8795

TNFRSF10B

tumor necrosis factor receptor superfamily, member 10b;TNFRSF10B;tumor necrosis factor receptor superfamily, member 10b

Fas-like protein|TNF receptor superfamily member 10b|TNF-related apoptosis-inducing ligand receptor 2|apoptosis inducing protein TRICK2A/2B|apoptosis inducing receptor TRAIL-R2|cytotoxic TRAIL receptor-2|death domain containing receptor for TRAIL/Apo-2L|d

8p22-p21

protein-coding

PURPOSE: metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer. EXPERIMENTAL DESIGN: Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo. RESULTS: Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab. CONCLUSION: Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer.

We previously reported that the chemopreventive agent lupulone induces apoptosis through activation of the extrinsic pathway via TRAIL DR4/DR5 death receptors overcoming SW620 cell resistance to TRAIL. However, the underlying molecular mechanisms remain unknown. Since the mitogen-activated protein kinases (MAPKs), Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 control fundamental cellular processes such as apoptosis, we determined the role of these MAPKs in lupulone-triggered apoptosis. We analyzed the effects of JNK, ERK and p38 MAPK inhibitors on lupulone-induced apoptosis by flow cytometry using specific antibodies and real-time RT-PCR. Our data showed that among the MAPKs, only p38 played a major role in lupulone-triggered apoptosis. In contrast to JNK and ERK inhibition, the specific inactivation of p38 inhibited the lupulone-triggered up-regulation of p53 and TRAIL-death receptor DR4/DR5 expression, and prevented DNA fragmentation. Lupulone treatment enhanced the expression of the anti-apoptotic Mcl-1 protein by 60% favoring the preservation of mitochondrial integrity. The inactivation of p38 initiated a 50% reduction in Mcl-1, Bcl-2 and Bax expression without changing the Mcl-1/Bax ratio suggesting that p38 was not involved in the protective effect of lupulone on mitochondria. Our data support the view that the lupulone-triggered enhanced expression of p38 plays a major role in the activation of p53 and of the TRAIL-death receptor apoptotic pathway in SW620 human colon cancer-derived metastatic cells.

PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) and its receptors have recently been known to be responsible for apoptotic signaling molecules in tumor cell lines and tissues. These molecules have been reported to be expressed on merely a transcription level, but not on a protein level. Moreover, little is known about TRAIL-mediated apoptosis in human carcinoma in vivo. METHODS: We investigated the presence and functional status of TRAIL and its receptors, DR4, DR5, and DcR2 on tumor as well as tumor-infiltrating lymphocytes (TIL) in primary ( n=37), and metastatic gastric carcinoma from malignant ascites ( n=37) by a flow cytometry. In addition, phenotypic proportions of major T-cell subsets or B-cells in TIL were also determined. RESULTS: Membrane-bound TRAIL/its receptors are constitutively expressed at high levels in primary and metastatic carcinomas in nearly all the patients. Apoptotic tumor cells detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) were barely identified in primary and metastatic carcinomas. TIL in primary carcinoma showed a very low level of expression of TRAIL/its receptors and TUNEL-positive cells. In metastatic carcinoma, however, there was significant overexpression of TRAIL/its receptors in TIL associated with a higher frequency of apoptotic cell death detected by TUNEL. The TIL within metastatic carcinoma, but not within primary carcinoma, revealed the increased proportions of CD3(+) T cells bearing CD8(+)CD11b(-), CD8(+)CD11b(+), and CD4(+)CD62L(-), CD4(+)CD62L(+) surface phenotype in patients. CONCLUSIONS: These results suggest that TRAIL(+) and DcR2(+) metastatic carcinoma from malignant ascites could not only have resistance to DR4/DR5-induced apoptosis, but also might take the TRAIL-mediated counterattack against activated CD3(+) T cells. These functions of the cancer cells would neutralize host immune responses at the effector phase, and accelerate further invasion and/or metastasis of carcinoma through the escape from immune attack.

Death receptor 5 (DR5) and caspase-8 are major components in the extrinsic apoptotic pathway. The alterations of the expression of these proteins during the metastasis of head and neck squamous cell carcinoma (HNSCC) and their prognostic impact have not been reported. The present study analyzes the expression of DR5 and caspase-8 by immunohistochemistry (IHC) in primary and metastatic HNSCCs and their impact on patient survival. tumor samples in this study included 100 primary HNSCC with no evidence of metastasis, 100 primary HNSCC with lymph node metastasis (LNM) and 100 matching LNM. IHC analysis revealed a significant loss or downregulation of DR5 expression in primary tumors with metastasis and their matching LNM compared to primary tumors with no evidence of metastasis. A similar trend was observed in caspase-8 expression although it was not statistically significant. Downregulation of caspase-8 and DR5 expression was significantly correlated with poorly differentiated tumors compared to moderately and well differentiated tumors. Univariate analysis indicates that, in HNSCC with no metastasis, higher expression of caspase-8 significantly correlated with better disease-free survival and overall survival. However, in HNSCC with LNM, higher caspase-8 expression significantly correlated with poorer disease-free survival and overall survival. Similar results were also generated when we combined both DR5 and caspase-8. Taken together, we suggest that both DR5 and caspase-8 are involved in regulation of HNSCC metastasis. Our findings warrant further investigation on the dual role of caspase-8 in cancer development.

OBJECTIVE: This study assesses TRAIL-R2 (TNF-related apoptosis-inducing ligand receptor 2) and BCL2 (B cell CLL/lymphoma 2) expression as well as CpG island methylation within the TRAIL-R2 promoter in ovarian serous tumors and primary and metastatic serous EOC (epithelial ovarian cancer). METHODS: RNA and DNA were obtained from women with normal ovarian tissues (n = 18), ovarian serous cystadenoma tumors (n = 11) and serous EOC (n = 16) using Trizol(R). Quantitative PCR was performed to quantify the relative levels of TRAIL-R2 and BCL2. The methylation frequency of the TRAIL-R3 promoter was assessed using a methylation-specific PCR assay after DNA bisulfite conversion. Differences between the groups were evaluated using the chi (2), Mann-Whitney U or Kruskal-Wallis tests, as indicated. RESULTS: We identified TRAIL-R2 and BCL2 mRNA expressed in all ovarian tumor groups, and there were significant differences between the groups. Both genes had low expression levels in ovarian serous cystadenoma and primary EOC tumors when compared with metastatic EOC. Methylation of the TRAIL-R2 promoter was frequently observed in all groups; however, there were no statistically significant associations. CONCLUSIONS: Primary EOC is associated with lower TRAIL-R2 and BCL2 expression levels, while metastatic EOC is associated with higher expression of these genes. Promoter DNA methylation was not related to this finding, suggesting there are other mechanisms involved in transcriptional control.