类似肿瘤微环境的条件会改变胰腺癌细胞的新陈代谢和行为

IF 5 2区 生物学 Q2 CELL BIOLOGY
Georgina Louise Gardner, Jeffrey Alan Stuart
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引用次数: 0

摘要

肿瘤微环境复杂多变,其特点是血管不畅、营养供应有限、缺氧和酸性 pH 值。这种环境在推动癌症进展方面起着至关重要的作用。然而,用于体外研究癌细胞生物学的标准细胞培养条件无法复制肿瘤的体内环境。最近,与人体血浆非常相似的 "生理性 "细胞培养基(如 Plasmax、HPLM)被开发出来,同时更频繁地采用生理性氧气条件(1-8% O2)。尽管如此,肿瘤特异性培养条件仍需进一步完善。在本研究中,我们介绍了基于小鼠胰腺导管腺癌(PDAC)肿瘤间质开发的肿瘤微环境培养基(TMEM)。我们利用 RNA 序列分析表明,与血浆样条件(小鼠血浆培养基,pH 7.4,5% O2)相比,在肿瘤样条件(TMEM,pH 7.0,1.5% O2)下培养的小鼠 PDAC 细胞(KPCY)在基因表达方面表现出很大差异。具体来说,与细胞迁移、生物合成、血管生成和上皮到间质转化相关的基因和通路的表达发生了改变,这表明类肿瘤条件促进了转移表型和代谢重塑。利用功能测试来验证 RNA-seq 数据,我们证实了在 1.5%O2/TMEM 条件下,尽管细胞增殖减少,但细胞的运动性却增加了。此外,通过测量葡萄糖摄取/乳酸生成和线粒体呼吸,我们还发现了向糖酵解代谢转变的特征。总之,这些研究结果表明,在 1.5%O2/TMEM 中生长会以与癌症生物学相关的方式改变几种生物反应,并更接近于在培养物中模拟标志性癌症表型。这凸显了在标准癌症研究中建立类似肿瘤微环境条件的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumor microenvironment-like conditions alter pancreatic cancer cell metabolism and behavior.

The tumor microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumors. Recently, "physiological" cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1%-8% O2). Nonetheless, further refinement of tumor-specific culture conditions may be needed. In this study, we describe the development of a tumor microenvironment medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumor interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumor-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared with plasma-like conditions (mouse plasma medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumor-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5% O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5% O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumor microenvironment-like conditions in standard cancer research. NEW & NOTEWORTHY Standard cell culture conditions do not replicate the complex tumor microenvironment experienced by cells in vivo. Although currently available plasma-like media are superior to traditional supraphysiological media, they fail to model tumor-like conditions. Using RNA-seq analysis and functional metabolic and migratory assays, we show that tumor microenvironment medium (TMEM), used with representative tumor hypoxia, better models cancerous phenotypes in culture. This emphasizes the critical importance of accurately modeling the tumor microenvironment in cancer research.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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