Role of L1-CAM in Melanoma Progression and Agiogenesis

L1-CAM 在黑色素瘤进展和血管生成中的作用

• 批准号: 6919211
• 负责人: ANTHONY Michael MONTGOMERY
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919211
• 关键词: SCID mouse; angiogenesis; biological signal transduction; cell adhesion molecules; cell growth regulation; cell line; cell migration; cell motility; gene expression; genetic transcription; host neoplasm interaction; integrins; melanoma; metastasis; mitogen activated protein kinase; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic cell; neoplastic process; platelets; posttranslational modifications; protein protein interaction; protein structure; protein structure function; transfection

DESCRIPTION (provided by applicant): Cell adhesion molecules have a profound influence on cancer development, effectively promoting or repressing the development of malignant disease. L1 (or L1-CAM) is a neural cell adhesion molecule that is overexpressed in neuroectodermal tumors. In malignant melanoma, L1-expression correlates with the development of metastatic disease. Recent evidence suggests that L1 may promote the vascularization of tumors and facilitate melanoma cell survival and invasion. The objective is to define the role of L1 in melanoma progression. This work will address a significant gap in our knowledge and will determine whether L1 is a suitable target for therapeutic intervention. There are three aims: AIM #1: L1 is proposed to result in the activation of signaling pathways that induce a highly motile and invasive phenotype in malignant melanoma. Induction of this phenotype is. further proposed to result from direct co-operation between L1 and integrins. This aim will test the hypothesis that direct L1-integrin interaction results in the activation of signaling pathways that promote melanoma cell motility, invasion, and gene transcription. Based on preliminary data, emphasis will be placed on interactions with the 'progression related' integrin alphavbeta3 and on the contribution of the mitogen-activated protein kinase (MAPK) pathway. AIM#2: Animal studies will directly assess the contribution of L1 to melanoma survival, growth, and metastasis. Metastasis will be evaluated in an experimental pulmonary metastasis model, while tumor cell survival and growth will be assessed in the dermal microenvironment. Further studies will test the hypothesis that L1 can promote metastasis by stabilizing tumor-platelet interactions or by promoting migration across the host vasculature. AIM #3: The goal is to demonstrate that L1 cleavage products contribute to the vascularization of malignant melanoma. We have identified two L1 fragments that are released by melanoma cells as a result of Iosttranslational cleavage. These cleavage products will be tested for proangiogenic activity and for their ability to promote tumor vascularization. Proangiogenic mechanisms will be identified.

描述（申请人提供）：细胞粘附分子对癌症的发展具有深远的影响，有效促进或抑制恶性疾病的发展。 L1（或 L1-CAM）是一种神经细胞粘附分子，在神经外胚层肿瘤中过度表达。在恶性黑色素瘤中，L1 表达与转移性疾病的发展相关。最近的证据表明，L1 可能促进肿瘤的血管化并促进黑色素瘤细胞的存活和侵袭。目的是确定 L1 在黑色素瘤进展中的作用。这项工作将弥补我们知识上的重大差距，并将确定 L1 是否是治疗干预的合适目标。共有三个目标： AIM #1：L1 被提议导致信号通路的激活，从而诱导恶性黑色素瘤的高度活动性和侵袭性表型。这种表型的诱导是。进一步提出是 L1 和整合素之间直接合作的结果。该目标将检验 L1-整合素直接相互作用导致信号通路激活的假设，从而促进黑色素瘤细胞运动、侵袭和基因转录。根据初步数据，重点将放在与“进展相关”整合素 alphavbeta3 的相互作用以及丝裂原激活蛋白激酶 (MAPK) 途径的贡献上。 AIM#2：动物研究将直接评估 L1 对黑色素瘤存活、生长和转移的贡献。转移将在实验性肺转移模型中进行评估，而肿瘤细胞的存活和生长将在真皮微环境中进行评估。进一步的研究将检验 L1 可以通过稳定肿瘤-血小板相互作用或促进跨宿主脉管系统迁移来促进转移的假设。目标#3：目标是证明 L1 裂解产物有助于恶性黑色素瘤的血管化。我们已经鉴定出黑色素瘤细胞由于 Iost翻译切割而释放的两个 L1 片段。将测试这些裂解产物的促血管生成活性及其促进肿瘤血管化的能力。将鉴定促血管生成机制。