Landscaper seeks remunerative position

Abstract

Juvenile polyposis syndrome (JPS) is an inherited genetic defect resulting in production of multiple hamartomas, some of which subsequently develop into carcinomas. About 30% of these patients are known to have a heterozygotic defect in the SMAD4 gene that codes for a mediator of transforming growth factor beta signalling. The loss of one of the two normal SMAD4 alleles is not thought to be suYcient to induce hamartomas but requires the additional loss of the residual normal allele as a secondary event. In patients with JPS, the hamartomas were thought to result from loss of the second normal allele in stem cells that produced stromal cells and equally importantly, that the overlying epithelium continued to have one copy of the normal allele. On this basis, the subsequent development of carcinoma of the epithelium was considered to be due to the epithelial cells being positioned in a highly abnormal microenvironment (“soil”, hence landscaper theory). In this paper, Woodford-Richens et al used fluorescence in situ hybridisation (FISH) directed against the SMAD4 gene to probe individual cells of the polyps to determine which had lost both copies of SMAD4. They found that cells of the stroma and epithelium, but not the inflammatory infiltrate, had lost both alleles. A complicated theory involving “cross talk” between a normal overlying epithelium and an abnormal stroma does, therefore, not have to be invoked to explain why the epithelial cells subsequently undergo malignant transformation. In addition, the finding of identical secondary genetic defects in both the epithelium and stroma of the hamartomas suggests that they originate from the same stem cells and not from distinct lineages as previously thought.