Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis.
Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis.
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DOI：
10.1158/0008-5472.can-09-3761
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Varner JA
中科院分区：
文献类型：
--
作者：
Garmy-Susini B;Avraamides CJ;Schmid MC;Foubert P;Ellies LG;Barnes L;Feral C;Papayannopoulou T;Lowy A;Blair SL;Cheresh D;Ginsberg M;Varner JA
最近的研究表明，肿瘤周围的淋巴管生成或淋巴管的生长促进了肿瘤向淋巴结的转移。我们发现纤维连接蛋白结合的整合素α4β1及其配体纤维连接蛋白是增殖性淋巴内皮的新型功能标志物。肿瘤以及淋巴管生成生长因子，如VEGF-C和VEGF-A，诱导淋巴管中整合素α4β1的表达。然后，整合素α4β1促进生长因子和肿瘤诱导的淋巴管生成，因为在Tie2Cre+ α4loxp/loxp小鼠中整合素α4β1基因表达缺失或α4Y991A敲入小鼠中α4信号的基因缺失会阻断生长因子和肿瘤诱导的淋巴管生成，以及肿瘤向淋巴结的转移。此外，整合素α4β1拮抗剂抑制淋巴管生成和肿瘤转移。我们的研究表明，整合素α4β1及其转导的信号调节增殖LECs的粘附、迁移、侵袭和存活。由于抑制肿瘤淋巴内皮中α4β1的表达、信号转导或功能不仅抑制肿瘤淋巴管生成，还能预防转移性疾病，这些结果表明整合素α4β1介导的肿瘤淋巴管生成促进转移，是抑制转移性疾病的有用靶点。
Recent studies have shown that lymphangiogenesis, or the growth of lymphatic vessels, at the periphery of tumors promotes tumor metastasis to lymph nodes. We show here that the fibronectin-binding integrin α4β1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium. Tumors, as well as lymphangiogenic growth factors, such as VEGF-C and VEGF-A, induce lymphatic vessel expression of integrin α4β1. Integrin α4β1 then promotes growth factor and tumor-induced lymphangiogenesis, as genetic loss of integrin α4β1 expression in Tie2Cre+ α4loxp/loxp mice or genetic loss of α4 signaling in α4Y991A knockin mice blocks growth factor and tumor-induced lymphangiogenesis, as well as tumor metastasis to lymph nodes. In addition, antagonists of integrin α4β1 suppress lymphangiogenesis and tumor metastasis. Our studies show that integrin α4β1 and the signals it transduces regulate the adhesion, migration, invasion and survival of proliferating LECs. As suppression of α4β1 expression, signal transduction or function in tumor lymphatic endothelium not only inhibits tumor lymphangiogenesis but also prevents metastatic disease, these results demonstrate that integrin α4β1-mediated tumor lymphangiogenesis promotes metastasis and is a useful target for the suppression of metastatic disease.