Malignant glial neoplasms, which account for almost half of all central nervous system (CNS) tumors, remain to date relatively incurable. One of the major contributors in the poor response of these tumors to therapy is their extensive biological variability. Glioblastoma multiforme (GBM) cells are extremely heterogenous, both phenotypically and genotypically, and exhibit diverse responses to biological response modifiers in vitro. The recognition of their biological and functional differences from normal glial cells (the astrocyte), and their profound heterogeneity, has led to an increased interest in understanding the highly specialized biology of GBM. Specifically, it will be critical to elucidate the humoral factors that modulate GBM growth, and to understand, at the cellular and molecular levels, the mechanism(s) underlying their aberrant growth patterns and gene expression. Recent studies have implicated GBM cells as being involved with both inflammatory and immunologic responses within the CNS. In particular, GBM cells can respond to and/or secrete a variety of cytokines. We have shown that GBM cells secrete tumor necrosis factor-alpha (TNF-alpha) in response to cytokine interleukin-1 (IL-1). This constitutes a novel and specific stimulatory pathway for GBM cell TNF-alpha expression. We propose that IL- 1 induced GBM TNF-alpha is involved in mediating some of the clinical/pathological manifestations of malignant gliomas such as inflammatory infiltration within the parenchyma of gliomas, aberrant growth patterns, changes in gene expression, and the invasiveness of these cells. We feel this stimulatory pathway (IL-1) is biologically relevant as IL-1 can be produced by cells within the CNS as well as by GBM cells themselves, and IL-1 has been shown to be present in the CNS during various inflammatory reactions. As such, it is critical to first understand the basic biological mechanisms underlying regulation of GBM TNF-alpha production.
The aims of this project are to study in detail the intracellular and molecular mechanisms involved with GBM TNF-alpha gene expression induced by IL-1beta. We will examine 1) the nature of the intracellular signals generated by IL-1beta stimulation that are involved in the induction of TNF-alpha such as protein kinase C, diacylglycerol, inositol triphosphates and Ca++; 2) specific cis- acting TNF-alpha regulatory elements and nuclear proteins utilized by IL- 1beta stimulated GBM cells; and 3) the effects of TNF-alpha on GBM gene expression and function, especially modulation of vitronectin receptor integrins and myosin II. The multiple effects of TNF-alpha on various cell populations in the CNS, including autocrine stimulation for glioblastomas, suggests that TNF-alpha has a central role in augmenting infiltration of inflammatory cells into the CNS, intracerebral immune responses, and altering the biology and function of glioblastomas.
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