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complex is stimulated by MDM2 and RAS. This results in unchecked cell growth.
CLONAL GROWTH
The abnormal mutated glioblastoma cells begin to proliferate. An autocrine loop is established as well as a paracrine loop which leads to changes in neighboring normal cells. The glioblastoma cells are then the most fit to compete in their manipulated environment. The tumor cells survive in low oxygen, low pH, and high calcium concentrations. The cells will further change their environment by affecting the extra cellular milieu.
EXTRA CELLULAR MILIEU
The tumor cells will migrate over the glial limitans. It is unusual to violate the glial limitans externa and for this reason glioblastomas usually do not invade the cisterns or subarachnoid space. The tumor cells increase the secretion of chondroitin, hyaluronan, gelatinase, protease, cathepsin and urokinase plasminogen activator as well as bFGF, TF, VEGF and angiogenin. This leads to angiogenesis. Angiogenesis is essential for tumor growth beyond a few millimeters and is an adaptation to hypoxia. During angiogenesis new vessels are formed form existing vessels as well as endothelial cells migrating to form new vessels. Angiogenesis is stimulated by TGF and inhibited by interferon gamma, endostatin, thrombospondin I and tissue inhibitor of metalloproteinase III (TIMP-3). These inhibitors of angiogenesis are themselves inhibited by methylation.
It is clear from the preceding discussion that the major protein alterations in glioblastoma are the stimulation of the EGFR and inactivation of the p53 protein and stimulation of TGF. Other factors may be inhibition of p16, p15, PTEN and stimulation of RAS, CDK4, and MDM2
CURRENT TREATMENTS
SURGERY: Surgery has advanced over the century. We know the pitfalls of biopsy and subtotal resection and even though we have additional advanced technology, which allows a gross total resection, we are still not able to prevent the reoccurrence of a glioblastoma with surgery.
RADIATION: Conventional radiation, focus beam radiation, brachytherapy, boron neutron capture therapy, proton beam therapy, hyperthermia and hypothermia are all applications of types of radiation. The glioblastoma cells are resistant to radiation, as they are resistant to hypoxia. Radiation does indeed induce DNA damage, however the mutated cells have the ability to fix some of the damage of DNA.
CHEMOTHERAPY: Future chemotherapy will eventually lead to the eradication of glioblastomas. Currently chemotherapy can be delivered orally, intravenous, intra-arterial or implanted into the (Continued on page 94)
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