New versus old


the tumour microenvironment, are known to have a profound effect on tumour development. However, in their recent Cell paper, Terry Van Dyke and colleagues show that the reverse is also true — that the tumour cells can provide selective pressure for mutations in the surrounding stromal cells. There has been some evidence that stromal fibroblasts that surround a carcinoma contain mutations that cause loss of expression of tumour suppressors such as p53. But it has been unclear if this loss is selected for during tumour evolution. To investigate further, the authors used a mouse model of prostate cancer in which a fragment of the SV40 large-T antigen was expressed in the prostate epithelium only, inactivating the tumour suppressor retinoblastoma (RB) and its related proteins p107 and p130. These mice, which have wild-type p53, were crossed into p53-heterozygous and p53-null backgrounds to investigate the effect of p53 on prostate tumour development. Surprisingly, the authors found that loss of p53 expression had an effect on the surrounding stromal cells rather than on the epithelial tumour cells. All the animals developed prostate tumours, but the p53-null animals developed tumours with extensive stromal tissue earlier than wild-type or p53heterozygous animals. This expansion of the stroma correlated with the induction of stromal fibroblast proliferation in the p53-null animals. These findings indicated that stromal cell proliferation was only possible once p53 expression was lost, and that loss of RB function in the epithelium promotes this proliferative environment. To verify this hypothesis, the authors took stromal and epithelial samples from the wild-type and p53heterozygous mice and analysed expression of p53. As expected, they found that loss of RB function induced p53 activation in the epithelial cells, but a subset of stromal cells also showed p53 activation. In addition, genetic loss of Trp53 in proliferating stromal cells was seen in established tumours from both p53-heterozygous and wild-type backgrounds, indicating that p53 loss is selected for in the stromal cells. Importantly, this occurred before the loss of p53 expression in the wild-type and heterozygous epithelial tumour tissue. The authors conclude that these studies further illustrate the complexity of the interactions between epithelial tumour cells and the surrounding stromal cells, and add to the evidence that drugs that target the tumour microenvironment could be useful for anticancer treatment. Nicola McCarthy

DOI: 10.1038/nrc1812

Cite this paper

@article{Goymer2006NewVO, title={New versus old}, author={Patrick Goymer}, journal={Nature Reviews Cancer}, year={2006}, volume={6}, pages={93-93} }