Stiffness heterogeneity-induced double-edged sword behaviors of carcinoma-associated fibroblasts in antitumor therapy
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Carcinoma-associated fibroblasts (CAFs) function as a double-edged sword in tumor progression. However, factors affecting the transition between tumor promotion and inhibition remain to be investigated. Here, we found that the transition was determined by stiffness heterogeneity of the tumor stroma in which tumor cells and CAFs were grown. When tumor cells were grown on a rigid plastic substrate, supernatants from CAFs inhibited the cytotoxic effects of 5- fluorouracil. In contrast, when tumor cells were grown on a soft substrate (5.3 kPa), supernatants from CAFs grown on a soft substrate increased the cytotoxicity of 5-fluorouracil. The diverse effects of CAFs were mediated by mechanotransduction factors, including stroma stiffness-induced cytokine expression in CAFs and signal transduction associated with stress fiber formation of CAFs. Moreover, we found that the cytokine expression in CAFs was regulated by nuclear Yesassociated protein, which changed according to cell stiffness, as characterized by atomic force microscopy. Overall, these findings suggested that modulating the mechanotransduction of the stroma together with CAFs might be important for increasing the efficacy of chemotherapy.
Keywordsstiffness carcinoma-associated fibroblast tumor microenvironment chemotherapy atomic force microscopy
肿瘤相关成纤维细胞(CAFs)在肿瘤的发展过程中发挥着双刃剑的作用, 但导致CAFs促进或者抑制肿瘤生存的关键因素还有待深入 研究. 本文中, 我们发现肿瘤细胞与CAFs所生长的基底的刚度异质性决定了上述两个相反的作用: 在化疗药物5-氟尿嘧啶作用下, 当肿瘤 细胞培养在硬基底(塑料基底)上时, CAFs的条件培养液促进了肿瘤细胞的生存; 当肿瘤细胞与CAFs分别培养在软基底(5.3 kPa)上时, CAFs的条件培养液抑制了肿瘤细胞的生存. 基于原子力显微镜技术、激光共聚焦技术以及细胞因子芯片技术, 我们发现CAFs中力学信 号传导下游的应力纤维分布以及YAP蛋白核迁移与CAFs的双刃剑行为密切相关. 因此调控肿瘤基质的力学传导有助于增强抗肿瘤药物 的疗效.
This work was financially supported by the Postdoctoral Science Foundation Program of Chinese Academy of Medical Sciences & Peking Union Medical College, the National Natural Science Foundation of China (NSFC) (31470905), and National Institutes of Health/National Cancer Institute (NIH/NCI) Grant R21, CA208196.
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