Staunton Jack R, Vieira Wilfred, Fung King Leung, Lake Ross, Devine Alexus, Tanner Kandice
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute (NIH), Bethesda, MD 20892, USA.
Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute (NIH), Bethesda, MD 20892, USA.
Cell Mol Bioeng. 2016 Sep;9(3):398-417. doi: 10.1007/s12195-016-0460-9. Epub 2016 Aug 4.
One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue's mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs. Here we investigate the effects of intrinsic spatial heterogeneities due to fibrillar architecture, pore size and ligand density on the microscale and bulk mechanical properties of the ECM. Type I collagen hydrogels with topologies tuned by polymerization temperature and concentration to mimic physico-chemical properties of a normal tissue and tumor microenvironment were measured by -calibrated ctive icrorheology by ptical rapping revealing significantly different microscale complex shear moduli at Hz-kHz frequencies and two orders of magnitude of strain amplitude that we compared to data from bulk rheology measurements. Access to higher frequencies enabled observation of transitions from elastic to viscous behavior that occur at ~200Hz to 2750Hz, which largely was dependent on tissue architecture well outside the dynamic range of instrument acquisition possible with SAOS bulk rheology. We determined that mouse melanoma tumors and human breast tumors displayed complex moduli ~5-1000 Pa, increasing with frequency and displaying a nonlinear stress-strain response. Thus, we show the feasibility of a mechanical biopsy in efforts to provide a diagnostic tool to aid in the design of therapeutics complementary to those based on standard histopathology.
上皮组织恶性转化的一个标志是微环境中基质成分的调节。特别是，异常的细胞外基质（ECM）重塑和硬化会促进肿瘤生长和存活，并促进转移。I型胶原蛋白是主要的ECM成分之一。它在基质中作为支架蛋白，有助于组织的机械性能，赋予皮肤、肌腱和肺等组织抗张强度和刚性。在这里，我们研究了由于纤维结构、孔径和配体密度引起的内在空间异质性对ECM微观和整体力学性能的影响。通过聚合温度和浓度调节拓扑结构以模拟正常组织和肿瘤微环境的物理化学性质的I型胶原蛋白水凝胶，通过光学陷阱校准的主动微流变学进行测量，发现在Hz-kHz频率和两个数量级的应变幅度下，微观尺度的复剪切模量有显著差异，我们将其与整体流变学测量数据进行了比较。能够获得更高的频率使得观察到在~200Hz至2750Hz发生的从弹性行为到粘性行为的转变成为可能，这在很大程度上取决于组织架构，而这超出了SAOS整体流变学仪器采集的动态范围。我们确定小鼠黑色素瘤肿瘤和人类乳腺肿瘤的复模量约为5-1000 Pa，随频率增加并呈现非线性应力-应变响应。因此，我们展示了机械活检的可行性，旨在提供一种诊断工具，以辅助设计与基于标准组织病理学的治疗方法互补的治疗方案。
