CELLULAR ADHESION AND PROSTATE TUMOR CELL PROGRESSION

我们以前的工作表明， 人前列腺癌细胞的部分决定于其表面 α 6整联蛋白的表达。在正常前列腺细胞中， 存在α 6 β 1整联蛋白。在前列腺肿瘤细胞表面， 在人组织样品中，α 6 β 1整联蛋白占主导地位。我们目前的工作 一种假设是，a6 b1整合素在细胞表面的持续表达， 前列腺肿瘤细胞表面允许肿瘤细胞沿着 层粘连蛋白包被的结构如血管和神经。的入侵 肿瘤细胞沿着这些结构出现， 功能性α 6 β 1整联蛋白层粘连蛋白受体。中断策略 侵袭包括B4的显性负突变的表达， 抑制α 6 β 1整联蛋白的粘附特性。 具体目标是： 1.确定b4整合素的转染是否改变了 使用SCID小鼠模型的DU 145 H前列腺癌细胞的表型 系统b4的不同结构将用于测试是否有任何 表型的变化取决于信号传导结构域， 没有胞质结构域的单位将降低a6 b1的表达 并阻断入侵表型。 2.确定存在于肿瘤细胞上的a6的a6 t形式是否是 入侵和/或迁移的活性受体。这些实验 包括确定α 6分子的哪一部分缺失， 将改变的A6形式转染入A6型前列腺癌 细胞将对a6 t参与入侵进程的情况进行测试。 使用SCID小鼠模型系统。 3.确定细胞表面a6的结合是否会使侵袭性细胞变黑。 表型合成的小分子配体和从合成的小分子配体获得的肽。 组合文库将通过它们结合A6的能力来筛选。 细胞表面和它们抑制α 6依赖性粘附的能力 层粘连蛋白。将测试这些分子抑制入侵的能力 使用SCID小鼠模型系统。

Our previous work has shown that the invasive and migratory potential of human prostate carcinoma cells is determined in part by the surface expression of the a6 integrin. On normal prostate cells the a6b4 and the a6b1 integrins are present. On prostate tumor cell surfaces within the human tissue samples, the a6b1 integrin dominates. Our current working hypothesis is that the continued expression of the a6b1 integrin on prostate tumor cell surfaces allows for invasion of tumor cells along laminin coated structures such as vessels and nerves. The invasion of the tumor cells occurs along these structures through the action of a functional a6b1 integrin laminin receptor. Strategies for interruption invasion includes expression of dominant negative mutations of b4 and inhibiting the adhesion properties of the a6b1 integrin. The specific aims are: 1. Determine if transfection of the b4 integrin alters the invasion phenotype of the DU145 H prostate cancer cells using the SCID mouse model system. Different constructs of b4 will be used to test whether any changes in phenotype is dependent upon the signaling domain and if the b4 unit without the cytoplasmic domain will decrease the expression of a6b1 and block the invasion phenotype. 2. Determine if the a6t forms of a6, which is present on tumor cells, is an active receptor for invasion and/or migration. These experiments include determining which portion of the a6 molecule is missing and transfection of the altered a6 form into a a6 minutes prostate cancer cells. The participation of the a6t in the invasion process will be tested using the SCID mouse model system. 3. Determine if binding of the cell surface a6 will black the invasive phenotype. Synthetic small molecule ligands and peptides obtained from a combinatorial library will be screened by their ability to bind to a6 on the cell surface and their ability to inhibit a6 dependent adhesion to laminin. The ability of the molecules to inhibit invasion will be tested using a SCID mouse model system.