Tumor microenvironment in a minipig model of spinal cord glioma

• Authors: Muhibullah S. Tora, Emory University; Stewart G. Neill, Emory University; Yuliya Lakhina, Emory University; Hemza Assed, Emory University; Michelle Zhang, Emory University; Purva P. Nagarajan, Emory University; Thais Federici, Emory University; Juanmarco Gutierrez, Emory University; Kimberly Hoang, Emory University; Yuhong Du, Emory University; Kecheng Lei, Emory University; Nicholas Boulis, Emory University
• Journal Title: JOURNAL OF TRANSLATIONAL MEDICINE
• Volume: Volume 21, Number 1
• Publisher: BMC | 2023-09-27, Pages 667-667
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12967-023-04531-7
• Subjects: Biology, Cell; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; Minipig model; Spinal cord glioma; Tumor microenvironment; Oxidative stress; OXIDATIVE STRESS; GLIOBLASTOMA; CELLS; PERICYTES; CANCER; BRAIN; CYTOKINES; XENOGRAFT; NECROSIS; HYPOXIA

Abstract

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.