LAMININ AND ITS RECEPTORS IN ORAL CANCER

项目I的长期目标是了解粘合机制 调节口腔鳞状细胞癌（SCC）迁移和侵袭 细胞上皮细胞使用两种不同的粘附系统：（1） 钙粘蛋白，一个家族的膜蛋白，介导同型细胞， 细胞粘附，和（2）整合素，异二聚体受体家族 在细胞和细胞外基质之间形成粘附。 癌的侵袭需要同时发生两种类型的粘连改变 系统.运动是癌细胞侵袭的重要组成部分， 一个连续的事件，其中细胞延伸伪足，形成新生的 通过整合素受体连接，组装和收缩 细胞骨架，最后，当它向前移位时， 粘连现在很明显，整联蛋白不仅仅与细胞结合， 基质，但也是有效的信号分子。的初始接合 整联蛋白诱导它们凝聚成焦点接触，形成 锚定细胞外基质和离散信号转导 细胞质表面的复合物。口腔鳞状细胞癌细胞，像他们正常的 对应物，粘膜角质形成细胞，合成并粘附于 基底膜富含细胞外基质成分， 层粘连蛋白和IV型胶原蛋白。有证据表明，迁移SCC 细胞使用新沉积的激肽（层粘连蛋白）来促进它们的 通过激活alpha-3-beta-1和alpha-6-beta-4的运动 整合素另一方面，口腔鳞癌细胞中的钙粘蛋白抑制肿瘤生长， 入侵有待检验的假设是，不受调节的分泌和 SCC细胞的激肽沉积提供了一条迁移途径 通过α-3和α-6整联蛋白的结合促进侵袭。 一个必然的假设是，钙粘蛋白的行为，以限制运动 由整合素-配体相互作用诱导。具体目标是：（1） 鉴定由口腔SCC细胞合成的层粘连蛋白同种型， 刺激细胞运动，（2）确定β-1和β-4整合素 表达在SCC细胞中变得不受调节，（3）定义钙粘蛋白如何 调节整联蛋白诱导的SCC细胞的迁移/侵袭，和（4） 评估激肽及其受体在肿瘤标本中的表达， 口腔鳞状细胞癌总之，这些研究将解决如何激活 通过激肽和其他配体的特异性整合素受体诱导 能动性和侵入性反应。其他实验将研究如何 激肽-整合素相互作用干扰钙粘蛋白依赖的细胞间 粘连最后，与生物统计学和 组织和组织学核心将决定 激肽及其受体作为肿瘤预后标志物的研究进展 行为

The long term goal of Project I is to understand the adhesive mechanisms that regulate migration and invasion by oral squamous carcinoma (SCC) cells. Epithelial cells use two distinct adhesion systems: (1) the cadherins, a family of membrane proteins that mediate homotypic cell- cell adhesion, and (2) integrins, a family of heterodimeric receptors that form adhesions between cells and their extracellular matrix. Carcinoma invasion requires concurrent changes in both types of adhesion systems. Motility, an essential component of carcinoma invasion, is a continuum of events in which the cell extends pseudopodia, forms nascent attachments via integrin receptors, assembles and contracts the cytoskeleton, and finally, as it translocates forward, disengages distal adhesions. It is now apparent that integrins do not simply bind cells to matrix but also are potent signaling molecules. Initial engagement of integrins induces their condensation into focal contacts, forming anchors to the extracellular matrix and discrete signal-transducing complexes on the cytoplasmic surface. Oral SCC cells, like their normal counterparts, the mucosal keratinocytes, synthesize and adhere to a basement membrane that is rich in extracellular matrix components such as laminins and type IV collagen. Evidence suggests that migrating SCC cells use newly deposited kalinin (laminins) to facilitate their locomotion through the activation of alpha-3-beta-1 and alpha-6-beta-4 integrins. On the other hand, cadherins in oral SCC cells restrain tumor invasion. The hypothesis to be tested is that unregulated secretion and deposition of kalinin by SCC cells provides a migratory pathway promoting invasion through engagement of alpha-3 and alpha-6 integrins. A corollary hypothesis is that the cadherins act to restrict motility induced by integrin-ligand interactions. The specific aims are to (1) identify the laminin isoforms synthesized by oral SCC cells that stimulate cell motility, (2) determine how Beta-1 and Beta-4 integrin expression becomes unregulated in SCC cells, (3) define how cadherins regulate integrin-induced migration/invasion of SCC cells, and (4) assess the expression of kalinin and its receptors in tumor specimens of oral SCC. In summary, these studies will address how activation of specific integrin receptors by kalinin and other ligands induces the motile and invasive response. Other experiments will examine how kalinin-integrin interactions disturb cadherin dependent cell-cell adhesions. Finally, studies in collaboration with the Biostatistics and the Tissue and Histopathology Cores will determine the potential value of kalinin and its receptors as prognostic markers in predicting tumor behavior.