Genetics

Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Hingorani, S. R. et al. Cancer Cell 7, 469–483 (2005)

Through endogenous expression of Trp53R172H and KrasG12D in the mouse pancreas, Hingorani et al. created a mouse model of pancreatic ductal adenocarcinoma that recapitulates the human disease. The primary carcinomas and metastases have a high degree of genomic instability, but no mutations were observed in several well-known tumour-suppressor gene pathways. This indicates that distinct genetic pathways lead to formation of these tumours.

Free Radicals

Nitric oxide synthase II suppresses the growth and metastasis of human cancer regardless of its up-regulation of protumor factors. Le, X. et al. Proc. Natl Acad. Sci. USA 6 June 2005 (10.1073/pnas.0409581102)

Le et al. report that in different human tumour cell types expressing inducible nitric oxide (NO) synthase II, production of NO leads to upregulation of multiple angiogenic molecules. However, the NO-producing tumour cells did not form tumours or metastases in mouse models, owing to NO-mediated apoptosis. The authors conclude that NO has a dose-dependent antitumour activity, in spite of its ability to upregulate pro-angiogenic factors.

Metastasis

Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. Dhawan, P. et al. J. Clin. Invest. 16 June 2005 (10.1172/JCI24543)

Disruption of tight junctions between cells is associated with tumour-cell invasion and metastasis. Dhawan et al. report increased expression of the tight junction protein claudin-1 in human primary colon carcinomas and metastases, along with mislocalization of this protein from the cell membrane to the cytoplasm and nucleus. Overexpression of claudin-1 promotes cellular transformation and invasive behaviour, whereas siRNA-mediated inhibition decreased the tumorigenic and metastatic potential of colorectal cancer cells.

Protein Kinases

A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Stephens, P. et al. Nature Genet. 37, 590–592 (2005)

To explore the mutational landscape in breast cancer genomes, Stratton and colleagues sequenced the coding regions of 518 protein kinases in tumours. Somatic mutations were distributed unevenly among the cancers examined. Whereas twelve primary breast cancers had no somatic mutations, two had a single mutation each and one had two mutations, one cancer had 52 mutations, all of which were base substitutions. The authors discuss how such mutations might arise and contribute to cancer development.