HYALURONAN BIOSYNTHESIS IN PROSTATE CARCINOMA

前列腺癌发病率是美国癌症死亡的第二大原因，通常由远处转移引起，是少数几种优先侵入骨髓的主要癌症之一。我们实验室之前的工作表明，前列腺肿瘤细胞与骨髓内皮细胞的强烈粘附是由前列腺细胞表面透明质酸（HA）基质介导的。这种高分子量糖胺聚糖的存在与正常和转化的细胞迁移有关。它的合成是由人体内三种血凝素合成酶（HAS）异构体中的一种或多种催化的。我们假设前列腺肿瘤细胞合成HA包被的能力将是异构体特异性的，并且在体外和小鼠模型中与侵袭性表型相关。我们建议通过表征HA涂层对侵袭性肿瘤行为的体外相关分析的要求来测试该模型，其中涉及到HAS异构体表达和转移倾向。我们将在体外和前列腺注射小鼠模型中，使用稳定转染反义或全长过表达HAS构建体的前列腺癌来评估每种HAS亚型与前列腺肿瘤恶性肿瘤的功能相关性，以测量HAS表达水平特异性改变后的侵袭性。

Prostate cancer morbidity is the second leading cause of cancer death in the United States, generally resulting from metastases in remote sites, and is one of a few major cancers that preferentially invade bone marrow. Previous work in our laboratory demonstrated that avid adhesion of prostate tumor cells to bone marrow endothelial cells was mediated by a prostate cell surface hyaluronan (HA) matrix. The presence of this high molecular weight glycosaminoglycan in elevated quantities is correlated with normal and transformed cell migration. Its synthesis is catalyzed by one or more of three HA synthase (HAS) isoforms in humans. We hypothesize that the ability of the prostate tumor cell to synthesize an HA coat will be isoform specific and correlate with invasive phenotype in vitro and in mouse models. We propose to test this model by characterizing the requirement of an HA coat for in vitro correlate assays of aggressive tumor behavior, with respect to HAS isoform expression and metastatic propensity. We will assess the functional relevance of each HAS isoform to prostate tumor malignancy using prostate carcinomas stably transfected with antisense or full length overexpression HAS constructs to measure invasiveness following specific alteration of HAS expression levels, both in vitro and in a prostate-injected mouse model.