While further evaluation of the role of TRAIL receptors in human cancer is ongoing, initial studies suggest that both KILLER/DR5 and DR4 may be targets for inactivation and that these pro-apooptotic receptors may be tumor suppressor genes.
The results presented in this study demonstrate that introduction of the human TRAIL gene into TRAIL-sensitive tumor cells using an adenoviral vector leads to the rapid production and expression of TRAIL protein, and subsequent death of the tumor cells.
Thus, the hFlex-TRAIL fusion protein may provide a novel approach, with the possible involvement of dendritic cell-mediated anti-cancer immunity, for the treatment of TRAIL-sensitive tumors.
To evaluate the antitumor activity and therapeutic value of the TRAIL gene, we constructed adenoviral vectors expressing the human TRAIL gene and transferred them into malignant cells in vitro and tumors in vivo.
The high expression of CD95 ligand, TRAIL, and FLIP in squamous cell carcinoma may then contribute to the immune escape of the tumor, whereas the lack of expression of CD95 and TRAIL receptors prevents autolysis of the tumor.
Furthermore, in vivo administration of Ad5-TRAIL at the site of tumor implantation suppressed the outgrowth of human prostate tumor xenografts in SCID mice.
Inhibition of NF-kappaB activation in H157 cells in response to genotoxin resulted in loss of cell surface expression of TRAIL and DR5, aggressive growth and chemotherapy resistance of tumors in nude mice.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis.
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.
These results indicate that the combination of TRAIL/Apo2L with either irradiation or sulindac may be highly effective against both p53-proficient and p53-deficient colorectal cancers; however, BAX-deficient tumors may evade elimination by TRAIL/Apo2L-based regimens.
In this review we will address the putative role of TRAIL in cancer treatment in the light of the emerging importance of TRAIL in tumor surveillance and discuss the molecular basis of the cooperation of TRAIL and chemotherapeutic drugs.
Taken together, these findings suggest that resistance to TRAIL by lack of TRAIL receptors on glioma is restored by genotoxic agents, which support the new strategies for tumour killing by TRAIL-bearing cytotoxic cells in combination with genotoxic treatment.
Caspase-3 activity and the expression of four types of TRAIL receptor mRNAs were quantitated in tumor and contiguous non-tumor tissues obtained from 27 patients with HCC (HBV-related in 10; HCV-related in 17).
Activation of multiple caspases and PARP cleavage were also observed in the C4-2 tumors treated with doses resulting in effective tumor control at 42 days after Apo2L/TRAIL plus CPT-11 treatment.