Du Wenqiang, Novin Ashkan, Liu Yamin, Afzal Junaid, Liu Shaofei, Suhail Yasir
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, USA.
Department of Cardiology, University of California San Francisco, San Francisco, CA, USA.
Mechanobiol Med. 2024 Sep;2(3). doi: 10.1016/j.mbm.2024.100070. Epub 2024 Apr 27.
As local regions in the tumor outstrip their oxygen supply, hypoxia can develop, affecting not only the cancer cells, but also other cells in the microenvironment, including cancer associated fibroblasts (CAFs). Hypoxia is also not necessarily stable over time, and can fluctuate or oscillate. Hypoxia Inducible Factor-1 is the master regulator of cellular response to hypoxia, and can also exhibit oscillations in its activity. To understand how stable, and fluctuating hypoxia influence breast CAFs, we measured changes in gene expression in CAFs in normoxia, hypoxia, and oscillatory hypoxia, as well as measured change in their capacity to resist, or assist breast cancer invasion. We show that hypoxia has a profound effect on breast CAFs causing activation of key pathways associated with fibroblast activation, but reduce myofibroblast activation and traction force generation. We also found that oscillatory hypoxia, while expectedly resulted in a "sub-hypoxic" response in gene expression, it resulted in specific activation of pathways associated with actin polymerization and actomyosin maturation. Using traction force microscopy, and a nanopatterned stromal invasion assay, we show that oscillatory hypoxia increases contractile force generation vs stable hypoxia, and increases heterogeneity in force generation response, while also additively enhancing invasibility of CAFs to MDA-MB-231 invasion. Our data show that stable and unstable hypoxia can regulate many mechnobiological characteristics of CAFs, and can contribute to transformation of CAFs to assist cancer dissemination and onset of metastasis.
随着肿瘤局部区域的氧供应不足，会出现缺氧情况，这不仅会影响癌细胞，还会影响微环境中的其他细胞，包括癌症相关成纤维细胞（CAF）。缺氧情况也不一定随时间保持稳定，可能会波动或振荡。缺氧诱导因子-1是细胞对缺氧反应的主要调节因子，其活性也可能出现振荡。为了了解稳定和波动的缺氧如何影响乳腺CAF，我们测量了常氧、缺氧和振荡性缺氧条件下CAF的基因表达变化，以及它们抵抗或协助乳腺癌侵袭能力的变化。我们发现缺氧对乳腺CAF有深远影响，会导致与成纤维细胞活化相关的关键通路激活，但会减少肌成纤维细胞活化和牵引力产生。我们还发现，振荡性缺氧虽然在基因表达上预期会导致“亚缺氧”反应，但它会导致与肌动蛋白聚合和肌动球蛋白成熟相关的通路特异性激活。使用牵引力显微镜和纳米图案化基质侵袭试验，我们表明振荡性缺氧与稳定缺氧相比会增加收缩力产生，并增加力产生反应的异质性，同时还会累加增强CAF对MDA-MB-231侵袭的侵袭性。我们的数据表明，稳定和不稳定的缺氧可以调节CAF的许多机械生物学特性，并有助于CAF转变以协助癌症扩散和转移的发生。
