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Lentiviral-Induced Spinal Cord Gliomas in Rat Model
Purva P Nagarajan1, Muhibullah S Tora1,2, Stewart G Neill3
1Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.
Insights
A novel rat model for high-grade spinal cord glioma was developed using a triple cocktail of PDGF-B, HRAS, and p53 knockdown vectors. This model efficiently replicates aggressive tumor characteristics, offering a promising platform for future therapeutic evaluations.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Animal Models
Background:
- Intramedullary spinal cord tumors are rare, understudied, and have limited treatment options.
- Previous research utilized a combination of PDGF-B, HRAS, and p53 knockdown in minipigs to induce high-grade glioma.
- This study aimed to create and characterize a more efficient rodent model for spinal cord glioma.
Purpose of the Study:
- To evaluate the efficacy of individual and combined lentiviral vectors (PDGF-B, HRAS, sh-p53) in generating high-grade spinal cord gliomas in rats.
- To compare the resulting tumor models based on behavioral, physiological, and histological outcomes.
- To establish a preclinical rat model for testing novel therapeutic strategies against spinal cord gliomas.
Main Methods:
- Rats underwent thoracolumbar laminectomy and injection of lentiviral vectors expressing PDGF-B, HRAS, sh-p53, or control vectors.
- Animals were monitored for 98 days for clinical deficits using scoring systems (Basso Beattie Bresnahan, Tarlov), weight, and survival.
- Tumor development was assessed via histological analysis (H&E) and immunohistochemistry (IHC) for proliferation (Ki67) and glial markers (GFAP, SOX2).
Main Results:
- The triple cocktail (PDGF-B+HRAS+sh-p53) induced significant declines in behavioral measures and survival rates compared to controls.
- Histological analysis confirmed tumor development in most groups, with the triple cocktail showing the most aggressive growth and pathological features.
- Immunohistochemistry revealed the highest increase in Ki67 proliferation and GFAP positivity in the triple cocktail group; PDGF-B+HRAS also showed increased proliferation, while PDGF-B and PDGF-B+sh-p53 showed increased SOX2 staining.
Conclusions:
- Different lentiviral vector combinations yield distinct high-grade spinal cord glioma models in rats.
- The triple cocktail (PDGF-B+HRAS+sh-p53) provides a highly efficient and aggressive preclinical model for spinal cord glioma.
- This rat model holds potential for evaluating future therapeutic interventions for this rare cancer.
