Malignant gliomas are brain tumors which remain extremely difficult to treat and ultimately incurable. Recent epidemiologic evidence indicates that they are also increasing the frequency, especially in the elderly. Conventional therapeutic strategies that view cancer cells as foreign aim control disease through selective killing but if cancer is viewed a s a dynamic disorder of growth regulation where tumor cells are closely related to normal ones, then this type of cytoreductive strategy may be counterproductive. Since certain infrequently occurring gliomas are extremely indolent, we propose to induce malignant glioma cells to behave similarly to these tumors by gene manipulation. Because of its association with benign rumor behavior in neuroblastoma, another tumor derived from neural tissues, we examined the effects of incorporating the high affinity nerve growth factor Trka receptor into receptor negative C6 glioma cells. In this model, glioma cells become responsive rather than dependent on nerve growth factor in vitro. Nevertheless, these cells produce much less aggressive tumors when injected into rat brain than those formed by parental C6 cells. Our subsequent studies examining mechanisms underlying this response indicate that this effect is due more to an inability of these cells to invade surrounding brain tissue and an increased rate of apoptosis than to a cessation of proliferation or immune response. The goals of this project are to continue to explore the mechanisms underlying why trkA promotes induction of a less aggressive glioma by assessing: the pathologic correlates of tumor growth; mutations of the trkA phosphorylation sites; NGF modulation of this response; whether benign behavior can be induced after implantation has already taken place; the effect of trkA expression on human glioma cell behavior.
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