TUMOR NECROSIS FACTOR ALPHA GENE EXPRESSION IN MALIGNANT GLIOMA CELLS

Project: Research project

Project Details

Description

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.
StatusNot started