Hyaluronic acid (HA) has been implicated in the proliferation and metastasis of tumor cells. However, most previous studies were conducted on extracellular matrix or pericellular HA, and the role of circulating HA in vivo has not been studied. HA is rapidly cleared from the bloodstream. The scavenger receptor Stabilin-2 (Stab2) is considered a major clearance receptor for HA. Here we report a dramatic elevation in circulating HA levels in Stab2-deficient mice without any overt phenotype. Surprisingly, the metastasis of B16F10 melanoma cells to the lungs was markedly suppressed in the Stab2-deficient mice, whereas cell proliferation was not affected. Furthermore, administration of an anti-Stab2 antibody in Stab2 + mice elevated serum HA levels and prevented the metastasis of melanoma to the lung, and also suppressed spontaneous metastasis of mammary tumor and human breast tumor cells inoculated in the mammary gland. Administration of the antibody or high-dose HA in mice blocked the lodging of melanoma cells to the lungs. Furthermore, HA at high concentrations inhibited the rolling/tethering of B16 cells to lung endothelial cells. These results suggest that blocking Stab2 function prevents tumor metastasis by elevating circulating HA levels. Stab2 may be a potential target in antitumor therapy.cancer | hyaluronan | imaging | antibody therapy | sinusoid

Junctional adhesion molecule-A (JAM-A

No abstract

Junctional adhesion molecule-A (JAM-A/JAM-1/F11R) is a cell adhesion molecule expressed in epithelial cells, endothelial cells and also hematopoietic cells such as leukocytes, platelets and erythrocytes. However, the expression of JAM-A in hematopoietic stem cell (HSC) had not been known. Here we show that JAM-A is expressed at a high level in the enriched HSC fraction, i.e. CD34+ c-Kit+ cells in embryonic day 11.5 (E11.5) aorta-gonod-mesonephros (AGM) and E11.5 fetal liver (FL) as well as c-Kit+ Sca-1+ Lineage- (KSL) cells in E14.5 FL, E18.5FL and adult bone marrow (BM). While the percentage of JAM-A+ cells in those tissues decreases during the development, the expression in HSC fraction is maintained throughout life. In fact, c-Kit+Sca-1+ cells are enriched approximately 200-fold from whole BM cells by anti-JAM-A antibody alone, i.e. the c-Kit+Sca-1+ cells in whole BM was about 0.15% and that in JAM-A+ cells was about 30%. Colony forming assays reveal that multi-lineage colony forming activity (CFU-mix) in JAM-A+ cells is higher than that in JAM-A- cells in the enriched HSC fraction in all those tissues. HSC transplantation assay revealed that long-term repopulating HSC (LTR-HSC) activity is present in the mice received 100 JAM-A+ KSL (7/9) cells and 300 KSL cells (5/6). Since the ratio of JAM-A+ cells to JAM-A- cells in the KSL fraction is about 6.5:3.5, 100 JAM-A- KSL cells are equivalent to 285 total KSL cells. In contrast to JAM-A+ cells, the mice received 1000 JAM-A- KSL cells, which are equivalent to more than 2850 total KSL cells, failed to engraft for long-term (0/6). These data revealed that long-term repopulating HSC (LTR-HSC) activity is present exclusively in the JAM-A+ cells, but not in JAM-A- cells. Moreover only 100 JAM-A+ cells isolated from whole BM cells by anti-JAM-A antibody alone reconstituted the hematopoietic system for long-term (4/7). Together these results indicate that JAM-A is expressed on hematopoietic precursors in various hematopoietic tissues and is an excellent and convenient marker to enrich LTR-HSC from BM cells.