Expression of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptors 1 and 2 in Melanoma

Abstract

Purpose: The proapoptotic receptors tumor necrosis factor^related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2 are targets of drugs in clinical development, and receptor expression levels may be important determinants of sensitivity to receptor agonists.We assessed TRAIL-R1and TRAIL-R2 expression patterns in a large cohort of melanomas and benign nevi. Experimental Design: We analyzed tissue microarrays containing 546 melanomas and 540 nevi using our automated quantitative method to measure protein levels in situ (AQUA). The system uses S100 to define pixels as melanoma (tumor mask) within the array spot and measures intensity of TRAIL-receptor expression using Cy5-conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathologic variables.Results: TRAIL-R1and TRAIL-R2 expression was higher in melanomas than in nevi (P < 0.0001), and higher in primary than in metastatic specimens (P = 0.0031and P < 0.0001, respectively).TRAIL-R1and TRAIL-R2 expression exceeding the 95th percentile for nevi was found in 19% and 74% of melanoma specimens, respectively. Although on univariate analysis, high TRAIL-R2 expression correlated with increased survival (P = 0.0439), it was not associated with survival within the primary or metastatic subcohorts. TRAIL-R1 expression was not associated with survival. Conclusions:TRAIL-R1andTRAIL-R2 expression is higher in malignant melanocytes than in their benign counterparts, suggesting that these receptors might be effective therapeutic targets in melanoma. Expression is higher in early-stage disease than in metastatic specimens, and expression exceeding that found in nevi is found in a substantially larger fraction of melanomas for TRAIL-R2 compared with TRAIL-R1. Assessment of baseline tumor TRAIL receptor expression may be important in analysis of clinical trials involvingTRAIL receptor agonists.

Tissue Prognostic Factors in Melanoma: Expression of B7 Family Members B7-H3 and B7-H4 and Death Receptors TRAIL-R1 and TRAILR2

“…The review of the results of the literature appears discordant. Indeed Zhuang et al, [20] reported that the progression of melanoma is associated with a decrease expression of both TRAIL-R1 and TRAIL-R2 [23], and McCarthy that a high TRAIL-R2 expression level correlated with increased survival [29]. However, our results are supported by studies published in other types of cancers.…”

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

“…They are activated by specific extracellular or type II transmembrane family member ligands, that rapidly trigger cellular death via an intracellular proteolytic cascade, which leads to irreversible cleavage of proteins involved maintenance of vital cell functions [39,87]. In melanocytes, 3 death receptor family members appear to be prominent: Fas (CD95) and TNF-related apoptosis-inducing ligand cell receptors 1 and 2 (TRAIL-R1 [DR-4] and TRAIL-R2 [DR-5], also known as DR4/TNFRSF10A and DR5/TNFRSF10B, respectively) [40,88,89]. Agents that can trigger Fas or TRAIL-mediated cell death may prove effective in the treatment of metastatic melanoma [89,90].…”

“…However, many melanoma lines that express DR4/DR5 are not susceptible to TRAIL-mediated apoptosis suggesting additional determinants that down-regulate sensitivity such as protein kinase C (PKC) activation [92]. Recent data confirm DR5 expression at relatively high levels in approximately 75% of primary cutaneous melanoma; interestingly, DR4 expression was significantly lower in both primary lesions and metastatic melanoma [88]. Novel therapeutics (recombinant ligands and monoclonal antibodies) specific for DR4/DR5 are currently in earlyphase clinical trials.…”

Combined treatment with Ad‐hTRAIL and DTIC or SAHA is associated with increased mitochondrial‐mediated apoptosis in human melanoma cell lines

“…The executioners cleave a number of substrates including PARP (poly(ADP-ribose)polymerase) and lead to fragmentation of DNA finally dismantling the cell. The expression of DR4 and DR5 is higher in melanomas than in benign nevi, suggesting that the DR pathway may be an effective therapeutic target in melanoma [8,9].…”