Research Interests:
The research in our laboratory is focused on identifying a variety of cell surface and extracellular molecules that contribute to specific pathological processes. The pathological processes that we study are tumor metastasis (the spread of primary cancer cells to distant organs) and tumor angiogenesis (the induction and formation of new blood vessels). In order to molecularly examine these pathological processes, a number of model systems have been established in the laboratory. These model systems recapitulate most of the actual steps that take place in the complex pathology occurring in the human cancer patient. The systems under study include in vivo models (use of live organisms), ex vivo models (organs examined outside the animal), in vitro models (cell cultures derived from the tumors or the tissues), and biochemistry models (specific chemical and enzymatic reactions occurring on the bench top). The overall goals of the research are first to identify key molecules that are functionally important in the model systems. Secondly, to determine the mechanism of action of the molecules in the specific pathological process. Thirdly, in collaboration with cancer pathologists, to determine if the identified molecules are present and/or altered in human malignancies. The long range goals are to determine if the characterized molecules can be used therapeutically or diagnostically.
Specifically, we are studying tumor metastasis using an in vivo model system that employs human tumor cells disseminating to specific organs in the developing chick embryo. A technique known as subtractive immunization is employed first to generate unique antibodies directed against antigens on the surface of highly-metastatic human tumor cells. The selected monoclonal antibodies are then tested for their ability to inhibit metastatic spread using quantitative real-time PCR to monitor the spreading human tumor cells. The tumor cell antigens that are the specific targets of the inhibitory antibodies are then molecularly cloned and identified. Similarly, those model systems that manifest the formation of new blood vessels also are being tested for their sensitivity to newly-generated monoclonal antibodies or recombinant molecules. The molecular targets of the specific inhibitors are isolated or cloned and then identified.
Our laboratory also is examining the differential expression of specific proteolytic enzymes, and how they may mediate angiogenesis and tumor cell migration, invasion and metastasis. The experimental approach is to employ highly-sensitive assays to detect those proteases which are elevated in angiogenic tissue or in invading tumor cells: we then purify the enzymes, clone their cDNAs, and raise neutralizing antibodies to them. Then we test the purified enzymes, the inhibitory antibodies and the expressed cDNAs in the various model systems that mimic the angiogenic or invasive phenotype. This approach allows for the clear identification of specific enzymes that are functionally involved in these biological processes. Two enzyme systems presently under study include the matrix metallo proteases (MMPs) and a new family of membrane-anchored serine proteases.
Track(s):
Molecular Pathology
BMS Focus Areas:
Cancer Biology
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