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Molecular mechanisms of cerebellar granule cell proliferation and medulloblastoma

The human cerebellar tumor medulloblastoma is the most common primary central nervous system childhood tumor. Current treatment methods highlight the substantial progress made in patient care in the last two decades while at the same time bring to our attention the major drawbacks of such approaches as well as demonstrate the need for further research efforts.

Medulloblastoma originates within the cerebellum, the region of the brain that controls movement and coordination. Thus, common symptoms are unsteadiness and balance impairment in addition to headaches and vomiting due to blockage of cerebrospinal fluid flow. Children are usually diagnosed quickly within one to three months of symptoms. However, this is a fast growing tumor that has the tendency to spread rapidly to other sites in the nervous system. Prognosis at later stages is grim especially for very young children or in cases where the tumor has spread to other parts of the brain.

The majority of patients with this disease are treated with surgery, radiation, and chemotherapy. Because medulloblastoma is a fast growing tumor and has the tendency to spread rapidly to other sites in the brain, extremely aggressive treatments are employed to treat this disease. However, such aggressive treatment approaches, especially in young children, can harm the developing brain and lead to significant learning problems later in life. Indeed, in some cases, the treatment of medulloblastoma is worse than the disease itself. For example, children who undergo surgery to remove the tumor have a better overall rate of survival compared with treatments that only involve radiation and chemotherapy. However, while surgery for children with medulloblastoma has become safer in the past two decades, a significant number of children (20%) will develop severe, and potentially irreversible, neurological problems such as speech loss and severe balance impairment. Moreover, there is increasing evidence that aggressive chemotherapy significantly improves survival for children whose tumors cannot be successfully removed by surgery. However, it is well known that children who undergo such full-dose radiotherapy will have significant learning problems and difficulties in school later in life. Thus, while significant progress has been made, it is clear that only through a better understanding of the biology of this tumor can the goal of curing children with medulloblastoma while simultaneously preserving their quality of life be achieved.

Medulloblastoma is thought to originate from cerebellar granule cell precursors in which the cell growth pathway is aberrantly activated by genetic mutations. However, we are only just beginning to understand the cellular origins and molecular mechanisms underlying this tumor. For instance, a molecule called sonic hedgehog (Shh), produced by neighboring cells in the cerebellum, controls growth of cerebellar granule cell precursors during normal development. Cerebellar tumors are thought to arise when the Shh pathway is over activated or when it fails to turn off after the normal phase of cell growth. A major breakthrough in the field has been the discovery that laboratory mice with genetic mutations in the Shh pathway develop tumors that resemble human medulloblastomas. These mice have opened up a wide avenue of research into understanding the biology of medulloblastoma, especially in studies that would be morally impossible to perform in humans. Even more exciting is the recent identification of new drug compounds such as cyclopamine that specifically inhibit the Shh pathway. Amazingly, treatment of mice with this drug significantly inhibits development of medulloblastoma. Taken together, these studies demonstrate that a better understanding of the mechanisms of the Shh pathway in tumorigenesis provide direct translational applications to treating the disease in children.

In our laboratory, we have identified a molecule called Mad3 that appears to be regulated by the Shh pathway in the developing cerebellum. In fact, if we simply produce more of this molecule in a culture system, we can significantly increase the level of cell growth in the absence of endogenous factors. Thus, it appears that Shh may exert its effect on cell growth by activating the mad3 gene. Importantly, if we take away Mad3, the granule cells no longer proliferate. Thus, we predict that taking away Mad3 in cerebellar tumors may actually inhibit the growth of this tumor in humans. We hypothesize that misregulation of Mad3 by Shh leads to uncontrolled cell growth of pre-tumor cells, the first step in developing medulloblastoma. Mad3 is a transcription factor that can control the expression of a large set of other molecules that are required for cell growth. Indeed, Mad3 target genes as well as Mad3 itself are excellent new drug targets to treat this disease. Therefore, understanding the role of Mad3 in granule cell growth will provide important insights into tumorigenesis that may result in novel therapies to treat medulloblastoma and even other cancers.