Malignant Gliomas account for over 60% of all primary brain tumors, of which malignant astrocytomas represent the most common histologic classification. Among the astrocytomas, there appear to be a continuum in malignant progression from low-grade astrocytoma to anaplastic astrocytoma to glioblastoma multiforme. While the clinical-pathological relationship among various types of astrocytomas is obvious, the specific molecular and cellular events leading to tumorigenesis and tumor progression are far from clear. This proposal is designed to examine the possible role of transforming growth factor alpha (TGF-alpha) and its interaction with epidermal growth factor receptor in tumorigenesis and progression of human gliomas. With the aid of our previous investigations demonstrating amplification of EGF receptor gene in untreated highly malignant glioblastoma, and amplification and rearrangement of TGF-alpha gene in recurrent astrocytomas, our efforts will be directed at examining the expression and activities of TGF-alpha, EGF and EGF-R receptor in fresh and cultured human glioma cells. Particular emphasis will be placed on identifying and characterizing alterations in TGF-alpha gene and protein products in recurrent gliomas. The role of TGF gene in tumorigenesis will be examined by transfection studies in normal glial cells with TGF-alpha gene, or altered TGF-alpha and EGF-receptor genes as identified during the course of this proposal. Molecular cloning of altered TGF-alpha and EGF- receptor genes will be performed to establish the biological significance of the potential altered protein products. An understanding of the purported autocrine growth regulatory mechanism involving TGF-alpha and EGF-R and the molecular control of tumor progression in human gliomas may allow us to discover new targets for specific therapy.
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