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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression
1University Children's Hospital, Germany.
Abstract:
Gene transfer vectors based on the adeno-associated virus (AAV) are used for various experimental and clinical therapeutic approaches. In the present study, we demonstrate the utility of rAAV as a tumoricidal agent in human colorectal cancer. We constructed an rAAV vector that expresses tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) and used it to transduce human colorectal cancer cells. TRAIL belongs to the TNF superfamily of cytokines that are involved in various immune responses and apoptotic processes. It has been shown to induce cell death specifically in cancer cells. Transduction with AAV.TRAIL gave rise to rapid expression of TRAIL, followed by induction of apoptosis, which could be inhibited by the caspase inhibitor z-VAD.fmk, in several human colon cancer cell lines. The apoptotic mechanism included activation of caspase-3, as well as cytochrome c release from mitochondria. The outgrowth of human colorectal tumors grown in mice was completely blocked by transduction with AAV.TRAIL in vitro, while in vivo transduction significantly inhibited the growth of established tumors. AAV vectors could provide a safe method of gene delivery and offer a novel method of using TRAIL as a therapeutic protein.
Insights
Adeno-associated virus (AAV) vectors expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) demonstrate potent tumoricidal effects against human colorectal cancer. This novel gene therapy approach effectively inhibits tumor growth by inducing apoptosis in cancer cells.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Adeno-associated virus (AAV) vectors are widely used in experimental and clinical settings for gene transfer.
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine known for its specific cancer cell-killing properties.
- Colorectal cancer remains a significant global health challenge, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of a recombinant AAV (rAAV) vector engineered to express TRAIL as a tumoricidal agent against human colorectal cancer.
- To investigate the mechanism of TRAIL-induced apoptosis in colorectal cancer cells mediated by AAV gene delivery.
Main Methods:
- Construction of an rAAV vector expressing TRAIL (AAV.TRAIL).
- Transduction of human colorectal cancer cell lines with AAV.TRAIL.
- Assessment of apoptosis induction using caspase inhibitors and analysis of apoptotic markers (caspase-3 activation, cytochrome c release).
- In vitro and in vivo studies using human colorectal tumor models in mice to evaluate tumor growth inhibition.
Main Results:
- AAV.TRAIL transduction led to rapid TRAIL expression and subsequent apoptosis in human colon cancer cell lines, which was reversible with caspase inhibition.
- The apoptotic pathway involved caspase-3 activation and mitochondrial release of cytochrome c.
- In vitro studies showed complete blockage of colorectal tumor outgrowth after AAV.TRAIL transduction.
- In vivo administration of AAV.TRAIL significantly inhibited the growth of established human colorectal tumors in mice.
Conclusions:
- Recombinant AAV vectors expressing TRAIL are effective tumoricidal agents against human colorectal cancer.
- AAV-mediated TRAIL gene delivery offers a novel and potentially safe therapeutic strategy for colorectal cancer by inducing apoptosis.
- This approach highlights the potential of gene therapy using AAV vectors for cancer treatment.
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