Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Taiwan.
Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Colloids Surf B Biointerfaces. 2020 Jun;190:110969. doi: 10.1016/j.colsurfb.2020.110969. Epub 2020 Mar 18.
Colorectal cancer (CRC) progression is highly associated with desmoplasia. Aerobic glycolysis is another distinct feature that appears during the CRC phase of the adenoma-carcinoma sequence. However, the interconnections between the desmoplastic microenvironment and metabolic reprogramming remain largely unexplored. In our in vitro model, we investigated the compounding influences of hypoxia and substrate stiffness, two critical physical features of desmoplasia, on the CRC metabolic shift by using engineered polyacrylamide gels. Unexpectedly, we found that compared to cells on a soft gel (approximately 1.5 kPa, normal tissue), cells on a stiff gel (approximately 8.7 kPa, desmoplastic tissue) exhibited reduced glucose uptake and glycolysis under both normoxia and hypoxia. In addition, the increasing substrate stiffness activated focal adhesion kinase (FAK)/phosphoinositide 3-kinase signaling, but not the mitochondrial respiratory inhibitor HIF-1α. However, the presence of aldolase B (ALDOB) reversed the CRC metabolic response to mechanosignaling; enhanced glucose uptake (approximately 1.5-fold) and aerobic glycolysis (approximately 2- to 3--fold) with significantly decreased mitochondrial oxidative phosphorylation. ALDOB also changed the response of CRC traction force, which is related to tumor metastasis, under hypoxia/normoxia. In summary, our data suggest a counter influence of hypoxia and substrate stiffness on glucose uptake, and ALDOB upregulation can reverse this, which drives hypoxia and stiff substrate to enhance the CRC aerobic glycolysis synergistically. The results not only highlight the potential impacts on metabolic reprogramming led by physical alterations in the microenvironment, but also extend our understanding of the essential role of ALDOB in CRC progression from a biophysical perspective.
结直肠癌（CRC）的进展与间质密切相关。有氧糖酵解是腺瘤-癌序列中 CRC 阶段的另一个明显特征。然而，间质微环境和代谢重编程之间的相互联系在很大程度上仍未得到探索。在我们的体外模型中，我们使用工程聚丙烯酰胺凝胶研究了缺氧和基质硬度这两种间质的关键物理特征对 CRC 代谢转变的复合影响。出乎意料的是，我们发现与在软凝胶（约 1.5kPa，正常组织）上的细胞相比，在硬凝胶（约 8.7kPa，间质组织）上的细胞在常氧和缺氧条件下葡萄糖摄取和糖酵解减少。此外，基质硬度的增加激活了黏着斑激酶（FAK）/磷酸肌醇 3-激酶信号通路，但没有激活线粒体呼吸抑制剂 HIF-1α。然而，醛缩酶 B（ALDOB）的存在逆转了 CRC 对机械信号的代谢反应；增强葡萄糖摄取（约 1.5 倍）和有氧糖酵解（约 2-3 倍），同时显著降低线粒体氧化磷酸化。ALDOB 还改变了 CRC 牵引力的反应，这与肿瘤转移有关，无论在缺氧/常氧条件下。总之，我们的数据表明缺氧和基质硬度对葡萄糖摄取有相反的影响，而 ALDOB 的上调可以逆转这种影响，从而导致缺氧和硬基质协同增强 CRC 的有氧糖酵解。研究结果不仅突出了微环境物理改变对代谢重编程的潜在影响，而且从生物物理的角度扩展了我们对 ALDOB 在 CRC 进展中的重要作用的理解。
