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.
Highlights
Spinal cord glioma (SCG) is a rare type of cancer, making up approximately 2–6% of all cancers of the central nervous system [1,2]
Broggi et al demonstrated that serine- and arginine-rich splicing factor 1 (SRSF1) immunohistochemical expression may be a diagnostic marker of astrocytomas and oligodendrogliomas
Our present study aims to determine the efficacy of each lentiviral vector on its own, as well as two-vector combinations, against the original three-vector cocktail and the control in producing a highgrade spinal cord glioma model in rats
Summary
Spinal cord glioma (SCG) is a rare type of cancer, making up approximately 2–6% of all cancers of the central nervous system [1,2]. Our present study aims to determine the efficacy of each lentiviral vector on its own, as well as two-vector combinations, against the original three-vector cocktail and the control in producing a highgrade spinal cord glioma model in rats. The present manuscript provides qualitative and quantitative confirmation of the production of high-grade glioma in the spinal cord using oncogenic cantly different scoring declines over time compared to the control (Figure 1C). Rats injected with the HRAS vector alone (group 3) exhibited statistically significant declines in BBB scoring over time when compared to the control. Groups injected with PDGF-B alone (group 2) and sh-p53 alone (group 4) did not display significantly different declines in Tarlov scoring when compared to the control (Figure 1D). The sh-p53 and control groups (group 4) contained no lesion cases
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