Tensional homeostasis and the malignant phenotype
Tensional homeostasis and the malignant phenotype
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DOI：
10.1016/j.ccr.2005.08.010
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发表时间：
2005-09-01
期刊：
影响因子：
50.3
通讯作者：
Weaver, VM
中科院分区：
文献类型：
--
作者：
Paszek, MJ;Zahir, N;Weaver, VM
肿瘤比正常组织更硬，并且肿瘤具有改变的整合素。因为整合素是调节细胞命运的机械传感器，我们询问组织硬度是否可以通过调节整合素促进恶性行为。我们发现，肿瘤是刚性的，因为它们具有坚硬的基质和升高的Rho依赖性细胞骨架张力，其驱动局灶性粘连，破坏粘附连接，扰乱组织极性，促进生长，并阻碍管腔形成。基质硬度通过聚集整合素来扰乱上皮形态发生，从而增强ERK活化并增加ROCK产生的收缩性和局灶性粘连。如果Rho产生的收缩性或ERK活性降低，则具有升高的ERK和Rho活性的收缩性EGF转化的上皮细胞可以表型地恢复为缺乏局灶性粘连的组织。因此，ERK和Rho构成了一个整合的机械调节回路的一部分，该回路通过整合素将基质硬度与细胞骨架张力联系起来以调节组织表型。
Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.