Abstract
Bone marrow is the primary site of metastasis in patients with advanced stage prostate cancer. Prostate carcinoma cells metastasizing to bone must initially adhere to endothelial cells in the bone marrow sinusoids. In this report, we have modeled that interaction in vitro using two bone marrow endothelial cell (BMEC) lines and four prostate adenocarcinoma cell lines to investigate the adhesion mechanism. Highly metastatic PC3 and PC3M-LN4 cells were found to adhere rapidly and specifically (70-90%) to BMEC-1 and trHBMEC bone marrow endothelial cells, but not to human umbilical vein endothelial cells (15-25%). Specific adhesion to BMEC-1 and trHBMEC was dependent upon the presence of a hyaluronan (HA) pericellular matrix assembled on the prostate carcinoma cells. DU145 and LNCaP cells were only weakly adherent and retained no cell surface HA. Maximal BMEC adhesion and HA encapsulation were associated with high levels of HA synthesis by the prostate carcinoma cells. Up-regulation of HA synthase isoforms Has2 and Has3 relative to levels expressed by normal prostate corresponded to elevated HA synthesis and avid BMEC adhesion. These results support a model in which tumor cells with up-regulated HA synthase expression assemble a cell surface hyaluronan matrix that promotes adhesion to bone marrow endothelial cells. This interaction could contribute to preferential bone metastasis by prostate carcinoma cells.
Highlights
Bone marrow is the primary site of metastasis in patients with advanced stage prostate cancer
Bone metastasis is an eventuality of advanced stage prostate cancer that results in severely reduced quality of life and ultimate morbidity
Metastasis is preceded by initial adhesion of circulating tumor cells to endothelial cells lining the vasculature of the secondary site
Summary
Overexpression of HA biosynthetic enzymes in tumor cell lines has been shown to increase tumorigenicity and metastatic potential [28, 29]. To investigate the molecular mechanism of initial adhesion to bone marrow endothelium, we modeled adhesion in vitro using the bone marrow endothelial cell lines BMEC-1 and trHBMEC and four prostate adenocarcinoma cell lines, PC3, PC3M-LN4, DU145, and LNCaP. Metastatic PC3 and PC3M-LN4 cells adhered rapidly to BMEC-1 but not to large vein endothelial cells (HUVEC). Presence of pericellular HA was correlated with elevated levels of HA synthesis and expression of HA synthase. Our data relate HA synthase overexpression to metastatic potential of prostate tumor cells and represent the first report of such a correlation. Our results implicate tumor cell-associated HA and up-regulation of HA synthase in prostate cancer progression and may directly impact metastatic potential or preferential tissue colonization of individual tumor cells
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