Several studies have shown that stro-mal alterations can cause epithelial tumours, but the mechanisms behind such crosstalk are unclear. Achyut etal. have analysed this phenomenon using a mouse model that develops squamous cell carcinoma (SCC) of the forestomach as a result of deletion of transforming growth factor- (TGF) receptor 2 (Tgfbr2) in stromal fibroblasts expressing fibroblast-specific protein 1 (FSP1; termed Tgfbr2Fsp1KO mice).

Tumours from Tgfbr2Fsp1KO mice had increased infiltration of CD45+ leukocytes compared with the fore-stomachs of control Tgfbr2flox/flox mice, suggesting that TGFBR2 loss in FSP1+ fibroblasts leads to an inflammatory reaction. How does this affect the sur-rounding epithelial cells? As inflamm-ation can lead to DNA damage, the authors examined two DNA damage markers, 8-oxo-2-deoxyguanosine and H2AX, and found that the levels of both were increased in the forestomachs of Tgfbr2Fsp1KO mice. Genetic analysis of isolated epithelial cells showed the loss of band C4 of chromosome 4, which contains the tumour suppressors cyclin-dependent kinase (CDK) inhibitor 2A (Cdkn2a; which encodes INK4A and ARF) and Cdkn2b (which encodes INK4B); loss of these at the protein level was also confirmed. The examination of other cell cycle regulators showed increased cyclin D1 expression and increased phosphorylation of p53. Interestingly,

expression of p21 (encoded by Cdkn1a), a downstream mediator of p53, was reduced in Tgfbr2Fsp1KO mice, and the authors showed that this was a result of increased methylation of the Cdkn1a promoter.

How does inflammation promote the loss of these cell cycle regulators in the epithelium? Tgfbr2Fsp1KO mice had increased expression of several inflammatory mediators, including cyclooxygenase 2 (COX2). Blocking COX2 with the inhibitor celecoxib decreased tumour burden and increased the survival of Tgfbr2Fsp1KO mice, which was accompanied by the reduced production of other inflammatory mediators, decreased CD45+ leukocyte infiltration and lower levels of DNA damage. Importantly, celecoxib treatment also reduced the methylation of the Cdkn1a promoter and increased p21 expression in the epithelial cells but not in the stroma.

The tumours observed in the fore-stomachs of Tgfbr2Fsp1KO mice closely resemble human oesophageal SCCs (ESCCs), in which downregulation of TGF receptors has previously been

reported. The authors observed more FSP1+ stromal cells, as well as lower TGFBR2 expression in those cells, in human ESCC samples. Direct immuno staining and analysis of tumour expression databases indicated that ESCCs have increased expression of markers of inflamm-ation and DNA damage, and loss of Cdkn2a and Cdkn2b, paralleling the changes observed in the mouse model.

Overall, these data suggest that inflammation induced by loss of TGF signalling in the stroma can lead to tumour-promoting genetic and epigenetic changes in adjacent epithelial cells.

Sarah Seton-Rogers

M I C R O E N V I R O N M E N T

Making connections

ORIGINAL RESEARCH PAPER Achyut, B. R. et al. Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF- signaling. PLoS Genet. 9, e1003251 (2013)

inflammation promote[s] the loss of these cell cycle regulators in the epithelium

Lara

Cro

w/N

PG

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | CANCER VOLUME 13 | APRIL 2013

Nature Reviews Cancer | AOP, published online 14 March 2013; doi:10.1038/nrc3492

2013 Macmillan Publishers Limited. All rights reserved