基于大量营养素和微量营养素的多重应激条件可调节体外乳腺癌球状体的肿瘤发生和侵袭性行为。
Macro- and micro-nutrient-based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids.
作者信息
Gayan Sukanya, Teli Abhishek, Nair Anish, Tomar Geetanjali, Dey Tuli
机构信息
Institute of Bioinformatics & Biotechnology, Savitribai Phule Pune University, Pune, India.
出版信息
In Vitro Model. 2021 Nov 25;1(1):85-101. doi: 10.1007/s44164-021-00006-5. eCollection 2022 Feb.
PURPOSE
The aggressive nature of a tumor is presumably its inherent one, but different environmental cues can manipulate it in many ways. In this context, the influence of metabolic stresses on tumor behavior needs to be analyzed to understand their far-reaching implications on tumor aggression and dormancy. This work investigates different facets of the tumor, such as tumorigenic capacity, tumor phenotype, and migration, under multiple metabolic stress conditions.
METHODS
Non-invasive and invasive multicellular spheroids (MTS) were created and subjected to multiple stress conditions, namely glucose, amino acid, and oxygen deprivation. Altered behavior of the MTS has been evaluated in the context of in vitro tumorigenesis, spheroid formation capacity, phenotype, mRNA profile, migration, and recruitment of mesenchymal stem cells.
RESULTS
The metabolic stress conditions were observed to negatively impact the in vitro tumorigenesis and spheroid formation process of invasive and non-invasive breast cancer cells. While the stress seemingly influences the growth and phenotype of spheroids, it does not alter the organization of sub-cellular entities significantly. Metabolic stress conditions impact the transcriptomic landscape of hypoxic, angiogenic, ECM deformation, glycolysis shift, and protein starvation-related gene clusters. MTSs do not adhere or migrate under stress, but they exhibit different modalities of migration when rescued. Invasive spheroids, after the rescue, exhibit increased aggressiveness. Furthermore, stressed spheroid was observed to control the migration and recruitment of mesenchymal stem cells.
CONCLUSION
Multiplex metabolic stresses could control the tumorigenesis while influencing the physiology of invasive and non-invasive breast cancer spheroids along with their migration pattern and tumor-stromal crosstalk.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s44164-021-00006-5.
目的
肿瘤的侵袭性可能是其固有的特性，但不同的环境线索可以通过多种方式对其进行调控。在此背景下，需要分析代谢应激对肿瘤行为的影响，以了解其对肿瘤侵袭和休眠的深远意义。本研究探讨了在多种代谢应激条件下肿瘤的不同方面，如致瘤能力、肿瘤表型和迁移能力。
方法
创建了非侵袭性和侵袭性多细胞球体（MTS），并使其处于多种应激条件下，即葡萄糖、氨基酸和氧剥夺。在体外肿瘤发生、球体形成能力、表型、mRNA谱、迁移以及间充质干细胞的募集等方面，评估了MTS行为的改变。
结果
观察到代谢应激条件对侵袭性和非侵袭性乳腺癌细胞的体外肿瘤发生和球体形成过程产生负面影响。虽然应激似乎会影响球体的生长和表型，但它不会显著改变亚细胞实体的组织。代谢应激条件会影响缺氧、血管生成、细胞外基质变形、糖酵解转变和蛋白质饥饿相关基因簇的转录组格局。MTS在应激条件下不粘附或迁移，但在恢复后表现出不同的迁移方式。侵袭性球体在恢复后表现出更高的侵袭性。此外，观察到应激球体能够控制间充质干细胞的迁移和募集。
结论
多重代谢应激可以控制肿瘤发生，同时影响侵袭性和非侵袭性乳腺癌球体的生理功能及其迁移模式和肿瘤-基质相互作用。
补充信息
在线版本包含可在10.1007/s44164-021-00006-5获取的补充材料。
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