Moving from the evidence that activation of type 4 metabotropic
glutamate (mGlu4) receptors inhibits proliferation and promotes differentiation of cerebellar granule cell neuroprogenitors, we examined the expression and function of mGlu4 receptors in
medulloblastoma cells. mGlu4 receptors were expressed in 46 of 60 human
medulloblastoma samples. Expression varied in relation to the histotype (nodular desmoplastic>classic>>large-cell anaplastic) and was inversely related to
tumor severity, spreading, and recurrence. mGlu4 receptors were also found in D283med, D341med, and DAOY
medulloblastoma cell lines, where receptor activation with the selective enhancer PHCCC inhibited
adenylyl cyclase and the phosphatidylinositol-3-kinase pathway without affecting the
mitogen-activated protein kinase, Sonic Hedgehog, and Wnt pathways. Interestingly, mGlu4 receptor activation reduced
DNA synthesis and cell proliferation in all three cell lines. This effect was abrogated by the phosphatidylinositol-3-kinase inhibitor
LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-
benzopyran-4-one]. In in vivo experiments, repeated
subcutaneous injections of N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) reduced the growth of D283med and DAOY cell xenografts in nude mice. More remarkably, subcutaneous or intracranial
injections of PHCCC during the first week of life prevented the development of
medulloblastomas in mice lacking one Patched-1 allele and x-irradiated 1 d after birth. These data suggest that mGlu4 receptor enhancers are promising drugs for the treatment of
medulloblastomas.