Glioma-associated microglia/macrophages augment tumorigenicity in canine astrocytoma, a naturally occurring model of human glioma

Ryan Toedebusch, Ana Cristina Grodzki, Peter J. Dickinson, Kevin Woolard, Nicole Vinson, Beverly Sturges, John Snyder, Chai Fei Li, Ori Nagasaka, Blaire Consales, Karen Vernau, Marguerite Knipe, Vishal Murthy, Pamela J. Lein, Christine M. Toedebusch

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background. Glioma-associated microglia/macrophages (GAMs) markedly influence glioma progression. Under the influence of transforming growth factor beta (TGFB), GAMs are polarized toward a tumor-supportive phenotype. However, neither therapeutic targeting of GAM recruitment nor TGFB signaling demonstrated efficacy in glioma patients despite efficacy in preclinical models, underscoring the need for a comprehensive understanding of the TGFB/GAM axis. Spontaneously occurring canine gliomas share many features with human glioma and provide a complementary translational animal model for further study. Given the importance of GAM and TGFB in human glioma, the aims of this study were to further define the GAM-associated molecular profile and the relevance of TGFB signaling in canine glioma that may serve as the basis for future translational studies. Methods. GAM morphometry, levels of GAM-associated molecules, and the canonical TGFB signaling axis were compared in archived samples of canine astrocytomas versus normal canine brain. Furthermore, the effect of TGFB on the malignant phenotype of canine astrocytoma cells was evaluated. Results. GAMs diffusely infiltrated canine astrocytomas. GAM density was increased in high-grade tumors that correlated with a pro-tumorigenic molecular signature and upregulation of the canonical TGFB signaling axis. Moreover, TGFB1 enhanced the migration of canine astrocytoma cells in vitro. Conclusions. Canine astrocytomas share a similar GAM-associated immune landscape with human adult glioma. Our data also support a contributing role for TGFB1 signaling in the malignant phenotype of canine astrocytoma. These data further support naturally occurring canine glioma as a valid model for the investigation of GAMassociated therapeutic strategies for human malignant glioma.

Original languageEnglish (US)
Article numbervdab062
JournalNeuro-Oncology Advances
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Canine
  • glioma
  • microglia
  • transforming growth factor beta 1

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Surgery

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