The cellular and developmental biology of medulloblastoma: current perspectives on experimental therapeutics.
Dysregulation of various signaling pathways that govern cerebellar development with respect to cell proliferation, growth arrest, apoptosis and differentiation has been postulated to contribute to medulloblastoma tumourigenesis. This review will highlight the unique nature of cerebellar development in terms of its derivation from two germinal matrices and significant postnatal expansion of the granule cell precursor (GCP) compartment resulting in granule cell development and migration to form the mature cerebellar cortex. The molecular signals that are critical for timely cell cycle exit and differentiation may become dysregulated leading to unrestrained cell proliferation and enhanced cell survival; indeed, changes in these molecular markers have been observed in medulloblastoma biopsy specimens. Furthermore, transgenic models that faithfully replicate these changes develop medulloblastoma that, by in large, recapitulates the clinico-histopathological features of these tumours. Cellular and developmental biological approaches have contributed greatly to the current debate on the relevance of the cancer stem cell hypothesis in understanding medulloblastoma initiation and propagation. Penultimately, research findings are being translated into experimental therapeutics that target the aberrant signal transduction machinery in medulloblastoma cells and that will hopefully lead to an improved risk-benefit profile.
Srivastava
Vinit Krishna
VK
Department of Neurology & Neurosurgery, McGill University and Montreal Neurological Institute, Montreal, Canada.
Nalbantoglu
Josephine
J
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006655:Histone Deacetylases / Q000627:therapeutic use; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D006655:Histone Deacetylases