Role of L1-CAM in Melanoma Progression and Agiogenesis

描述（由申请人提供）：细胞粘附分子对癌症发展具有深远的影响，有效地促进或抑制恶性疾病的发展。L1（或L1-CAM）是一种神经细胞粘附分子，在神经外胚层肿瘤中过表达。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可以促进肿瘤血管化，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空白，并将确定L1是否是治疗干预的合适靶点。有三个目标：目标1：L1被认为是导致恶性黑色素瘤中诱导高度运动和侵袭性表型的信号通路活化的原因。这种表型的诱导是。进一步提出是由L1和整联蛋白之间的直接合作引起的。这一目标将测试的假设，直接L1整合素的相互作用的结果，在激活的信号通路，促进黑色素瘤细胞的运动性，侵袭性和基因转录。基于初步数据，重点将放在与“进展相关”整合素α v β 3的相互作用和促分裂原活化蛋白激酶（MAPK）途径的贡献上。目标2：动物研究将直接评估L1对黑色素瘤生存、生长和转移的贡献。将在实验性肺转移模型中评估转移，而将在真皮微环境中评估肿瘤细胞存活和生长。进一步的研究将测试L1可以通过稳定肿瘤-血小板相互作用或通过促进穿过宿主血管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L1片段，这是由黑色素瘤细胞释放的结果丢失翻译切割。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形成的能力。将确定促血管生成机制。

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.