Epigenetics

Deficiency of Mbd2 suppresses intestinal tumorigenesis. Sansom, O. J. et al. Nature Genet. 5 May 2003 (doi:10.1038/ng1155)

Mbd2 functions as a transcriptional repressor by binding to methylated CpG islands. As mouse intestinal tumorigenesis requires methylation, does loss of Mbd2 affect tumour formation? Loss of Mbd2 in the tumour-prone ApcMin/+ mouse resulted in fewer and smaller intestinal adenomas, and the mice survived for longer. Mbd2-null mice are viable and fertile, so if MBD2 is also not essential in humans, MBD2 could be a useful therapeutic target.

Tumour suppressors

NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Lallemand, D. et al. Genes Dev. 17, 1090–1100 (2003)

The NF2 tumour suppressor is homologous to the ERM family of membrane–cytoskeletal-associated proteins, but how it regulates cell proliferation from this location is unclear. McClatchey and colleagues have now addressed this question and have shown that Nf2 localizes to adherens junctions in wild-type cells, and its loss prevents the formation of stable cell–cell junctions. This, in turn, means that cells are unable to undergo contact-dependent growth arrest, so they continue to proliferate. This provides a mechanism by which Nf2 might act as both a tumour and metastasis suppressor.

Genomic analysis

Mutational analysis of the tyrosine kinome in colorectal cancer. Bardelli, A. et al. Science 300, 949 (2003)

Bardelli et al. have used a sequencing and bioinformatic approach to address the extent to which tyrosine kinase genes are mutated in colorectal cancer. They analysed one branch of the kinase tree by sequencing 138 genes from 35 colorectal cancer cell lines, and then the mutated genes in another 147 colorectal cancers. A minimum of 30% of colorectal cancers might contain a mutated tyrosine kinase gene. Seven genes were mutated more than once, and the mutations might be activating. Interestingly, few of the mutated genes had previously been linked with human cancer, which emphasizes the benefit of this approach.

Therapeutics

A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects. Samlowski, W. E. et al. Nature Med. 5 May 2003 (doi:10.1038/nm874)

Interleukin-2 is a valuable therapy for metastatic renal-cell carcinoma and malignant melanoma, but severe hypotension is a frequent side effect. Samlowski et al. now show that the superoxide dismutase mimetic M40403 can block IL-2-induced hypotension in mice. This allows the dose of IL-2 to be increased, which, in turn, increases its anticancer effect.