Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, United States of America.
PLoS One. 2010 Nov 15;5(11):e15451. doi: 10.1371/journal.pone.0015451.
Nearly 70% of breast cancer patients with advanced disease will develop bone metastases. Once established in bone, tumor cells produce factors that cause changes in normal bone remodeling, such as parathyroid hormone-related protein (PTHrP). While enhanced expression of PTHrP is known to stimulate osteoclasts to resorb bone, the environmental factors driving tumor cells to express PTHrP in the early stages of development of metastatic bone disease are unknown. In this study, we have shown that tumor cells known to metastasize to bone respond to 2D substrates with rigidities comparable to that of the bone microenvironment by increasing expression and production of PTHrP. The cellular response is regulated by Rho-dependent actomyosin contractility mediated by TGF-ß signaling. Inhibition of Rho-associated kinase (ROCK) using both pharmacological and genetic approaches decreased PTHrP expression. Furthermore, cells expressing a dominant negative form of the TGF-ß receptor did not respond to substrate rigidity, and inhibition of ROCK decreased PTHrP expression induced by exogenous TGF-ß. These observations suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis, which is especially important in metastatic cancer since many cancers (such as those of the breast and lung) preferentially metastasize to bone.
近 70%的晚期乳腺癌患者会发生骨转移。肿瘤细胞一旦在骨中定植，就会产生导致正常骨重塑改变的因子，如甲状旁腺激素相关蛋白（PTHrP）。虽然已知增强的 PTHrP 表达会刺激破骨细胞吸收骨，但驱动肿瘤细胞在转移性骨病发展的早期表达 PTHrP 的环境因素尚不清楚。在这项研究中，我们已经表明，已知会转移到骨骼的肿瘤细胞通过增加 PTHrP 的表达和产生来响应与骨骼微环境相当的刚性 2D 基质。细胞反应受 Rho 依赖性肌动球蛋白收缩调节，由 TGF-β 信号转导介导。使用药理学和遗传方法抑制 Rho 相关激酶（ROCK）会降低 PTHrP 的表达。此外，表达 TGF-β 受体显性负形式的细胞对基质刚性没有反应，而 ROCK 的抑制会降低外源性 TGF-β 诱导的 PTHrP 表达。这些观察结果表明，矿化骨骼微环境的差异刚性在肿瘤诱导的溶骨性的早期阶段发挥作用，这在转移性癌症中尤为重要，因为许多癌症（如乳腺癌和肺癌）优先转移到骨骼。
