Development and characterization of murine models of medulloblastoma extraneural growth in bone.

Medulloblastoma is a malignant pediatric brain neoplasm with an unusual predilection for metastasis to the skeleton. The objective of this study was to generate and characterize murine models of medulloblastoma extraneural growth in bone as 'discovery tools' for the identification of unrecognized signal transduction pathways and factors driving metastatic bone disease. To this end, the human Daoy and D283 medulloblastoma cell lines were inoculated into the intratibial medullary space of athymic nude mice. Daoy injected mice developed a primarily osteolytic radiographic and histological phenotype. In contrast, both areas of osteolytic and osteosclerotic activity were evident in D283 inoculated bones. D283 and Daoy cell conditioned media increased in vitro osteoblast differentiation and is consistent with the enhanced bone turnover characteristic of bone metastases. Daoy cells also significantly increased bone marrow osteoclast formation, consistent with the robust in vivo osteolytic phenotype. A survey of secreted factors implicated in bone metastasis and expressed by D283 and Daoy was performed. High expression of the bone-homing factor, CXCR4, was observed in both Daoy and D283 tissues. Consistent with the skeletal phenotypes, Daoy cells, while secreting the osteoblastic factor ET-1, abundantly produced the osteolytic factors RANKL, PTHrP and TNFα. D283 cells produced high levels of both RANKL and ET-1. These newly described animal models of medulloblastoma bone metastasis are expected to serve as platforms to aid in the elucidation of novel bone metastasis signaling cascades and to test therapeutics that target both medulloblastoma metastasis and the primary tumor.