Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis
Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis
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DOI：
10.1073/pnas.1117560109
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发表时间：
2012-03-13
影响因子：
11.1
通讯作者：
Miyajima, Atsushi
中科院分区：
文献类型：
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作者：
Hirose, Yoshikazu;Saijou, Eiko;Miyajima, Atsushi
透明质酸（HA）与肿瘤细胞的增殖和转移有关。然而，以往的研究大多是针对细胞外基质或细胞周围的HA，而循环HA在体内的作用尚未得到研究。血凝素迅速从血液中清除。清道夫受体stabin -2 （Stab2）被认为是HA的主要清除受体。在这里，我们报告了在没有任何明显表型的stab2缺陷小鼠中循环HA水平的显著升高。令人惊讶的是，在stab2缺陷小鼠中，B16F10黑色素瘤细胞向肺部的转移明显受到抑制，而细胞增殖不受影响。此外，在Stab2（+）小鼠中注射抗Stab2抗体可提高血清HA水平，阻止黑色素瘤向肺转移，并抑制乳腺肿瘤和人乳腺肿瘤细胞在乳腺接种后的自发转移。给小鼠注射抗体或高剂量的透明质酸阻断了黑色素瘤细胞向肺部的转移。此外，高浓度的透明质酸抑制了B16细胞对肺内皮细胞的滚动/系聚。这些结果表明，阻断Stab2功能通过提高循环HA水平来阻止肿瘤转移。Stab2可能是抗肿瘤治疗的潜在靶点。
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.