The major objective of this proposal is to define the role of the human neural cell adhesion molecule L1-CAM (L1) in the progression and neovascularization of human malignant melanoma. Despite widespread expression of this CAM on malignant melanoma, little is known of its function with respect to tumor progression. Two central hypotheses will be tested. First, that L1 ligation will directly influence tumor progression by affecting melanoma cell aggregation, survival, proliferation and translocation. Second, that L1 will regulate tumor growth and metastasis by inducing tumor neovascularization or angiogenesis. These hypotheses are primarily based on two novel findings presented in this proposal. First, that L1 can function as a heterophilic ligand for alphavbeta3; an integrin closely associated with melanoma progression and second that shet L1 polypeptides can induce a significant angiogenic response.
The specific aims are three-fold. First, they will test the hypothesis that as a result of homophilic or heterophilic ligation, L1 will regulate melanoma cell behavior central to tumorigenicity, including adhesion, migration, survival, and proliferation. This will be assessed by using purified native L1 and defined recombinant L1 fragments. These fragments will allow a determination of those molecular domains or regions that are important for specific tumor cell responses. Second, the focus will be on defining L1- mediated interactions that will influence tumor progression or metastasis in the host, including homotypic melanoma interaction and heterotypic interactions with vascular cells and extracellular matrix (ECM). The consequences of L1 shedding will also be investigated with emphasis on inhibition of melanoma aggregation and modification of ECM to promote attachment and migration. Third, they will determine the role of L1 in melanoma neovascularization or angiogenesis. In this regard, they will first substantiate the hypothesis that L1 shed by melanoma cells can induce a significant angiogenic response and will, therefore, potentiate tumor growth and hematogenous metastasis. As a further objective of this aim, an attempt will be made to define the mechanism by which L1 induces an angiogenic response. Among other possibilities tested, it will be determined whether L1 is angiogenic by virtue of its ability to interact with the integrin alphavbeta3 expressed on host vasculature. Finally, they will further assess the significance of a preliminary observation reported in this proposal that describes the expression of L1 on angiogenic vessels. Achieving the objectives of this proposal should significantly further the understanding of the role of the L1 cell-adhesion molecule in the progression of highly metastatic neural crest derived tumors; a role that to date has remained largely unresolved.
