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，通常是由偏远部位的转移引起的，也是少数几种优先侵犯骨髓的主要癌症之一。我们实验室以前的工作表明，前列腺肿瘤细胞与骨髓内皮细胞的亲和黏附是由前列腺细胞表面透明质酸(HA)基质介导的。这种高相对分子质量的糖胺多聚糖的存在与正常和转化的细胞迁移有关。它的合成是由人类三种HA合成酶(HAS)亚型中的一种或多种催化的。我们假设，前列腺肿瘤细胞合成HA涂层的能力将是同型特异性的，并与体外和小鼠模型中的侵袭性表型相关。我们建议通过表征体外侵袭性肿瘤行为与HAS异构体表达和转移倾向相关分析对HA涂层的要求来测试这一模型。我们将使用稳定转染反义或全长过表达Has的前列腺癌来评估每种Has异构体与前列腺癌恶性程度的功能相关性，以测量体外和前列腺注射小鼠模型中Has表达水平的特定变化后的侵袭性。

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.