Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium.
Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium.
复制标题
DOI：
10.15252/embj.201694912
复制
发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Zanivan S
中科院分区：
文献类型：
--
作者：
Reid SE;Kay EJ;Neilson LJ;Henze AT;Serneels J;McGhee EJ;Dhayade S;Nixon C;Mackey JB;Santi A;Swaminathan K;Athineos D;Papalazarou V;Patella F;Román-Fernández Á;ElMaghloob Y;Hernandez-Fernaud JR;Adams RH;Ismail S;Bryant DM;Salmeron-Sanchez M;Machesky LM;Carlin LM;Blyth K;Mazzone M;Zanivan S
肿瘤进展改变了细胞外基质的组成和物理性质。特别是，基质硬度的增加对肿瘤的生长和转移有深远的影响。虽然内皮细胞是肿瘤进展的关键因素，但肿瘤僵硬对内皮细胞的影响及其对转移的影响尚不清楚。通过定量质谱分析，我们发现基质细胞蛋白CCN1/CYR61受内皮细胞刚性的高度调控。我们发现，在体外，僵硬诱导的CCN1激活了β-连环蛋白的核转位和信号转导，这有助于上调内皮细胞表面的N-钙粘附素水平。这有助于N-钙粘附素依赖的癌细胞与内皮细胞的相互作用。利用活体成像，我们发现在内皮细胞中敲除CCN1可以抑制黑色素瘤癌细胞与血管的结合，这是癌细胞通过血管系统转移到转移的关键步骤。因此，靶向僵硬诱导的血管系统变化，如CCN1，是一种潜在的但尚未被认识的损害转移的机制。
Tumor progression alters the composition and physical properties of the extracellular matrix. Particularly, increased matrix stiffness has profound effects on tumor growth and metastasis. While endothelial cells are key players in cancer progression, the influence of tumor stiffness on the endothelium and the impact on metastasis is unknown. Through quantitative mass spectrometry, we find that the matricellular protein CCN1/CYR61 is highly regulated by stiffness in endothelial cells. We show that stiffness‐induced CCN1 activates β‐catenin nuclear translocation and signaling and that this contributes to upregulate N‐cadherin levels on the surface of the endothelium, in vitro. This facilitates N‐cadherin‐dependent cancer cell–endothelium interaction. Using intravital imaging, we show that knockout of Ccn1 in endothelial cells inhibits melanoma cancer cell binding to the blood vessels, a critical step in cancer cell transit through the vasculature to metastasize. Targeting stiffness‐induced changes in the vasculature, such as CCN1, is therefore a potential yet unappreciated mechanism to impair metastasis.