MOLECULAR CHANGES DURING PROSTATE CARCINOMA PROGRESSION

前列腺癌是目前男性最常见的内脏恶性肿瘤。 其临床进展是可变的。 原因（S） 变异性是未知的，但可能是由于差异， 细胞侵袭和转移扩散的效率。 的细胞侵袭 是一个三步骤的过程：1）将细胞附着到细胞的组分上， 细胞外基质; 2）释放蛋白水解酶和/或其 特异性抑制剂（TIMPs）;以及，3）细胞通过 组织侵入血管床 在本建议中，我们将审查 细胞外基质分子（ECM）（纤连蛋白， 玻连蛋白、腱生蛋白、层粘连蛋白和IV型胶原蛋白），因为它们涉及 在癌前和恶性的各个阶段的肿瘤进展 疾病 此外，我们还将研究粘合剂的表达 正常人前列腺表面的整联蛋白分子，和 随着肿瘤进展观察到的变化。 我们亦会研究 整合素的表达与中间丝的关系 细胞骨架 最后，我们将检查三个的表达式， 人多基因胶原酶家族的已知成员 前列腺癌前病变和恶性疾病的各个阶段。 细胞外基质分子、表面整合素的表达 分子和金属蛋白酶将在组织中检测， 用特异性抗体进行间接免疫荧光。 的检测 还将在转录水平上检测金属蛋白酶 在冷冻切片中使用原位杂交以及北方印迹 使用提取的总RNA进行分析。 这些分子之间的关系 将与肿瘤分级和病理分期进行比较。 这些的作用 分子将在附着和早期侵入中进行研究， 将各种不同的前列腺细胞系注射到SCID小鼠中。

Prostate carcinoma is now the most common visceral malignancy in males. It is variable in its clinical progression. The cause(s) of this variability are unknown, but are likely due to differences in the efficiency of cellular invasion and metastatic spread. Cellular invasion is a three step process: 1) attachment of the cells to components of the extracellular matrix; 2) release of proteolytic enzymes and/or their specific inhibitors (TIMPs); and, 3) migration of the cells through the tissue to invade the vascular bed. In this proposal we will examine the relationship of the extracellular matrix molecules (ECM) (fibronectin, vitronectin, tenascin, laminin, and type IV collagen) as they relate to tumor progression in the various stages of premalignant and malignant disease. In addition We will examine the expression of the adhesive integrin molecules on the surface of normal human prostate glands, and the changes observed with tumor progression. We will also investigate the relationship of integrin expression to the intermediate filaments of the cytoskeleton. Finally, we will examine the expression of three of the known members of the multigene collagenase family in the human prostate in the various stages of premalignant and malignant disease. Expression of the extracellular matrix molecules, surface integrin molecules, and metalloproteinase will be detected in tissue using indirect immunofluorescence with specific antibodies. The detection of the metalloproteinases will also be examined at the transcriptional level in frozen sections using in situ hybridization as well as northern blot analysis using extracted total RNA. The relationship of these molecules will be compared to tumor grade and pathologic stage. The role of these molecules will be investigated in attachment and early invasion by injecting various variant prostate cell lines into the SCID mice.