Prognostic significance of TRAIL-R1 and TRAIL-R3 expression in metastatic colorectal carcinomas
Introduction
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein that belongs to the tumour necrosis factor (TNF) superfamily. TRAIL activates apoptosis through the death receptors TRAIL-R1 (DR4) or TRAIL-R2 (DR5/KILLER) which carry cytoplasmic death domains. TRAIL also binds to two other membrane-bound receptors, TRAIL-R3 (DcR1/TRID) and TRAIL-R4 (DcR2/TRUNDD), which cannot transmit the apoptotic signal because they lack a functional intra-cytoplasmic domain. Consequently, TRAIL-R3 and TRAIL-R4 are thought to protect cells from TRAIL-induced apoptosis by acting as decoy receptors and thus interfering with the binding of the pro-apoptotic TRAIL-R1 and -R2.1 Importantly, unlike other TNF family members, TRAIL kills a wide variety of tumour cells with limited effects on normal tissues invivo.2, 3 This finding has aroused a great interest in the development of TRAIL-targeted therapies, and currently several clinical trials are being carried out in cancer patients.4, 5
Colorectal cancer (CRC) is the second most frequent cause of cancer death in Europe and United States. Chemotherapeutic agents can improve survival in patients with CRC, and 5-Fluorouracil (5-FU)-based chemotherapy, modulated with folinic acid, has long been a standard regimen. To enhance its efficiency in CRC patients, 5-FU is often administered in combination with other chemotherapeutic agents, such as oxaliplatin or irinotecan. Moreover, molecularly targeted therapies against epidermal growth factor receptor (such as cetuximab) and vascular endothelial growth factor (such as bevacizumab) have also shown promising effects in CRC.6, 7 However, despite the increasing therapeutic options, drug resistance remains a major problem for the treatment of this disease. As the ultimate goal of cytotoxic chemotherapies is to induce death of tumour cells, the presence of an imbalance between functional and decoy TRAIL receptors may be one of the mechanisms involved in the development of drug resistance. Preclinical data have shown that the use of TRAIL in combination with chemotherapeutic agents, such as 5-FU, CPT-11 or doxorubicin, sensitises CRC cells to apoptosis,8, 9 possibly through over-expression of TRAIL-R2.10 Conversely, over-expression of TRAIL-R3 or -R4 has been correlated with resistance to apoptosis.11, 12 Therefore, invivo analysis of TRAIL receptors’ expression in CRC tumour samples might be of clinical relevance. To this aim we analysed, using tissues micro arrays, TRAIL-R1 to -R4 expression in metastatic CRC of patients treated with 5-FU-based chemotherapy as the first-line treatment. We then correlated these findings with response to treatment, disease progression and survival.
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Patients and treatment
For this study, we selected 60 patients with metastatic CRC who were enrolled in controlled trials to evaluate the effect of first-line 5-FU-based chemotherapy at the CRLC Val d’Aurelle-Paul Lamarque Cancer Centre in Montpellier, France, between 1991 and 2002. All our patients had a histological diagnosis of advanced colorectal adenocarcinoma with hepatic metastases either at the time of the diagnosis (i.e. synchronous disease) or after resection of the primary tumour (i.e. metachronous
TRAIL receptors’ expression in primary CRC and hepatic metastases
In primary CRC and hepatic metastases, the four TRAIL receptors were localised mainly in the cytoplasm (Fig. 1a), and their expression was quite variable amongst the different samples. Therefore, we decided to rank our samples in three different classes (low, medium and high) according to the number of positive cells for each TRAIL receptor (Fig. 1b). We then looked at the distribution of the three classes (Fig. 2) and observed that, in both primary CRC and hepatic metastases, the decoy
Discussion
Drug resistance remains a major issue in cancer treatment. In this study, we explored the potential role of the expression level of the four TRAIL receptors in the response to 5-FU-based chemotherapy in patients with metastatic CRC. Our results indicate that concomitant low/medium TRAIL-R1 and high TRAIL-R3 expression in primary CRC is significantly associated with a poor response to 5-FU-based first-line chemotherapy and with shorter progression-free survival. Then, by combining the levels of
Conflict of interest statement
None declared.
Acknowledgement
This work was supported by the French Ministry of Health (Programme Hospitalier de Recherche Clinique – PHRC Régional 2003).
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