This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Primary brain tumors are insidious and can be lethal within weeks to months, even with current aggressive treatments. Unfortunately, the most common primary brain tumors in adults (glioblastomas) are ones with the worst prognosis. This is primarily because of their tendency and ability to spread within the brain along blood vessels and axon tracts, making their complete resection often impossible. Breast cancer metastases to brain also result in poor patient survival of only months. We have developed a new model in which to study these tumors and have uncovered a mechanism that these tumor cells use to be so aggressive. We are able to inject human and rat brain tumor cell lines into the early chicken embryo brain to produce aggressive brain tumors in less than 2 weeks. We have also injected human breast cancer cell lines into embryonic blood vessels to show that they metastasize to the brain in less than 2 weeks. We now use this system to study mechanisms that contribute to the aggressive behavior of these two cancer types. Our laboratory has also developed a sophisticated time-lapse microscopy system that is capable of recording movies of the migratory behavior of live tumor cells in a dish, and that can precisely measure their minute velocities and directions over time. During the last few years, we have begun to elucidate a mechanism in these cancer cells whereby the neural recognition transmembrane protein L1 is aberrantly expressed and proteolytically cleaved to become """"""""shed"""""""" so that it interacts with the cancer cell's own cell surface receptors in an autocrine/paracrine manner to stimulate cell motility. We have shown that L1 is expressed by all surgical high-grade glioma samples analyzed to date and that high-grade glioma and metastatic breast cancer cell lines express and cleave L1 and express L1-binding receptors.
Aims : Here, we are investigating 1) how L1 is produced and released by brain and breast cancer cells, 2) the mechanism of how L1 stimulates them to become more migratory in simple cell culture, 3) whether or not this mechanism controls their invasive and metastatic behavior in our chicken embryo model, 4) whether or not cancer cells from patient surgical samples use this stimulatory mechanism, and 5) whether or not the aberrant production and cleavage of L1 can transform normal adult human brain progenitors (AHNPs) into a cancerous phenotype. This project involves collaborative efforts between the University of Delaware, the Helen F. Graham Cancer Center, and surgeons at Christiana Care Hospitals.
Aim (5) above is a new aim of the INBRE 2 grant, while the others are continuations of the INBRE 1 grant.
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