Studies examining the biological pathways used by tumors to sustain and augment their growth will further our understanding of cancer and identify novel therapeutic targets. Malignant gliomas represent 40 percent of primary brain tumors and have the highest mortality among CNS tumors, with death usually occurring in less than a year. Our long-range goal is to improve our comprehension of molecular and biological mechanisms leading to the malignant progression of human astrocytoma. The experiments proposed in this application will clarify the role of the IL-8, TSP-1 and BAI-1 angiogenesis modulators in astrocytoma progression using in vivo glioma models and will evaluate their importance as targets (IL-8) or tools (TSP-1, BAI-1) for therapy. The role of IL-8 as a growth/angiogenic stimulator and the biological basis of this activity will be functionally tested by three independent lines of research: i) overexpression of IL-8, ii) downmodulation of IL-8 and iii) antagonizing IL-8 receptor signalling. The relationship between IL-8 and VEGF will be investigated in an animal tumor model using a glioma cell line which contains a conditional VEGF gene knockout. The role of DARC and infiltrating inflammatory cells in mediating IL-8- induced angiogenesis will also be evaluated. The ability of TSP- 1 or its type 1 repeats to inhibit glioma growth/angiogenesis and the biological mechanism(s) underlying this effect will be examined by overexpression studies. In addition, the expression of TSP-1 in normal brain and during astrocytoma progression, in paired low grade/high grade tumors, will be analyzed. BAI-1 is a recently cloned brain specific inhibitor of angiogenesis which is downregulated in gliomas. The expression of BAI-1 will be examined in normal and tumoral brian using two anti-BAI-1 antibodies that were recently generated in our laboratory. In addition, the anti-angiogenic properties of BAI-1 and its ability to inhibit glioma growth will be also examined. Moreover, whether BAI-1 is the previously identified p53 regulated GD-AIF angiogenesis inhibitor will be determined. Finally, the therapeutic potential of combining these anti-angiogenic approaches will be tested and then subsequently conjugated with anti-VEGF or BCNU chemotherapy administration. Improving the treatment of malignant gliomas, an incurable disease, is an important human health goal.
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