Expression of tumor necrosis factor related apoptosis inducing ligand (TRAIL) and trail receptors in renal cell carcinoma

Renal cell carcinoma (RCC) is a cancer with a very high risk of metastatic disease and mortality. Also, it's resistant to chemotherapy in case of metastasis. So, several studies are going on to search out new molecules which have prognostic value to detect high risk patients and which can be used for targeted therapy in metastatic cases. TRAIL and its receptors have a regulation role on immune surveillance and tumor development by using apoptotic pathways. In this study, we analyzed the expression of TRAIL and its receptors and their possible affect on the clinical and pathological prognostic factors in patients with RCC. We examined the data of 137 patients retrospectively who had RCC diagnosis. Tissue samples, containing tumor and corresponding normal tissue were prepared from the paraffin blocks. Eleven of the patients were excluded from further analysis because of insufficient tumor tissue in paraffin blocks. Expression levels of TRAIL and its receptors were searched by immunohistochemistry method. Then the association of TRAIL's and its receptors' expression level with the prognostic factors and survival was examined. Because of staining weakly and only in eight patient's tumor tissue, TRAIL-R4 was excluded from statistical analysis. Analyses results have shown that, high TRAIL-R1 expression levels were significiantly associated with high pT stages (pt3/pT4) (p=0.043) and high TRAIL-R3 expression levels were significiantly associated with high pT stages (p=0.042) and with high nuclear grades (G3/G4) (p=0.006). High TRAIL expression levels were significiantly more common in clear cell subtypes compared to group which consists of other subtypes (p=0.005) and contrarily high TRAIL-R1 expression levels were significiantly more common in the group of other subtypes compared to clear cell subtypes (p=0.033). Also high TRAIL expression levels were significiantly more common in the males compared to females (p=0.019). TRAIL-R2 expression levels were not associated with any of the clinical and pathological features. For all RCC patients univariate survival analyses showed that the expression levels of TRAIL and TRAIL receptors were not associated with cancer spesific survival. But in subgroup analyses, it was shown that high TRAIL expression levels were significiantly associated with lower cancer spesific survival rates in the subgroup of non-clear cell histological subtypes (p=0.035). This finding can be interpreted as the answer of the receptors to TRAIL is in favor of antiapoptosis in non-clear cell histological subtypes of RCC and it can give direction to targeted therapy strategies of this group of patients. Staining of TRAIL-R4 only in a small proportion should be evaluated in larger series. Because an actual low expression of TRAIL-R4 (the receptor which induces antiapoptotic genes by NF-κB in case of overexpression) may point a problem for intracellular signal pathways of TRAIL-R4. As a result, the association of high TRAIL-R1 expression levels with high pT stage and the association of high TRAIL-R3 expression levels with high pT stage and high nuclear grade, points the importance of these receptors in targeted therapy strategies. The effect of TRAIL and its receptors on survival should be evaluated in larger series and in prospective studies