem cell, that might also contribute to adenocarcinoma development.

Fisher et al. used a different trick to turn on the K-ras^G12D allele — they created bi-transgenic mice that express both a tetracycline (Tet)-activatable form of K-ras^G12D and a reverse Tet transactivator protein expressed in alveolar type II cells that can only activate K-ras^G12Din the presence of doxycycline. This elegant approach allowed them to look at the events required for the initiation, maintenance and regression of lung tumours. Within one week of receiving doxycycline in their drinking water, these mice developed hyperplastic alveolar type II cells; after two months, their lungs became laden with large adenomas and adenocarcinomas. Nevertheless, within days of doxycycline withdrawal, these tumours regressed and underwent apoptosis. When these mice were crossed to two mouse strains, each null for a well-known tumour suppressor gene — Trp53 or p16 ^ink4a — they developed more-aggressive tumours much more rapidly. Surprisingly, however, these tumours still underwent rapid apoptosis-mediated regression following doxycycline withdrawal, showing that this regression occurs via a p53-independent apoptotic pathway.

The fact that lung tumours with p16^ink4a and Trp53 mutations can be induced to regress is good news indeed for those developing anticancer therapeutics, because TP53 mutations are associated with tumour resistance to chemotherapy. But what is the pathway that mediates the p53-independent regression of these tumours? Fisher et al. have already found some clues to this question in their data, and to investigate it further, plan to use microarray expression analysis to identify key transcriptional changes that occur during tumour induction and regression in these mice.