Integrin αvβ6 promotes an osteolytic program in cancer cells by upregulating MMP2.
Integrin αvβ6 promotes an osteolytic program in cancer cells by upregulating MMP2.
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DOI：
10.1158/0008-5472.can-13-1796
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发表时间：
2014-03-01
期刊：
影响因子：
11.2
通讯作者：
Languino LR
中科院分区：
文献类型：
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作者：
Dutta A;Li J;Lu H;Akech J;Pratap J;Wang T;Zerlanko BJ;FitzGerald TJ;Jiang Z;Birbe R;Wixted J;Violette SM;Stein JL;Stein GS;Lian JB;Languino LR
已知控制骨前列腺转移的分子电路依赖于多种途径的活性，包括整合素信号传导。在这里，我们证明αvβ6整合素在人前列腺癌骨转移中上调。在前列腺癌细胞中，这种整联蛋白是纤连蛋白和潜伏相关肽-TGF β1的功能活性受体;它介导配体结合后的附着和迁移，并定位于局灶性接触中。考虑到前列腺癌细胞形成骨转移病灶的倾向，我们研究了αvβ6整合素是否促进这种类型的转移。我们首次发现，αvβ6在体外选择性诱导多种前列腺癌细胞中的基质金属蛋白酶2（MMP 2），并通过上调MMP 2（而非MMP 9）在免疫缺陷小鼠骨转移模型中促进体内骨质溶解。在所分析的前列腺癌细胞中，αvβ6对MMP 2表达和活性的影响不依赖于雄激素受体。在αvβ6表达细胞中也观察到PTHrP水平升高，已知PTHrP可诱导破骨细胞生成。然而，使用MMP 2 shRNA，我们证明αvβ6对骨丢失的影响是由于癌细胞上调可溶性MMP 2，而不是肿瘤生长速率的变化。另一种相关的含α v的整合素αvβ5没有显示出类似的反应，强调了αvβ6活性的重要性。总体而言，这些机制研究确定了单个整合素αvβ6的表达通过MMP 2诱导基质降解而促进癌细胞介导的骨质溶解程序。我们的研究结果为转移性骨疾病的分子治疗开辟了新的前景。
The molecular circuitries controlling osseous prostate metastasis are known to depend on the activity of multiple pathways, including integrin signaling. Here, we demonstrate that the αvβ6 integrin is upregulated in human prostate cancer bone metastasis. In prostate cancer cells, this integrin is a functionally active receptor for fibronectin and latency associated peptide-TGFβ1; it mediates attachment and migration upon ligand binding and is localized in focal contacts. Given the propensity of prostate cancer cells to form bone metastatic lesions, we investigated whether the αvβ6 integrin promotes this type of metastasis. We show for the first time that αvβ6 selectively induces matrix metalloproteinase 2, MMP2, in vitro in multiple prostate cancer cells, and promotes osteolysis in vivo in an immunodeficient mouse model of bone metastasis through upregulation of MMP2, but not MMP9. The effect of αvβ6 on MMP2 expression and activity is independent of androgen receptor in the analyzed prostate cancer cells. Increased levels of PTHrP, known to induce osteoclastogenesis, were also observed in αvβ6 expressing cells. However, using MMP2 shRNA, we demonstrate that the αvβ6 effect on bone loss is due to upregulation of soluble MMP2 by the cancer cells, not to changes in tumor growth rate. Another related αv-containing integrin, αvβ5, fails to show similar responses, underscoring the significance of αvβ6 activity. Overall, these mechanistic studies establish that expression of a single integrin, αvβ6, contributes to the cancer cell mediated program of osteolysis by inducing matrix degradation through MMP2. Our results open new prospects for molecular therapy of metastatic bone disease.