2015-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/666993Cancer is a major health concern of worldwide significance. Hepatocellular carcinoma (HCC) is a common cancer and the leading cancer death in Taiwan. Anti-angiogenesis therapy is the mainstream treatment for patients with advanced HCC. High extracellular matrix (ECM) stiffness hinders drug penetration into tumor and leads to treatment failure. Increasing evidence suggests that the magnitude of tumor-specific T cell immune response to HCC may impact on the clinical evolution of the disease and on survival. Several studies have shown that greater tumor antigens-specific CD8+ T cell responses in HCC patients correlate with favorable prognosis. Therefore, to enhance drug penetration and to induce abundant tumor-infiltrating T cells bear therapeutic potentials. ECM in tumor milieu not only maintains tissue architecture and biochemical functions of the cells but also paves the way for tumor cells with regard to its biophysical properties. High ECM stiffness is evident in HCC microenvironment and more advanced stage correlates with the higher matrix stiffness. ECM stiffness expedites tumor cell migration and enhances tumor cell invasion by driving focal adhesion assembly. Moreover, investigators have shown that cancer cells preferentially invade along stiff collagen fibers into the adjacent stroma. ECM stiffness also promotes angiogenesis by the physical property. These findings indicate that ECM stiffness induced by tumor-ECM interaction can further trigger biochemical and physical changes in the tissue that can influence the behavior of tumor cells, and as a result, promotes tumor progression. In addition, evidence has shown that T cells motility was impeded by dense fiber surrounding the tumor. Whether the tumor-targeting and -killing capabilities are regulated by ECM stiffness remains unclear. Cumulated evidence has shown that anti-angiogenesis therapy results in ECM remodeling. Drug penetration and T cells infiltration are also enhanced during therapy. It is intriguing to answer whether the therapeutic effect of anti-angiogenesis therapy act through lowering ECM stiffness. The shear wave elasticity imaging (SWEI) is a newly developed technique for quantitative measurement of elasticity based on propagating shear wave in samples. The sample with higher stiffness reveals the faster shear wave speed. The ECM stiffness is determined by quantifying the tissue elasticity. The advent of the SWEI allows us to real time monitor the dynamics of ECM stiffness noninvasively for a longer time. The aims of the study are (1) to establish 3D culture system for HCC-ECM-T cells interaction and further investigate the impact on T cells migration and chemotaxis by ECM stiffness alteration; (2) to explore the interaction between T cell migration and tumor-killing capability and ECM stiffness and further to incorporate novel shear wave computed tomography and membranous elastic culture platform; (3) to screen the anti-HCC drug candidates that are mediated through regulating ECM stiffness and improving tumor-infiltrating and killing capabilities of T cells.ECM stiffnessshear wave elasticity imaging (SWEI)T cellHepatocellular carcinoma (HCC)anti-angiogenesis