Short-Term Environmental Conditioning Enhances Tumorigenic Potential of Triple-Negative Breast Cancer Cells
Short-Term Environmental Conditioning Enhances Tumorigenic Potential of Triple-Negative Breast Cancer Cells
复制标题
DOI：
10.18383/j.tom.2019.00019
复制
发表时间：
2019-12-01
期刊：
影响因子：
1.9
通讯作者：
Luker, Gary D.
中科院分区：
文献类型：
--
作者：
Eckley, Samantha S.;Buschhaus, Johanna M.;Luker, Gary D.
肿瘤微环境通过改变营养物质、生长因子和代谢物的可用性，使癌细胞暴露于异质的动态环境中。细胞整合各种输入以产生决定随后表型轨迹的细胞记忆。在这里，我们报告了三阴性乳腺癌细胞短期暴露于生长因子或靶向抑制剂可调节随后的肿瘤起始。我们使用具有不同驱动突变的乳腺癌细胞，将细胞系在各种刺激条件下培养4小时，然后将这些细胞作为肿瘤异种移植物植入，并通过生物发光成像来量化肿瘤进展。在原位模型中，用胎牛血清调节低数量的癌细胞导致肿瘤启动电位、肿瘤体积和肝转移增强。表皮生长因子和mTORC1抑制剂瑞达福莫司对致瘤潜能的影响相似，但相对较低。这些数据表明，短期刺激会增加基于细胞记忆的致瘤表型。在体外实验中，调节方案不能改变癌细胞的增殖或粘附，也不能改变体内多光子显微镜通过Akt和ERK测量的激酶信号，这表明其他机制促进了肿瘤的发生。鉴于肿瘤环境的动态性和小分子药物浓度随时间变化，这项工作强调了肿瘤环境中的可变条件如何影响肿瘤的形成、转移和对治疗的反应。
Tumor microenvironments expose cancer cells to heterogeneous, dynamic environments by shifting availability of nutrients, growth factors, and metabolites. Cells integrate various inputs to generate cellular memory that determines trajectories of subsequent phenotypes. Here we report that short-term exposure of triple-negative breast cancer cells to growth factors or targeted inhibitors regulates subsequent tumor initiation. Using breast cancer cells with different driver mutations, we conditioned cells lines with various stimuli for 4 hours before implanting these cells as tumor xenografts and quantifying tumor progression by means of bioluminescence imaging. In the orthotopic model, conditioning a low number of cancer cells with fetal bovine serum led to enhancement of tumor-initiating potential, tumor volume, and liver metastases. Epidermal growth factor and the mTORC1 inhibitor ridaforolimus produced similar but relatively reduced effects on tumorigenic potential. These data show that a short-term stimulus increases tumorigenic phenotypes based on cellular memory. Conditioning regimens failed to alter proliferation or adhesion of cancer cells in vitro or kinase signaling through Akt and ERK measured by multiphoton microscopy in vivo, suggesting that other mechanisms enhanced tumorigenesis. Given the dynamic nature of the tumor environment and time-varying concentrations of small-molecule drugs, this work highlights how variable conditions in tumor environments shape tumor formation, metastasis, and response to therapy.