The neurotrophin growth factor family is extremely important for the normal development and function of the nervous system, including regulation of cell proliferation, survival and differentiation. It stands to reason that de-regulation of neurotrophin signalling also could result in abnormal growth states such as brain tumors. This idea is strengthened by the recent discovery that the trk proto-oncogenes are tyrosine kinase receptors for the neurotrophins. Although indirect evidence supports neurotrophin involvement in brain tumors, their role has not been thoroughly evaluated, in large part, because many of the neurotrophin and trk family members have only recently been discovered. Previous studies have focused on Nerve Growth Factor as a potential "differentiation" signal for reducing tumor proliferation, an idea that continues to merit consideration. However, we propose that the neurotrophins are also likely to stimulate tumor cell proliferation, acting either as a primary transforming agent through over-expression or trk receptor mutation or as a secondary mitogenic agent involving autocrine or paracrine signalling. The goals of our study will be to evaluate neurotrophin and trk receptor expression by established cell lines and in samples of various brain tumors, including primitive neuroectodermal tumors, e.g., medulloblastomas, and astrocytomas. In addition, we will examine cell lines for expression of novel or mutated neurotrophins and trk receptors. The identification of novel trk receptors unique to certain brain tumors could be useful as a diagnostic tool and as means for selectively targeting tumors for antibody-mediated killing. Finally, we will test the idea that neurotrophins support tumor cell growth by assessing the ability of neurotrophin and trk receptor antibodies to block cell proliferation in vitro. Identification of neurotrophin involvement or altered receptor function could lead to an improved understanding of neoplastic development, improved pathologic classification, and potentially new treatment modalities involving neurotrophin blockade.