Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer.
Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer.
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DOI：
10.1186/1476-4598-13-112
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发表时间：
2014-05-19
期刊：
影响因子：
37.3
通讯作者：
Rouzaut A
中科院分区：
文献类型：
--
作者：
Salvo E;Garasa S;Dotor J;Morales X;Peláez R;Altevogt P;Rouzaut A
转化生长因子β（TGF-β）在癌发生的早期作为肿瘤抑制因子，但在疾病的后期阶段转变为肿瘤促进因子。事实上，TGF-β是肿瘤细胞的整合素表达的已知诱导物，其有助于癌症转移扩散，并且TGF-β抑制已显示减弱小鼠模型中的转移。然而，癌细胞通常变得对TGF-β介导的生长抑制难以抵抗。因此，识别可能受益于抗TGF-β治疗的患者需要仔细选择。我们进行了体外分析暴露于TGF-β对NSCLC细胞趋化性和粘附淋巴管内皮细胞的影响。我们还在NSCLC原位模型中研究了在抑制TGF-β信号传导、β3整合素表达或两者后淋巴结转移的发生率。我们提供了TGF-β暴露后β3-整合素依赖性NSCLC与淋巴管内皮细胞粘附增加的证据。体内实验表明，靶向TGF-β和β3整合素可显著降低淋巴结转移的发生率。甚至，在对TGF-β抑制无反应的肿瘤中阻断β3整联蛋白表达严重损害了肿瘤向淋巴结转移的能力。这些发现表明，TGF-β单药治疗难治性肺癌肿瘤可以使用双重治疗有效治疗，该双重治疗将抑制肿瘤细胞粘附到淋巴管与基质TGF-β抑制相结合。
Transforming Growth Factor beta (TGF-β) acts as a tumor suppressor early in carcinogenesis but turns into tumor promoter in later disease stages. In fact, TGF-β is a known inducer of integrin expression by tumor cells which contributes to cancer metastatic spread and TGF-β inhibition has been shown to attenuate metastasis in mouse models. However, carcinoma cells often become refractory to TGF-β-mediated growth inhibition. Therefore identifying patients that may benefit from anti-TGF-β therapy requires careful selection. We performed in vitro analysis of the effects of exposure to TGF-β in NSCLC cell chemotaxis and adhesion to lymphatic endothelial cells. We also studied in an orthotopic model of NSCLC the incidence of metastases to the lymph nodes after inhibition of TGF-β signaling, β3 integrin expression or both. We offer evidences of increased β3-integrin dependent NSCLC adhesion to lymphatic endothelium after TGF-β exposure. In vivo experiments show that targeting of TGF-β and β3 integrin significantly reduces the incidence of lymph node metastasis. Even more, blockade of β3 integrin expression in tumors that did not respond to TGF-β inhibition severely impaired the ability of the tumor to metastasize towards the lymph nodes. These findings suggest that lung cancer tumors refractory to TGF-β monotherapy can be effectively treated using dual therapy that combines the inhibition of tumor cell adhesion to lymphatic vessels with stromal TGF-β inhibition.
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影响因子：
3.3
作者：
Parvani JG;Galliher-Beckley AJ;Schiemann BJ;Schiemann WP
通讯作者：
Schiemann WP
影响因子：
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作者：
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影响因子：
64.8
作者：
Laemmermann, Tim;Bader, Bernhard L.;Sixt, Michael
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Sixt, Michael