In 1993, 14,500 new cases of central nervous system tumors were diagnosed in the U.S. The most malignant of these, glioblastoma multiforme, remain a uniformly fatal disease with mean survival of less than one year from the time of diagnosis despite aggressive therapeutic interventions with surgery, chemotherapy, and radiotherapy. Patients die with diffuse invasion of the brain by tumor cells often without significant tumor bulk. The role of these invasive tumor cells in the demise of the patient is not clearly understood. Glial tumor cell locomotion is well documented in vitro and in vivo, but characterization of the exact nature of this locomotion remains limited. Preliminary studies completed in Dr. Silbergeld's (Pi's co-sponsor) laboratory indicate fundamental differences between human glial tumor cells which remain stationary, and those that are motile. Glioma invasion into normal brain represents the culmination of a series of events involving cellular locomotion, chemo- attractants, cell-cell interactions, adherence molecules (immunoglobulins, integrins, selectins), tumor cell proteinases, and proteinase inhibitors. The PI intends to further characterize the locomotion component of in vivo glial tumor cell invasion, and evaluate specific aspects of the cell biology in vitro that confer differences in locomotion upon subpopulations of these cells. Establishment of tumor cell lines from bulk tumor, and from histologically normal brain from outside bulk tumor utilizing genetically labeled tumor cells will enable focused comparison of these two cell lines with respect to motility, growth kinetics, and sensitivity to chemotherapeutic agents. An understanding of the biology of invasive malignant glioma cells is the first step toward the development of therapies specifically designed to target these important cells. The question addressed by this proposal are fundamental to this understanding, and should help provide avenues critical to the development of new treatment modalities.
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