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.
|Simpson, Melanie A; Wilson, Christopher M; McCarthy, James B (2002) Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice. Am J Pathol 161:849-57|
|Simpson, Melanie A; Wilson, Christopher M; Furcht, Leo T et al. (2002) Manipulation of hyaluronan synthase expression in prostate adenocarcinoma cells alters pericellular matrix retention and adhesion to bone marrow endothelial cells. J Biol Chem 277:10050-7|
|Simpson, M A; Reiland, J; Burger, S R et al. (2001) Hyaluronan synthase elevation in metastatic prostate carcinoma cells correlates with hyaluronan surface retention, a prerequisite for rapid adhesion to bone marrow endothelial cells. J Biol Chem 276:17949-57|