L1 CAM AND MELANOMA PROGRESSION AND ANGIOGENESIS

描述：(改编自调查人员的摘要)少校 这项建议的目的是定义人类神经的作用 细胞黏附分子L1-CAM(L1)在细胞黏附中的作用 人类恶性黑色素瘤的新生血管形成。尽管广泛存在 这种细胞黏附分子在恶性黑色素瘤中的表达，目前对其知之甚少 在肿瘤进展方面发挥作用。两个中心假设将 接受测试。首先，L1结扎会直接影响肿瘤 通过影响黑色素瘤细胞聚集、存活、 增殖和易位。第二，L1将调节肿瘤 诱导肿瘤新生血管的生长和转移 血管生成。这些假设主要基于两个新的发现。 在本提案中提出。首先，L1可以作为一个 αvbeta3的异亲配基；一种与 黑色素瘤进展和SHET L1多肽可以诱导 显著的血管生成反应。具体目标有三个方面。 首先，他们将检验这一假设，即由于同性恋或 异嗜性连接，L1将调节黑色素瘤细胞的中央行为 致瘤性，包括黏附、迁移、存活和 扩散。这将通过使用纯化的本机L1和 确定了重组L1片段。这些碎片将允许 确定哪些分子结构域或区域是重要的 针对特定的肿瘤细胞反应。其次，重点将放在定义 L1介导的相互作用将影响肿瘤进展或 宿主转移，包括同型黑色素瘤相互作用和 与血管细胞和细胞外基质的异型相互作用 (ECM)。L1脱落的后果也将通过 重视抑制黑色素瘤聚集和细胞外基质的修饰 以促进依恋和迁徙。第三，他们将确定角色 L1在黑色素瘤新生血管或血管生成中的作用。在这方面， 他们将首先证实L1由黑色素瘤脱落的假设 细胞可以诱导显著的血管生成反应，因此， 促进肿瘤生长和血行转移。作为进一步的 为了达到这一目的，我们将尝试界定这一机制 L1通过其诱导血管生成反应。在其他可能性中 检测，将确定L1是否具有血管生成功能 与宿主表达的整合素Alphavbeta3相互作用的能力 脉管系统。最后，他们将进一步评估一项 本提案中报告的初步观察结果描述了 L1在新生血管上的表达。实现这一目标 提案应显著加深对 高转移性肿瘤进展中的L1细胞黏附分子 神经脊源性肿瘤；到目前为止，这一作用在很大程度上仍然存在 悬而未决。

DESCRIPTION: (adapted from the investigator's abstract) 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.