Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Abstract

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

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

“…Stab2 ibl2 mutants survived throughout embryonic development without defects in either blood or lymphatic vascular systems, which were described previously for stab2 morphants, 50,51 and fertile adults were identified in normal Mendelian ratios (Figure 3d,e). Consistent with the increase in circulating HA levels observed in mouse Stab2 knockouts, 52 a complete loss of fluoHA uptake by SECs was observed in zebrafish stab2 ibl2 mutants, showing a conserved role for stab2 in HA clearance in vertebrates (Figure 3f). Importantly, when either DOPG or DSPC liposomes were injected in stab2 ibl2 mutants, a strong reduction of liposome endocytosis by SECs was observed, offset by an increase in circulating liposome levels and an increase in macrophage uptake (Figure 3g,h).…”

Hyaluronan Regulation of Endothelial Barrier Function in Cancer

“…Interestingly, Hirose et al (2012) reported that inhibition of the scavenger receptor, Stabilin-2, in mice increases circulating HA which does not affect primary tumor size but inhibits tumor metastasis. The increased circulating HA was found to be ~40 kDa in size which did not affect tumor cell proliferation, migration, or invasion (Hirose et al, 2012). This size of HA was not tested in our experiments on EC barrier function.…”

Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses

“…In vitro, expression of Stab2 in cultured cells stimulates the binding and Rac-dependent internalization of apoptotic cells and also stimulates TGFβ production (91). Interestingly, Stab1/Stab2 double knockout mice have shorter lifespans and increased tissue inflammation compared to wild-type mice, although these results likely stem from the loss of hyaluronic acid scavenging mediated by these receptors (95, 96). How Stabilin signaling regulates cytokine expression during efferocytosis is still unclear, although STAB1-mediated engulfment requires the intracellular adaptor protein GULP which has been shown to regulate cytokine production downstream of other receptors including LRP1 (97, 98).…”