TUMOR CELL ADHESIVE GLYCOPROTEINS AND METASTASIS

临床和基础科学领域的众多研究人员 假设血小板、血小板血栓和/或 凝血级联反应在肿瘤细胞的转移中起作用。 一种被提出的机制是血小板增强肿瘤细胞的增殖， 粘附于内皮细胞或内皮下基质， 转移级联的停滞阶段。 然而，一个因果 肿瘤细胞与血小板的关系 互动尚未建立。 大量资料 血小板糖蛋白在血小板中的作用 粘附在血管壁上。 血小板的因果作用 糖蛋白Ib和糖蛋白IIb/IIIa与血小板粘附 内皮下基质牢固建立。 我们最近 获得了存在免疫相关 糖蛋白（IR GP）在几种肿瘤细胞系的表面上。 在本提案中，我们将测试以下工作 假说. 首先，血小板糖蛋白Ib和IIb/IIIa （Gpllb/IIIa）在肿瘤细胞-血小板相互作用中起主要作用 如肿瘤细胞诱导血小板聚集和血小板 增强的肿瘤细胞与内皮细胞的细胞外粘附 基质和/或其单个组分。 第二，肿瘤细胞 具有IR的表面糖蛋白，如果不相同， 血小板Gp 1B和Gp 11b/111 a，这些肿瘤细胞 糖蛋白（lRGplb; lRGpllb/llla）在肿瘤中起主要作用 细胞诱导的血小板聚集，肿瘤细胞粘附， 内皮细胞和肿瘤细胞与内皮细胞粘附 细胞外基质和/或其单个组分。 初步数据表明，这些糖蛋白的存在， 通过免疫荧光法检测肿瘤细胞表面， 免疫电镜分析。 此外， 血小板糖蛋白和肿瘤细胞糖蛋白 两种细胞类型之间的相互作用及其随后的 已经获得了相互作用。 其他证据表明， 肿瘤细胞骨架可能调控其表达和功能 这些肿瘤细胞膜糖蛋白。 在本提案中，我们 将确定lR Gpib和GpIIb/IIIa在肿瘤细胞中的作用 与内皮细胞、细胞外基质的粘附及其 静态条件下和流动条件下的单个组件 显示不同剪切速率的条件。 此外，我们将 确定血小板GpIB和Gp 11b/111 a在血小板聚集中的作用。 肿瘤细胞相互作用和血小板促进肿瘤细胞粘附 与生物相关的基质。 肿瘤细胞的作用 细胞骨架在这些过程中也将被检查。 血小板 GPIB作为凝血酶的受体。 所以我们会 确定肿瘤细胞IR Gplb是否将作为凝血酶起作用 受体和IF凝血酶可影响肿瘤的表达 细胞lR Gpllb/llla，并影响其功能关系， 细胞外基质 最后我们将确定这些肿瘤 细胞糖蛋白在细胞上异源表达， 不同的转移能力和瞬时表达， 细胞暴露在不同的环境条件下。 这项建议 因此，将寻求确定这些功能的重要性， 生物过程中的糖蛋白（即，粘合等）相关 肿瘤转移。

Numerous investigators in both the clinical and basic sciences have postulated that platelets, platelet thrombi, and/or the coagulation cascade play a role in the metastasis of tumor cells. One proposed mechanism is that platelets enhance tumor cell adhesion to endothelial cells or subendothelial matrix during the arrest phase of the metastatic cascade. However, a causal relationship between tumor cells and platelets in the above interactions has not been established. Considerable information does exist for the role of platelet glycoproteins in platelet adhesion to the vessel wall. A causal role for platelet glycoprotein lb and glycoprotein llb/llla and platelet adhesion to the subendothelial matrix is firmly established. We have recently obtained evidence for the presence of immunologically related glycoproteins (lR GP) on the surface of several tumor cell lines. In the present proposal, we will test the following working hypothesis. First, that platelet glycoproteins lb and llb/llla (Gpllb/llla) play a major role in tumor cell-platelet interactions such as tumor cell induced platelet aggregation and platelet enhanced tumor cell adhesion to endothelial cells, extracellular matrix and/or its individual components. Second, that tumor cells possess surface glycoproteins which are lR, if not identical, to platelet GpIB and Gpllb/llla and that these tumor cell glycoproteins (lR Gplb; lR Gpllb/llla) play a major role in tumor cell induced platelet aggregation, tumor cell adhesion to endothelial cells, and tumor cell adhesion to endothelial cell extracellular matrix and/or its individual components. Preliminary data indicate the presence of these glycoproteins on the tumor cell surface by immunofluorescence and immunoelectron microscopic analysis. In addition, a role for the platelet glycoproteins and tumor cell glycoproteins in the interaction between the two cell types and in their subsequent interactions has been obtained. Other evidence suggests the tumor cell cytoskeleton may regulate the expression and function of these tumor cell membrane glycoproteins. In this proposal we will determine the role of lR Gpib and Gpllb/llla in tumor cell adhesion to endothelial cells, extracellular matrix, and its individual components under static conditions and under flow conditions exhibiting different shear rates. In addition, we will determine the role of platelet GpIB and Gpllb/llla in platelet tumor cell interaction and platelet facilitated tumor cell adhesion to biologically relevant substrata. The role of the tumor cell cytoskeleton in these processes will also be examined. Platelet Gpib serves as receptor for thrombin. Therefore, we will determine if tumor cell lR Gplb will function as a thrombin receptor and if thrombin can influence the expression of tumor cell lR Gpllb/llla and affect its functional relationship with the extracellular matrix. Finally we will determine if these tumor cell glycoproteins are heterogenously expressed on cells of different metastatic capabilities and transiently expressed on cells exposed to different environmental conditions. This proposal will therefore seek to establish functional significance for these glycoproteins in biological processes (i.e., adhesion, etc.) relevant to tumor metastasis.