Somatic-genetic aberrations, specific protein levels and their prognostic value in colon cancer

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in developed countries. The overall 5-year survival rate is around 45%. Several factors including depth of tumour invasion into the bowel wall (stage II) and presence of node metastasis (stage III) determine the prognosis. The 5-year survival rate rapidly drops from ≥90% in stage I to 75% and 50% in stages II and III, respectively. Adjuvant chemotherapy significantly reduces the recurrence rate, improving the disease-specific survival (Moertel et al., 1995; IMPACT, 1995; IMPACT B2, 1999). Although disease-free survival has improved during the last decades, about half of the patients will still develop recurrent disease, usually presented as distant metastases to the liver (Gatta et al., 1998). Molecular biological tumour markers are thought to be helpful in discriminating long-term and short-term survivors and might predict chemosensitivity of these tumours making a more tailored adjuvant treatment possible (molecular stratification) (Wright et al., 2000; Goel et al., 2003).

Expression of tumour necrosis factor-related apoptosis-inducing ligand death receptors in sporadic and hereditary colorectal tumours:Potential targets for apoptosis induction

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and antibodies against TRAIL receptors death receptor 4 (DR4) and death receptor 5 (DR5) are under investigation for cancer therapy. To study the potential application of these agents, the expression of DR4 and DR5 were studied immunohistochemically in colorectal adenomas and carcinomas from patients with sporadic disease (n = 74 and 56, respectively), familial adenomatous polyposis (FAP, n = 41 and 4, respectively) and hereditary non-polyposis colorectal cancer (HNPCC, n = 50 and 21, respectively). BAX, which is frequently mutated in tumours with high-frequency microsatellite instability (MSI-H) may play a role in sensitivity to TRAIL. Therefore, MSI-H carcinomas (n = 42, of which 27 sporadic and 15 HNPCC) were analysed for apoptotic activity, assessed by M30 immunoreactivity, and BAX mutations. Most adenomas from all three patient groups expressed DR4 and DR5. Most carcinomas expressed DR4, except for six cases, all with mucinous histology. All carcinomas, including mucinous carcinomas, showed DR5 expression. BAX mutations were found in 6/ 42 MSI-H cancers with similar apoptotic indices and expression of DR4, DR5 and TRAIL in BAX mutant and wild-type cases. Since most sporadic and hereditary colorectal neoplasms express DR4 and DR5, targeting of these receptors may be a potential prevention or treatment strategy. (c) 2005 Elsevier Ltd. All rights reserved

Prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand and its receptors in adjuvantly treated stage III colon cancer patients

PURPOSE: In preclinical models, there is synergism between chemotherapy and recombinant human tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL) on apoptosis induction in tumor cells. Therefore, the prognostic relevance was analyzed of the expression of TRAIL and its death receptors DR4 and DR5 on disease-free survival and overall survival in stage III colon cancer patients treated with adjuvant chemotherapy. METHODS: Tissue microarrays were constructed of primary tumor tissue from 376 stage III colon cancer patients treated in a randomized adjuvant chemotherapy study (fluorouracil/levamisole v fluorouracil/levamisole/leucovorin) and stained immunohistochemically for TRAIL, DR4, and DR5. Log-rank tests and Cox proportional hazard analysis, with adjustment for treatment arm, sex, age, N stage, microsatellite instability status, and p53 mutation status, were performed. RESULTS: The majority of tumors showed high expression of TRAIL (83%), DR4 (92%), and DR5 (87%). Median follow-up was 43 months. High DR4 expression was associated with worse disease-free survival (odds ratio [OR] = 2.19; 95% CI, 1.06 to 4.53; P = .03), worse overall survival (OR = 2.22; 95% CI,1.03 to 4.81; P = .04) and shorter time to recurrence (P = .02) compared with those with low DR4 expression. TRAIL or DR5 expression had no prognostic value. CONCLUSION: High DR4 expression is associated with worse disease-free and overall survival in stage III adjuvant-treated colon cancer patients. Evaluation of DR4 expression in stage III colon cancer patients may identify a subset requiring more aggressive adjuvant treatment