Integrin α5β1 promotes survival of growth-arrested breast cancer cells:: An in vitro paradigm for breast cancer dormancy in bone marrow
Integrin α5β1 promotes survival of growth-arrested breast cancer cells:: An in vitro paradigm for breast cancer dormancy in bone marrow
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DOI：
10.1158/0008-5472.can-03-3853
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发表时间：
2004-07-01
期刊：
影响因子：
11.2
通讯作者：
Wieder, R
中科院分区：
文献类型：
--
作者：
Korah, R;Boots, M;Wieder, R
隐匿性乳腺癌细胞在骨髓微环境中长期存活的机制尚不清楚。使用选定的骨髓基质成分，证明在促进乳腺癌细胞的生长停滞和生存的作用，我们重建了一个体外模型，在骨髓中的乳腺癌细胞的休眠。根据该模型，碱性成纤维细胞生长因子，一种在骨髓基质中丰富的乳腺分化因子，诱导相对分化良好的乳腺癌细胞的生长停滞，诱导扩散外观，并通过上调整合素α 5 β 1将其存活限制于纤连蛋白。大多数碱性成纤维细胞生长因子阻滞的细胞未能建立与纤连蛋白的最佳连接并经历细胞死亡。纤维连接蛋白是骨髓微环境的另一个主要组成部分，细胞附着在纤维连接蛋白上，保持存活并生长停滞数周。虽然能够粘附到其他基质蛋白质胶原和层粘连蛋白，休眠细胞不会从这些相互作用中获得生存优势。使用功能阻断肽，我们显示了一个特定的贡献，α 5 β 1-纤连蛋白相互作用，在维持生存的生长停滞细胞，可能通过负调节凋亡反应，通过信号通路。阻断磷脂酰肌醇3 '-激酶和Akt抑制休眠克隆的存活，证明这是这些途径之一。人骨髓基质共培养实验证实了纤连蛋白连接在维持休眠克隆存活中的作用。
The mechanisms of long-term survival of occult breast cancer cells in the bone marrow microenvironment are not known. Using selected bone marrow stromal components with demonstrated roles in promoting growth arrest and survival of breast cancer cells, we reconstituted an in vitro model for dormancy of breast cancer cells in bone marrow. According to this model, basic fibroblast growth factor, a mammary differentiation factor abundant in the bone marrow stroma, induces growth arrest of relatively well-differentiated breast cancer cells, induces a spread appearance, and restricts their survival to fibronectin by up-regulating integrin alpha5beta1. Most of the basic fibroblast growth factor-arrested cells fail to establish optimal ligation to fibronectin and undergo cell death. Cells that do attach to fibronectin, another major constituent of the bone marrow microenvironment, stay alive and growth-arrested for many weeks. Although capable of adhering to other stromal proteins collagen and laminin, dormant cells do not gain a survival advantage from these interactions. Using function-blocking peptides, we show a specific contribution of alpha5beta1-fibronectin interaction in maintaining survival of growth-arrested cells, potentially by negatively modulating apoptotic response via signaling pathways. Blocking of phosphatidylinositol 3'-kinase and Akt inhibits survival of dormant clones, demonstrating this as one of those pathways. Experiments with human bone marrow stroma cocultures confirm the role of fibronectin ligation in maintaining survival of dormant clones.