Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth

Abstract

Glioblastoma (GBM) remains incurable, despite state-of-the-art treatment involving surgical resection, chemotherapy, and radiation. GBM invariably recurs as a highly invasive and aggressive phenotype, with the majority of recurrences within the radiation therapy treatment field. Although a large body of literature reporting on primary GBM exists, comprehensive studies of how prior irradiation alters recurrent tumor growth are lacking. An animal model that replicates the delayed effects of radiation therapy on the brain microenvironment, and its impact on the development of recurrent GBM, would be a significant advance. Cohorts of mice received a single fraction of 0, 20, 30, or 40Gy Gamma Knife irradiation. Naïve, nonirradiated mouse GBM tumor cells were implanted into the ipsilateral hemisphere 6weeks postirradiation. Tumor growth was measured by magnetic resonance imaging, and animal survival was assessed by monitoring weight loss. Magnetic resonance imaging results were supported by hemotoxylin and eosin histology. Tumorous lesions generated from orthotopic implantation of nonirradiated mouse GBM tumor cells into irradiated mouse brain grew far more aggressively and invasively than implantation of these same cells into nonirradiated brain. Lesions in irradiated brain tissue were significantly larger, more necrotic, and more vascular than those in control animals with increased invasiveness of tumor cells in the periphery, consistent with the histologic features commonly observed in recurrent high-grade tumors in patients. Irradiation of normal brain primes the targeted cellular microenvironment for aggressive tumor growth when naïve (not previously irradiated) cancer cells are subsequently introduced. The resultant growth pattern is similar to the highly aggressive pattern of tumor regrowth observed clinically after therapeutic radiation therapy. The mouse model offers an avenue for determining the cellular and molecular basis for the aggressiveness of recurrent GBM.