Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in melanoma by interaction with death receptors TRAIL-R1 (DR4) or TRAIL-R2 (DR5) on melanoma cells or resists apoptosis by interaction with decoy receptors TRAIL-R3 (DcR1) or TRAIL-R4 (DcR2). Studies on cell lines suggest that there is a wide variation in TRAIL death receptor expression; however, their expression on excised human melanoma is not well documented. In view of this, we studied death receptor expression on melanomas using monoclonal antibodies specific for these receptors. Immunohistochemical staining for DR4, DR5, and DcR1/DcR2 was performed on formalin-fixed paraffin-embedded sections of 100 cases of primary melanoma, metastatic melanoma, and benign nevi. Percentage expressions of DR4 versus DR5 in benign nevi, primary melanoma, and melanoma metastases were 40% versus 90%, 69% versus 98%, and 55% versus 66%, respectively. There were significant differences in the mean percentage of DR5-positive cells between different groups of melanocytic lesions. Percent expression was higher in thin (< or =1.0 mm) compared with thick primary melanoma (88.9% versus 66.9%), and expression was less in subcutaneous metastases (49%) and lymph node metastases (30.6%) (P < .005). Expression was also higher in compound nevi (57%) than dysplastic nevi (49%). DcR1/DcR2 was found in 75% of benign nevi, 62% of primary melanomas, and 74% melanoma metastases. The results showed a wide variation in the expression of death receptors for TRAIL between and within primary and metastatic melanoma and a decreased expression on the thick primary melanoma and metastatic melanoma. This suggests that melanoma may not respond to treatment with TRAIL unless given with agents that increase the expression of TRAIL death receptors.
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PMID:Progression in melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand. 1694 35

TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) is a major cytotoxic mechanism employed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to eradicate malignant cells. TRAIL/Apo2L interacts with its cognate receptors located on tumor cell surface namely, TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and osteoprotegerin (OPG). The exact function of DcR1 and DcR2 remains elusive. TRAIL/Apo2L or agonistic monoclonal antibodies directed against TRAIL/Apo2L death-inducing receptors (DR4, DR5) have become an attractive immunological therapeutic tools in clinical oncology due to their selective killing of tumors and lack of affinity towards healthy cells. Though a potent anti-cancer modality, some cancer cells exhibit inherent or acquired resistance to TRAIL/Apo2L. Postulated resistance mechanisms include up-regulation of c-FLIP, down-regulation of caspase-8, down-regulation/shedding of death receptors and an imbalanced ratio of pro- to anti-apoptotic genes due to aberrant activity of cellular survival signal transduction pathways. The development of resistance has spurred the use of combination therapy, in particular using small molecule sensitizing agents, to restore apoptosis sensitivity. A novel category of such compounds is histone deacetylase inhibitors (HDACi), which block HDACs from removing acetyl groups from histone tails thereby preventing silencing of pro-apoptotic genes and regulating the expression of non-histone proteins (i.e., apoptosis-associated genes), are effective agents in some malignancies. Some HDACi, such as Suberoylanilide Hydroxamic Acid (SAHA), have received FDA approval for cancer treatment. In various melanoma preclinical models, HDACi in conjunction with TRAIL/Apo2L, via modulation of apoptotic machinery, have proven to overcome acquired/inherent resistance to either agent. Here, we discuss recent findings on the role of TRAIL/Apo2L and its agonistic mAbs in melanoma immunotherapy with discussions on potential cellular and molecular events by which HDACi can sensitize metastatic melanoma to TRAIL/Apo2L-mediated immune-therapy, thereby, overcoming resistance.
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PMID:Epigenetic regulation of the TRAIL/Apo2L apoptotic pathway by histone deacetylase inhibitors: an attractive approach to bypass melanoma immunotherapy resistance. 2388 25