Tumor Microenvironments of A New Murine Astrocytoma

Abstract

Gliomas are the most common type of primary central nervous system tumors and are often aggressive with a poor prognosis. In this study, a new murine brain tumor model, ALTS1C1was established to investigate the alteration of tumor microenvironments after radiation therapy (RT). This new brain tumor model is derived from SV40 large T antigen-transfected astrocytes, ALTS1C1 recapitulates several histopathological features of human high-grade glioma, such as: increased cellularity, active mitosis, prominent cellular pleomorphism, geographic necrosis, abundant infiltrating microglia/macrophages and extensive invasion of tumor cells into adjacent brain tissues. Microarray data and immunohistochemical staining indicated that ALTS1C1 tumors expressed a relatively high level of angiogenesis/vasculogenesis-associated genes and a higher microvascular density (MVD) in vivo than GL261 tumors. To further define the role of angiogenesis/vasculogenesis-associated gene SDF-1 on tumor growth and the responses to RT, lentiviral shRNA particles were used to down-regulate SDF-1 expression in ALTS1C1 cells. SDF-knock down (SDFkd) ALTS1C1 cells formed tumors more slowly than parental ALTS1C1 cells. In contrast to the wild type tumors, they had well-defined regular borders, lacked infiltration tracts, and exhibited a lower MVD and more hypoxic areas. A single dose of irradiation decreased tumor microvasculature network and led to the development of avascular hypoxia associated with the aggregation of tumor-associated macrophages (TAMs) in both ectopic and orthotopic models, a response that was diminished in SDFkd tumors. This study not only provides a new insight into the role of SDF-1 in brain tumor invasion and into the relationship between TAMs and hypoxia, but also provides a new pre-clinical brain tumor model to design new treatment options for invasive cases.