Compressive Remodeling Alters Fluid Transport Properties of Collagen Networks - Implications for Tumor Growth
Compressive Remodeling Alters Fluid Transport Properties of Collagen Networks - Implications for Tumor Growth
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DOI：
10.1038/s41598-019-50268-z
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发表时间：
2019-11-20
影响因子：
4.6
通讯作者：
Zaman, M. H.
中科院分区：
文献类型：
--
作者：
Ferruzzi, J.;Sun, M.;Zaman, M. H.
肿瘤微环境的生物力学改变包括固体应力的积累、细胞外基质(ECM)硬化和肿瘤间质和瘤周间隙液体压力的增加。血管肿瘤间质加压与细胞外基质重塑之间的关系已有较好的研究，而肿瘤周围细胞外基质内无血管肿瘤生长过程中早期的生物力学变化尚不清楚。I型胶原是细胞外基质的主要纤维性成分，在压缩下屈曲时承受拉伸载荷。我们假设，肿瘤产生的压力通过致密化导致胶原重塑，从而产生对流液体运输的障碍，并可能在肿瘤进展和恶性肿瘤中发挥作用。为了更好地理解这一过程，我们从实验和计算两个方面表征了胶原网络在压缩下的结构-功能关系。在这里，我们显示上皮癌的生长诱导ECM的压缩重塑，文献中记录为Tacs-2表型，这代表了瘤周胶原的局部致密化和切向排列。这种压缩重塑是由胶原网络力学的独特特征引起的，如纤维屈曲和交联断裂，并降低了基质的整体水力渗透性。
Biomechanical alterations to the tumor microenvironment include accumulation of solid stresses, extracellular matrix (ECM) stiffening and increased fluid pressure in both interstitial and peri-tumoral spaces. The relationship between interstitial fluid pressurization and ECM remodeling in vascularized tumors is well characterized, while earlier biomechanical changes occurring during avascular tumor growth within the peri-tumoral ECM remain poorly understood. Type I collagen, the primary fibrous ECM constituent, bears load in tension while it buckles under compression. We hypothesized that tumor-generated compressive forces cause collagen remodeling via densification which in turn creates a barrier to convective fluid transport and may play a role in tumor progression and malignancy. To better understand this process, we characterized the structure-function relationship of collagen networks under compression both experimentally and computationally. Here we show that growth of epithelial cancers induces compressive remodeling of the ECM, documented in the literature as a TACS-2 phenotype, which represents a localized densification and tangential alignment of peritumoral collagen. Such compressive remodeling is caused by the unique features of collagen network mechanics, such as fiber buckling and cross-link rupture, and reduces the overall hydraulic permeability of the matrix.