HYALURONAN BIOSYNTHESIS IN PROSTATE CARCINOMA

在美国，前列腺癌发病率是癌症死亡的第二大原因，通常是由偏远部位的转移引起的，并且是优先侵入骨髓的少数主要癌症之一。 本实验室先前的工作表明，前列腺肿瘤细胞与骨髓内皮细胞的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含量升高与正常和转化细胞迁移相关。 其合成由人类中三种HA合酶（HAS）同种型中的一种或多种催化。 我们假设前列腺肿瘤细胞合成HA涂层的能力将是同种型特异性的，并且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HA涂层对侵袭性肿瘤行为的体外相关测定的要求来测试该模型，关于HAS同种型表达和转移倾向。 我们将评估每种HAS亚型与前列腺肿瘤恶性肿瘤的功能相关性，使用用反义或全长过表达HAS构建体稳定转染的前列腺癌来测量HAS表达水平特异性改变后的体外和前列腺注射小鼠模型中的侵袭性。

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.