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Handling of the Cotton Rat in Studies for the Pre-clinical Evaluation of Oncolytic Viruses
Published on: November 24, 2014
Preclinical evaluation of oncolytic potential human rotavirus Wt 1-5 in gastric adenocarcinoma
Henry Sossa-Rojas1, Pedro Gabriel Franco-Maz2,3, Carlos Zapata-Acevedo4,5
1Departamento de Ciencias Básicas y Medicina Oral, Facultad de Odontología, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia.
Abstract:
Despite advances in biomedical research, gastric cancer remains the leading cause of morbidity and mortality worldwide due to the limited efficacy of conventional therapies. In recent decades, oncolytic viruses have emerged as a biological therapeutic alternative to cancer due to their selectivity, effectiveness, and low toxicity. However, clinical trials have shown that developing a virus with selectivity for multiple tumor receptors and the ability to penetrate and diffuse through the tumor microenvironment to reactivate the immune system remains challenging. This study aimed to examine the oncolytic potential of tumor cell-adapted rotavirus Wt1-5 in gastric adenocarcinoma samples. This study focused on determining the propagation capacity of the RV Wt1-5 through the tumor and the importance of the expression of cell surface co-receptors, including integrin β3, protein disulfide isomerase (PDI), and heat shock proteins (Hsp-90, -70, -60, -40, and Hsc 70), during infection of tumor cells. These proteins were found to be differentially expressed in tumor cells compared to adjacent non-tumor cells. Preincubation of gastric tumor cells with antibodies against these proteins decreased rotavirus infections, validating their importance in the binding and entry of RV Wt1-5 into tumor cells, as previously reported. Upon RV infection, apoptosis was one of the types of death that was observed. This was evidenced by evaluating the expression of CASP-3, -9, PARP, cytochrome C, Bax, Bid, p53, and Bcl-2, as well as observing morphological changes such as chromatin margination, nuclear condensation, and fragmentation. Finally, at 60 h.p.i, histological analysis revealed that oncolysis compromised the entire thickness of the tumor. Therefore, the results suggest that RV Wt1-5 could be a novel therapeutic agent co-adjuvant agent for conventional and targeted therapies in managing GC. Ex vivo infection of the tumor tissue model showed characteristics of an immune response that could be explored in future studies.
Insights
Tumor-adapted rotavirus Wt1-5 shows oncolytic potential against gastric cancer by inducing apoptosis and tumor destruction. This virus may serve as a novel therapeutic agent for gastric adenocarcinoma, potentially enhancing conventional treatments.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Gastroenterology
Background:
- Gastric cancer poses a significant global health challenge with limited therapeutic options.
- Oncolytic viruses offer a promising, low-toxicity alternative for cancer treatment.
- Challenges remain in developing viruses that target multiple receptors and penetrate the tumor microenvironment.
Purpose of the Study:
- To evaluate the oncolytic potential of rotavirus Wt1-5 (RV Wt1-5) in gastric adenocarcinoma.
- To determine RV Wt1-5's tumor penetration and diffusion capabilities.
- To investigate the role of co-receptors in RV Wt1-5 infection of gastric tumor cells.
Main Methods:
- Assessed RV Wt1-5 propagation in gastric tumor tissue.
- Quantified expression of co-receptors (integrin β3, PDI, Hsp family) in tumor vs. non-tumor cells.
- Utilized antibody blocking to validate co-receptor function in viral entry.
- Analyzed apoptosis markers (CASP-3, -9, PARP, etc.) and morphological changes post-infection.
- Performed histological analysis to assess tumor oncolysis at 60 hours post-infection.
Main Results:
- Co-receptors integrin β3, PDI, and heat shock proteins were differentially expressed in gastric tumor cells.
- Antibody blockade of these co-receptors reduced RV Wt1-5 infection, confirming their role in viral binding and entry.
- RV Wt1-5 infection induced apoptosis in tumor cells, evidenced by marker expression and morphological changes.
- Histological analysis showed RV Wt1-5 effectively compromised the entire tumor thickness via oncolysis.
- Ex vivo models indicated potential immune response characteristics.
Conclusions:
- RV Wt1-5 demonstrates significant oncolytic activity against gastric adenocarcinoma.
- The identified co-receptors are crucial for RV Wt1-5's tumor cell binding and entry.
- RV Wt1-5 presents potential as a novel therapeutic or co-adjuvant agent for gastric cancer management.
- Further studies should explore the immune response elicited by RV Wt1-5 in vivo.
