PARACRINE REGULATION OF COLONY-STIMULATING FACTOR-I IN MEDULLOBLASTOMA - IMPLICATIONS FOR PATHOGENESIS AND THERAPEUTIC INTERVENTIONS

OBJECTIVE: Colony-stimulating factor (CSF)-1, a chemotactic and mitoge nic factor for macrophages and microglia, is expressed in a variety of nervous system tumors and when present in nonneural malignancies, is associated with marked inflammatory infiltrates, dissemination, and po orer prognosis. This study investigated the paracrine effects of CSF-1 production by medulloblastoma cells on the macrophage/microglial line age. METHODS: A recurrent metastatic desmoplastic medulloblastoma was isolated from a 26-year-old man and propagated in tissue culture. Cell ular phenotype and proliferation were assessed by immunocytochemical t echniques; transcript expression for CSF-1, granulocyte macrophage-CSF , interleukin-3, and c-fms (the receptor for CSF-1) was examined with reverse transcriptase-polymerase chain reaction; and conditioned media and coculture paradigms were used to study cytokine effects on cellul ar proliferation. RESULTS: Serially passaged cells were uniformly immu noreactive for two lineage-independent neuroepithelial markers, nestin and vimentin. A subpopulation of cells with morphological characteris tics of early differentiation stained for neurofilament 66 (7%) and mi crotubule-associated protein (5%) (markers of early neuronal precursor s and postmitotic neurons, respectively) and for the Yp subunit of glu tathione-S-transferase (3%) (a marker of early oligodendroglial progen itors). Tumor cells expressed transcripts for CSF-1, but not for granu locyte macrophage-CSF, interleukin-3, or c-fms. Treatment of microglia with serum-free medulloblastoma-conditioned media significantly incre ased proliferation (P < 0.001), suggesting the secretion of CSF-1. Coc ulture of medulloblastoma cells and microglia significantly increased proliferation of both cell types (each condition, P < 0.01). CONCLUSIO N: These observations suggest that CSF-1 mediates important paracrine interactions between transformed cells and the immune system, resultin g in increased growth rate and metastatic potential. Future therapeuti c goals need to include immunotherapeutic protocols to modulate this i nteraction.