Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis.
Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis.
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DOI：
10.1158/0008-5472.can-13-0602
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发表时间：
2013-10-15
期刊：
影响因子：
11.2
通讯作者：
Pilch J
中科院分区：
文献类型：
--
作者：
Knowles LM;Gurski LA;Engel C;Gnarra JR;Maranchie JK;Pilch J
凝血级联选择性参与肺转移，但这种选择性的原因尚不清楚。在这里，我们表明，主要转移到肺的肿瘤细胞，如肾细胞癌（RCC）和软组织肉瘤（STS），有一个固有的能力，产生广泛的侵袭伪足时嵌入血凝块。与检测的其他转移性癌细胞相比，RCC和STS细胞表现出纤连蛋白和整合素αvβ3的活化形式的表达水平增加，这协同支持在纤维蛋白包埋的肿瘤细胞中产生精细的纤连蛋白基质和肌动蛋白应力纤维。纤连蛋白和αvβ3共同诱导转录因子Slug的上调，Slug介导上皮-间质转化（EMT）以及纤维蛋白侵袭和肺转移。这种机制具有临床意义，因为来自转移性RCC患者的原发性癌细胞强烈侵入纤维蛋白，这与纤连蛋白基质形成和Slug表达相关。相比之下，来自局部RCC患者的肿瘤细胞在很大程度上是非侵入性的。总之，我们的研究结果确定了活化的整合素αvβ3和纤连蛋白通过上调Slug促进肺转移，从而定义了癌细胞可以在肺血管系统中定植血凝块的机制。
The blood clotting cascade is selectively involved in lung metastasis, but the reason for this selectivity is unclear. Here we show that tumor cells that metastasize predominantly to the lung, such as renal cell carcinoma (RCC) and soft tissue sarcoma (STS), have an inherent capacity to generate extensive invadopodia when embedded in a blood clot. Compared to other metastatic cancer cells tested, RCC and STS cells exhibited increased levels of expression of fibronectin and an activated form of the integrin αvβ3, which coordinately supported the generation of an elaborate fibronectin matrix and actin stress fibers in fibrin-embedded tumor cells. Together, fibronectin and αvβ3 induced upregulation of the transcription factor Slug, which mediates epithelial-mesenchymal transition (EMT) as well as fibrin invasion and lung metastasis. This mechanism is clinically significant, because primary cancer cells from patients with metastatic RCC strongly invaded fibrin and this correlated with fibronectin matrix formation and Slug expression. In contrast, tumor cells from patients with localized RCC were largely non-invasive. Together, our findings establish that activated integrin αvβ3 and fibronectin promote lung metastasis by upregulating Slug, defining a mechanism through which cancer cells can colonize blood clots in the lung vasculature.