Drug resistance

Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo.Fulda, S. et al. Nature Med. 15 Jul 2002 (doi:10.1038/nrm735)

Most cancer therapeutics induce apoptosis, but tumours can become resistant to this. However, Smac agonists can improve the therapeutic response by sensitizing cells to apoptosis. Smac is released by the mitochondria in response to apoptotic stimuli, and potentiates apoptosis by antagonizing the activity of inhibitor of apoptosis proteins (IAPs). Smac peptides sensitized resistant melanoma and neuroblastoma cells to apoptosis and enhanced the antitumour activity of TRAIL therapy in a xenograft model.

Genomic instability

Suppressed CpG mutability and enhanced tumorigenesis in MBD4-deficient mice.Millar, C. B. et al. Science 297, 403–405 (2002)

Cytosine-to-thymine transitions occur frequently in the human genome, as the methylated cytosine at a CpG site can be deaminated to form thymine. Many of these mutations are repaired by thymine DNA glycosylases, such as MBD4. So might loss of MBD4 increase mutations and hence tumorigenesis? Mbd4−/− mice have three times more cytosine-to-thymine transitions, and that tumour formation is increased in a cancer-susceptible ApcMin/+ background.

Cancer epidemiology

Geographical variation in the penetrance of CDKN2A mutations for melanoma.Bishop, D. T. et al. J. Natl Cancer Inst. 94, 894–903 (2002)

Inherited mutations in the CDKN2A gene — which encodes INK4A and ARF —increase susceptibility to melanoma. An analysis of 80 susceptible families from Europe, the United States and Australia revealed that gender and alterations in ARF did not affect CDKN2A penetrance, but the incidence rate of melanoma in the population did. Whereas the average penetrance increased from 0.3 to 0.67 between the ages of 50 and 80, the incidence in Australia increased from 0.32 to 0.91, indicating that the same factors affect population incidence of melanoma and CDKN2A penetrance.

Oncogenesis

Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours.Malliri, A. et al. Nature 417, 867–871 (2002)

Rho proteins are crucial mediators of many aspects of tumorigenesis, so loss of a Rho-protein activator could reduce the incidence of tumour formation. Mice were generated that were deficient for the Rac activator Tiam1. These were resistant to the formation of Ras-induced skin tumours, and the few that did develop grew slowly. Interestingly, these were more malignant than those that developed in a wild-type background.