METALLOPROTEINASES AND NEUROBLASTOMA METASTASIS

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Neuroblastoma, one of the most common solid tumors of childhood, has a poor prognosis in advanced stages despite advances in chemotherapy. However it may be possible to develop alternate, novel modes of therapy to improve the outcome after delineating the molecular mechanisms of neuroblastoma behavior. The metalloproteinases 72 and 92-ketoDa type IV collagenases, may mediate metastasis by facilitating tissue degradation and cellular invasion. This study examines the role of these collagenases in the metastatic and invasive properties of murine and human neuroblastoma. Endogenous activity of 72 and 92-keto-Da type IV collagenases and their natural inhibitor, tissue inhibitor of metalloproteinases (TIMP) will be assayed in various cultured murine and human neuroblastoma cell lines. Their role in neuroblastoma invasion and metastasis will be investigated by gene transfer methods using 72- keto-Da and 92-keto-Da collagenase, and TIMP. Changes in metastatic and invasive potential will be evaluated by in vivo murine experiments and in vitro transwell assay. The clinical relevance of metalloproteinase activity will be determined by immunohistochemical assays of collagenase activity in archival specimens of human neuroblastoma. Correlations will be made to clinical and biochemical parameters of tumor aggressiveness. Elevated collagenase activity may be an effective new marker by which to identify which tumors are at risk for metastasis and require aggressive therapy. Therapy using collagenase inhibitors such as TIMP may be able to inhibit neuroblastoma metastasis. The candidate has completed 12 years of training after medical school, all directed toward achieving Pediatric Surgery training, which was recently completed at Baylor College of Medicine in 1991 and has actively pursued research training at every level of her career development. She was recruited to her current position of Assistant Professor of Surgery at University of Kentucky because of the department~s strong commitment to research. This award will provide the candidate an opportunity to broaden her foundation of basic research skills with supervised expansion into the important field of molecular biology. She is dedicated to a career in academic Surgery, and this award will enhance her knowledge base, personal scientific development, and secure her position as an independent investigator and trainer of student in research.