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(Continued from page 91)
initiates a cascade resulting in genetic expression. It has been shown that the initial stimulation is on the cell surface by an oncogene. The cell surface receptor, e.g. the epidermal growth factor receptor (EGFR) may then lead to a secondary step of protein kinase-C activation (PKC). Protein Kinase-C may also be activated independent of the growth factors and it is also the normal response after injury. In tumor genesis even though the cell surface receptor is stimulated and internalized it is not recognized as a foreign reaction. There is no immunological reaction to this cascade.
The lack of immunological reaction may be due to several reasons. The internalized molecule may not be cleaved and returned to the surface, it may be that the reaction is inhibited by transforming growth factor beta (TGF-b) or it may be that there is a defect in the T cell. Transforming grown factor beta is what is responsible for inhibiting interferon gamma, which leads to an immunological reaction. Interferon gamma is usually stimulated by monocyte chemoattractive protein (MCP), macrophage inflammatory protein 1-alpha (MIP-1a), macrophage inflammatory protein- 1-beta (MIP-1b), or tumor necrosis factor alpha (TNF-a). Interferon is also secreted by T lymphocytes. We know that interferon gamma is inhibited by transforming growth factor beta. Transforming growth factor beta also decreases the proliferation of T-cells, decreases interleukin receptor expression, decreases the proliferation of these cells, decreases the secretion of IgG and IgM, and increases the secretion of IgA. Transforming growth factor beta (TGFB) will also decrease the activation of NK cells, LAK cells, and CTL cells. Transforming growth factor beta decreases the production of tissue necrosis factor alpha, tissue necrosis factor beta, interleukin II. It leads to macrophage chemotaxis and the decrease release of oxygen radicals and nitric oxide. TGF beta is stimulated by RAS and by p53 deletion. The stimulation of TGF beta essentially inhibits the immunological reaction. If there is no immunological reaction there is no T-cell mediated cell death.
Other glioblastoma tumor cell changes include increased PGE2, which suppresses interleukin II production as well as suppressing CTL cell, NK cell and B cell activation. It decreases cell mediated cytotoxicity and decreases the expression of MCL class II molecules. Over production of interleukin V leads to the inhibition of interleukin I, interleukin gamma, tissue necrosis factor and interleukin VI. Interleukin V works with TGF beta to inhibit macrophage cytotoxicity.
CELLULAR CHANGES
One of the earliest changes in tumor growth is the inhibition of tumor suppressive gene p53. When p53 is disabled cyclin dependent kinase 4 (CDK4) forms and active complex with cyclin Dl cross-phosphorylating the retinal blastoma protein thereby stimulating cell growth. The formation of the cyclin D1-CDK4 active complex is stimulated by the lack of p16, p15 and p21. The cyclin Dl -CDK4 (Continued on page 93)
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