Malignant gliomas are the most common brain tumors and are associated with extremely high rates of morbidity and mortality. The long-term goal of our research is to reveal the molecular mechanisms underlying glioma development and progression, of which very little is currently known. Recent studies using oligonucleotide microarray analysis have shown that alteration to the Forkhead box M1 (FoxM1) transcription factor is one of the most frequent molecular alterations in malignant gliomas. Our preliminary results indicate a direct correlation between FoxM1 expression level and the grade of gliomas. Enforced FoxM1 expression in immortalized normal human astrocytes (NHAs) was sufficient to transform the cells into glioma cells. Enforced FoxM1 expression in anaplastic astrocytoma cells promoted their progression into glioblastomas in nude mouse models, and suppressed FoxM1 expression inhibited the anchorage-independent growth of glioblastoma cells. Moreover, gliomas arisen from FoxM1-transfected cells were highly proliferative, invasive, and angiogenic. FoxM1-transfected glioma cells had increased expression of activated Akt, VEGF and MMP-2, whereas FoxM1-siRNA-transfected glioma cells had decreased expression of activated Akt. Here, we propose to determine the causal effects and mechanisms of aberrant FoxM1 expression on glioma development and progression. We hypothesize that aberrant expression of FoxM1 contributes to glioma development and progression by promoting uncontrolled cell proliferation, invasion, and angiogenesis.
Our Specific Aims are 1) To determine the effect of altered FoxM1 expression on glioma biology. We will determine the critical contribution of FoxM1 to glioma cell proliferation, invasion, and angiogenesis in vitro and in vivo by using the FoxM1-siRNA inhibition system, FoxM1-overexpressing cell lines, and in vivo mouse models. 2) To determine the cooperation between FoxM1 overexpression and Rb loss in glioma development and progression. We will investigate whether FoxM1 transgene expression accelerates glioma formation and promotes glioma progression in a genetic mouse glioma model with an inactivated pRb pathway. 3) To determine whether FoxM1 overexpression contributes to glioma development and progression via activation of Akt pathway. 4) To identify the molecular mechanisms by which FoxM1 regulates glioma invasion and angiogenesis. The mechanisms of FoxM1 regulating invasion and angiogenesis will be investigated with a particular focusing on how it regulates the expression of the MMP-2, and VEGF genes. The findings from our proposed studies will contribute to a better understanding of the molecular mechanisms of glioma development and progression and will identify potential targets for novel therapeutic strategies against malignant glioma.
