L1 CAM AND MELANOMA PROGRESSION AND ANGIOGENESIS

描述：（改编自研究者摘要）主要 该提案的目的是定义人类神经系统的作用， 细胞粘附分子L1-CAM（L1）在进展中的作用， 人恶性黑色素瘤的新生血管形成。尽管人们普遍 这种CAM在恶性黑色素瘤中的表达，很少有人知道其 与肿瘤进展有关。 两个核心假设将 得到考验首先，L1结扎将直接影响肿瘤的发生， 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 通过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 在这个提案中提出。首先，L1可以作为一个 alphavbeta 3的嗜异性配体;与alphavbeta 3密切相关的整合素 第二，shet L1多肽可以诱导黑色素瘤进展， 显著的血管生成反应。 具体目标有三个方面。 首先，他们将检验一个假设，即由于同性恋或 异嗜性连接，L1将调节黑色素瘤细胞的行为中枢 致瘤性，包括粘附、迁移、存活和 增殖这将通过使用纯化的天然L1和 定义的重组L1片段。这些碎片将允许 确定那些重要的分子结构域或区域 针对特定的肿瘤细胞反应。第二，重点将是界定 L1介导的相互作用将影响肿瘤进展，或 转移，包括同型黑色素瘤相互作用， 与血管细胞和细胞外基质的异型相互作用 （ECM）。还将研究L1脱落的后果， 强调抑制黑色素瘤聚集和修饰ECM 促进依恋和迁移。第三，他们将决定作用 L1在黑色素瘤新生血管或血管生成中的作用。在这方面，委员会注意到， 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， 增强肿瘤生长和血行转移。作为另一 为了实现这一目标，将尝试确定该机制 L1通过其诱导血管生成反应。以及其他可能性 通过测试，将确定L1是否是血管生成的， 与宿主上表达的整合素α v β 3相互作用的能力 脉管系统最后，他们将进一步评估 本提案中报告的初步意见描述了 L1在血管生成血管上的表达。实现本组织的目标 建议应大大促进对作用的理解， L1细胞粘附分子在高转移性肝癌进展中的作用 神经嵴源性肿瘤;迄今为止， 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.