Platelet and osteoclast β3 integrins are critical for bone metastasis
Platelet and osteoclast β3 integrins are critical for bone metastasis
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DOI：
10.1073/pnas.2234372100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Weilbaecher, KN
中科院分区：
文献类型：
--
作者：
Bakewell, SJ;Nestor, P;Weilbaecher, KN
靶向缺失β(3)整合素的小鼠被用来研究肿瘤细胞转移和破坏骨骼的过程。将B16黑色素瘤细胞注射到左心室，在14天内，74%的β(3)（+/+）小鼠发生溶骨性骨转移。相比之下，只有4%的β(3)（-/-）小鼠出现骨损伤。直接在胫骨内接种肿瘤导致β(3)（-/-）小鼠的骨髓被肿瘤替代，但在β(3)（+/+）小鼠中未见相关的骨小梁吸收。骨髓移植研究表明，骨转移的易感性是由骨髓来源的细胞赋予的。为了分析破骨细胞和血小板β(3)整合素在骨转移模型中的作用，我们使用了破骨细胞缺陷的src（-/-）小鼠。Src-null小鼠可以免受肿瘤相关的骨破坏，但不能防止肿瘤细胞转移到骨。相反，活化α (IIb) β(3)的高度特异性血小板聚集抑制剂可阻止B16转移。这些数据证明了血小板α (IIb) β(3)在肿瘤进入骨中的关键作用，并提示抗血小板治疗可能有助于预防实体瘤转移的机制。
Mice with a targeted deletion of beta(3) integrin were used to examine the process by which tumor cells metastasize and destroy bone. Injection of B16 melanoma cells into the left cardiac ventricle resulted in osteolytic bone metastasis in 74% of beta(3)(+/+) mice by 14 days. In contrast, only 4% of beta(3)(-/-) mice developed bone lesions. Direct intratibial inoculation of tumor resulted in marrow replacement by tumor in beta(3)(-/-) mice, but no associated trabecular bone resorption as seen in beta(3)(+/+) mice. Bone marrow transplantation studies showed that susceptibility to bone metastasis was conferred by a bone marrow-derived cell. To dissect the roles of osteoclast and platelet beta(3) integrins in this model of bone metastasis, osteoclast-defective src(-/-) mice were used. Src-null mice were protected from tumor-associated bone destruction but were not protected from tumor cell metastasis to bone. In contrast, a highly specific platelet aggregation inhibitor of activated alpha(IIb)beta(3) prevented B16 metastases. These data demonstrate a critical role for platelet alpha(IIb)beta(3) in tumor entry into bone and suggest a mechanism by which antiplatelet therapy may be beneficial in preventing the metastasis of solid tumors.