CELLULAR ADHESION AND PROSTATE TUMOR CELL PROGRESSION

我们之前的工作已经表明，入侵和迁移的潜力 人类前列腺癌细胞部分由表面决定 A6整合素的表达。在正常前列腺细胞上a6b4和 A6b1整合素存在。在前列腺肿瘤细胞表面上 人类组织样本中，a6b1整合素占主导地位。我们目前的工作 假设a6b1整合素的持续表达 前列腺肿瘤细胞表面允许肿瘤细胞沿 层粘连蛋白被包裹的结构，如血管和神经。侵略者的入侵 肿瘤细胞沿着这些结构发生，通过一种 A6b1整合素层粘连蛋白受体的功能。中断策略 侵袭包括b4和b4的显性负突变的表达。 抑制a6b1整合素的黏附特性。 具体目标是： 1.确定b4整合素的转染是否改变了侵袭性 应用SCID小鼠模型研究DU145H前列腺癌细胞的表型 系统。将使用b4的不同构造来测试是否有 表型的变化取决于信号域，如果b4 没有胞浆结构域的单位会降低a6b1的表达 并阻断侵袭表型。 2.确定肿瘤细胞上存在的A6T形式的A6是否 侵袭和/或迁移的活性受体。这些实验 包括确定A6分子的哪一部分缺失以及 将改变后的A6型基因导入A6分钟前列腺癌 细胞。将测试a6t在入侵过程中的参与情况。 使用SCID鼠标模型系统。 3.确定细胞表面a6的结合是否会使侵袭性变黑 表型。人工合成的小分子配体和多肽 组合文库将根据它们与A6结合的能力进行筛选 细胞表面及其抑制a6依赖的黏附的能力 层粘连蛋白。这些分子抑制入侵的能力将得到测试。 使用SCID鼠标模型系统。

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.