Related Experiment Videos
Pancreatic adenocarcinoma cell lines show variable susceptibility to TRAIL-mediated cell death
S M Ibrahim1, J Ringel, C Schmidt
1Department of Immunology, University of Rostock, Germany.
Background And Aims:
Programmed cell death via the Fas receptor/Fas Ligand and DR4, DR5/TRAIL plays a major role in tumor escape and elimination mechanisms. It also promises to be an effective therapy alternative for aggressive tumors, as has been recently shown for colon, breast, and lung cancer cells. We attempted to clarify the role of these molecules in aggressivity of pancreatic carcinomas and to identify possible pathways as targets for therapy.
Methods:
Five pancreatic cell lines were investigated for the expression of FasL/Fas, DcR3, DR4, DR5/TRAIL, DcR1, DcR2, and other death pathways related molecules such as Bax, bcl-xL, bcl-2, FADD, and caspase-3 by flow cytometry, immunoblotting, and RT/PCR, both semiquantitative and real time (TaqMan). The susceptibility of these cell lines to apoptosis mediated by recombinant TRAIL was investigated. The effect of therapeutic agents (gemcitabine) on their susceptibility to TRAIL induced apoptosis was studied as well.
Results:
Pancreatic adenocarcinomas expressed high levels of apoptosis-inducing receptors and ligands. They showed differential susceptibility to cell death induced by TRAIL, despite expressing intact receptors and signaling machineries. Treatment with commonly used therapeutic agents did not augment their susceptibility to apoptosis. This could be explained by the fact that they expressed differentially high levels of decoy receptors, as well as molecules known as inhibitors of apoptosis.
Conclusions:
The data suggest that pancreatic carcinoma cells have developed different mechanisms to evade the immune system. One is the expression of nonfunctional receptors, decoy receptors, and molecules that block cell death, such as bcl2 and bcl-xL. The second is the expression of apoptosis-inducing ligands, such as TRAIL, that could induce cell death of immune cells. The success in treating malignant tumors by recombinant TRAIL might apply to some but not all pancreatic tumors because of their differential resistance to TRAIL-induced cell death.
Insights
Pancreatic cancer cells evade immune attack by expressing decoy receptors and apoptosis inhibitors. This differential resistance limits the effectiveness of TRAIL-based therapies for some pancreatic tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Programmed cell death via Fas/Fas Ligand and DR4, DR5/TRAIL is crucial for tumor elimination and a potential therapy for aggressive cancers.
- Pancreatic carcinomas exhibit complex mechanisms for immune evasion and resistance to apoptosis.
Purpose of the Study:
- To investigate the role of apoptosis-related molecules in pancreatic carcinoma aggressiveness.
- To identify potential therapeutic targets within these pathways for pancreatic cancer treatment.
Main Methods:
- Analysis of FasL/Fas, TRAIL/DR4/DR5, decoy receptors (DcR1-3), and apoptosis-related molecules (Bax, bcl-xL, bcl-2, FADD, caspase-3) in five pancreatic cell lines using flow cytometry, immunoblotting, and RT/PCR.
- Assessment of TRAIL-induced apoptosis susceptibility and the effect of gemcitabine on this process.
Main Results:
- Pancreatic adenocarcinomas express high levels of apoptosis-inducing receptors and ligands.
- Cell lines displayed variable susceptibility to TRAIL-induced apoptosis, despite intact signaling machinery.
- Decoy receptors and apoptosis inhibitors (bcl-2, bcl-xL) contribute to TRAIL resistance, and gemcitabine did not enhance TRAIL sensitivity.
Conclusions:
- Pancreatic cancer cells employ multiple strategies to evade immune surveillance, including expressing nonfunctional/decoy receptors and apoptosis inhibitors.
- Expression of apoptosis-inducing ligands like TRAIL can lead to immune cell death.
- Differential resistance to TRAIL-induced apoptosis indicates that recombinant TRAIL therapy may only be effective for a subset of pancreatic tumors.