Koornstra JJ et al. (2005) Expression of tumour necrosis factor-related apoptosis-inducing ligand death receptors in sporadic and hereditary colorectal tumours: potential targets for apoptosis induction. Eur J Cancer 41: 1195–1202

Novel strategies to treat or prevent colorectal neoplasms are urgently required. One potential target is tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), which causes apoptosis by binding to death receptor (DR) 4 and DR5. Both receptors are expressed in the majority of tumors, providing the potential for targeted apoptosis. A mutation in the BAX gene, however, commonly found in high-frequency microsatellite instability tumors, could have a role in TRAIL sensitivity and affect the potential use of TRAIL-receptor agonists.

Using immunohistochemical staining, Koornstra and co-workers explored DR4 and DR5 expression in 74 colorectal adenomas and 56 carcinomas from patients with sporadic disease, 41 colorectal adenomas and 4 carcinomas from patients with familial adenomatous polyposis, and 50 colorectal adenomas and 21 carcinomas from patients with hereditary nonpolyposis colorectal cancer. In 15 individuals with high-frequency microsatellite instability carcinomas, the association between BAX mutations, apoptosis and expression of DR4, DR5 and TRAIL were assessed.

DR4 and DR5 were expressed in almost all adenomas analyzed, with TRAIL expressed in approximately 75%. Similarly, DR5 was detected in all carcinomas, DR4 was identified in most, and TRAIL expression ranged between 37–81%. Notably, all carcinomas negative for DR4 were mucinous. Interestingly, in adenomas and carcinomas negative for DR4, TRAIL expression was also absent. BAX gene inactivation showed no correlation with DR4, DR5 or TRAIL expression, or apoptotic indices.

With widespread expression of DR4 and DR5, and no link with BAX mutation, TRAIL-receptor agonists could be used for targeted apoptosis as treatment for sporadic and hereditary colorectal neoplasms.