Abstract

Astrocytomas are the most common forms of brain tumor in human, among which glioblastoma mutliforme is highly malignant and exhibits high invasiveness and resistance to chemo- and radiotherapy, leading to high recurrence rate even after radical surgical resection of the tumor and a median survival of only 15 months after initial diagnosis. This calls for the development of novel effective treatment regimens, which apparently requires a more thorough
understanding of the pathoetiology of glioblastomas at both cellular and molecular levels. Recently, accumulating evidence points to the emerging role of axon guidance molecules such as semaphorins, neuropilins and plexins in glioma progression. We have demonstrated the effects of semaphorin
5A (Sema5A) and its receptor plexin-B3 in inhibiting glioma cell migration, invasion and proliferation. Notably, analysis of clinical specimens revealed a marked decline in Sema5A protein level in high-grade human glioblastomas, suggesting a correlation between its loss of function and tumor progression. Restoration of Sema5A level by forced expression or exogenous supply of Sema5A protein successfully counteracts tumorigenicity of glioblastoma cells. These findings provide compelling evidence that Sema5A and plexin-B3 subserve anti-tumorigenic functions, which are compromised in glioblastomas due to a downregulation of Sema5A protein expression, hence contributing to high infiltration and malignancy. In this presentation, the mechanisms of tumor suppressor effect of Sema5A and the exploration of its therapeutic potential will be discussed.