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Surgical Transplantation of Tumor Cells into the Spinal Cord of Mice
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Tumor microenvironment in a minipig model of spinal cord glioma
Muhibullah S Tora1,2, Stewart G Neill3, Yuliya Lakhina1
1Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.
Background:
Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs.
Methods:
Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo.
Results:
We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1β, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model.
Conclusions:
Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.
Insights
This study reveals spinal cord glioma (SCG) tumor edges exhibit increased inflammation, oxidative stress, and proliferation. This minipig model aids research into treatments for aggressive, unresectable tumor borders.
Area of Science:
- Neuro-oncology
- Comparative Pathology
- Tumor Microenvironment Research
Background:
- Spinal cord glioma (SCG) is an orphan disease with limited treatment options, particularly for surgically inaccessible margins.
- The tumor microenvironment, especially the unresectable edge, is crucial for treatment and modeling.
- A novel high-grade spinal cord glioma (SCG) model was developed in Göttingen minipigs.
Purpose of the Study:
- To characterize the microenvironmental features of a Göttingen minipig high-grade spinal cord glioma (SCG) model.
- To investigate differences between the tumor core and the aggressive tumor edge.
- To validate the utility of this SCG model for therapeutic development.
Main Methods:
- Immunofluorescence and ELISA were used to analyze microenvironmental features and cytokines.
- Protein carbonyl and GSH/GSSG assays assessed oxidative stress in core and edge lesions.
- In vitro proliferation assays and a xenotransplantation model evaluated cell growth.
Main Results:
- The tumor edge showed higher Ki-67 proliferation, CD31, and desmin compared to the core.
- Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and oxidative stress markers were elevated at the tumor edge.
- Hypoxic markers were present in both core and edge, with higher staining in the core.
- Edge-derived cells exhibited increased proliferation in vitro and in vivo.
Conclusions:
- The minipig SCG model displays significant heterogeneity, with the tumor edge exhibiting a more aggressive phenotype.
- The edge phenotype is characterized by increased oxidative stress, proliferation, inflammation, and neovascularization.
- This model is valuable for studying therapeutic strategies targeting the unresectable tumor border in spinal cord gliomas.
