Role of L1-CAM in Melanoma Progression and Agiogenesis

描述(申请人提供)：细胞黏附分子对癌症的发展有深远的影响，有效地促进或抑制恶性疾病的发展。L1(或L1-CAM)是一种神经细胞黏附分子，在神经外胚层肿瘤中高表达。在恶性黑色素瘤中，L1的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形成，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。这项工作将解决我们知识中的一个重大差距，并将确定L1是否为治疗干预的合适靶点。有三个目的：目的#1：L1被认为是导致恶性黑色素瘤高运动性和侵袭性表型的信号通路的激活。这种表型的诱导是。进一步建议由L1和整合素之间的直接合作产生。这一目标将检验L1-整合素直接相互作用导致激活促进黑色素瘤细胞运动、侵袭和基因转录的信号通路的假设。根据初步数据，重点将放在与“进展相关”的整合素αvbeta3的相互作用以及丝裂原活化蛋白激酶(MAPK)途径的贡献上。目的#2：动物研究将直接评估L1在黑色素瘤存活、生长和转移中的作用。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。进一步的研究将验证L1可以通过稳定肿瘤-血小板相互作用或通过促进宿主血管系统的迁移来促进转移的假设。目的#3：目的是证明L1裂解产物有助于恶性黑色素瘤的血管形成。我们已经确定了两个由黑色素瘤细胞释放的L1片段，这是Iost翻译切割的结果。这些切割产物将被测试促血管生成活性和促进肿瘤血管形成的能力。促血管生成机制将被确定。

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.