Tumor cell intrinsic mechanisms regulating brain tumor initiation and progression
Medulloblastoma is the most common malignant brain tumor in children. Hedgehog group MB accounts for 30% MB cases in human, predominately resulting from aberrant activation of hedgehog pathway in cerebellar granule neuron precursors. Hedgehog pathway activation is also required for the progression of MB tumor cells. However, it remains elusive how tumor cells sustain activation of the hedgehog pathway. Our studies revealed that MB tumor cells highly express Nestin, an intermediate filament protein that is commonly considered as a stem cell marker. By physical interaction, Nestin inhibits the inhibitory effect of Gli3, thereby facilitating hedgehog pathway activation in MB tumor cells. Nestin expression in tumor cells relies on leukotriene biosynthesis, and inhibition of leukotriene synthesis by antagonists of 5-lipoxygenase, significantly represses Nestin expression and hedgehog signaling in tumor cells, and suppresses MB growth. These studies demonstrate the important functions of Nestin in MB tumorigenesis, revealing leukotriene biosynthesis as a promising therapeutic target for MB treatment.
Tumor microenvironment in supporting brain tumor growth
Astrocytes represent the most abundant glial cells in the brain, which are also present in tumor tissues of human and mouse MB. However, it was not known what functions astrocytes have in MB growth. In our previous studies, genetic ablation of astrocytes significantly inhibits MB progression in vivo, indicating that astrocytes play a critical role in supporting MB progression. Our studies further revealed that astrocytes support tumor cell proliferation through paracrine secretion of sonic hedgehog ligand. Consistent with the indispensable functions of astrocytes for tumor growth, tumor cells even can generate astrocytes by trans-differentiation to facilitate MB relapse. Trans-differentiation of tumor cells is driven by the BMP signaling. Tumor relapse occurs in approximately 30% of human MB, represents the most adverse prognostic factor in MB. Our studies demonstrate the important role of astrocytes in MB growth and relapse, and establish a promising approach to treat MB recurrence through interfering with tumor cell trans-differentiation.
Terminal differentiation of tumor cells in medulloblastoma
Our recent studies found that a proportion of tumor cells in human and mouse MB, undergo spontaneous terminal differentiation. After the terminal differentiation, tumor cells have lost their proliferative capacity and tumorigenic potential. These studies suggest that MB can be treated by inducing tumor cell differentiation. The differentiation of tumor cells is driven by NeuroD1, a helix-loop-helix transcription factor regulating normal neuronal differentiation. However, NeuroD1 expression is epigenetically repressed by the tri-methylation of lysine 27 (H3K27me3) on histone H3 protein. Inhibition of H3K27me3 by using EZH2 antagonists, promotes tumor cell differentiation through upregulation of NeuroD1. Our studies demonstrate that MB can be treated by inducing tumor cell differentiation. Such differentiation therapy is a promising approach for tumor treatment in that it is more targeted and less toxic, compared with conventional cytotoxic drugs or radiation that non-selectively kill dividing cells.
