辐照哺乳动物球状体阐明巨噬细胞介导的乳腺癌症复发的机制。

IF 2.3 4区 医学 Q3 BIOPHYSICS Cellular and molecular bioengineering Pub Date : 2023-08-01 DOI:10.1007/s12195-023-00775-x
Benjamin C Hacker, Erica J Lin, Dana C Herman, Alyssa M Questell, Shannon E Martello, Rebecca J Hedges, Anesha J Walker, Marjan Rafat
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引用次数: 0

摘要

简介:虽然大多数癌症三阴性患者接受放射治疗以改善预后,但仍有相当一部分患者出现复发。在临床前模型中,巨噬细胞对辐射损伤部位的浸润已被证明可促进癌症复发。然而,导致复发的机制尚不清楚。在这里,我们开发了一个新的球体模型来评估巨噬细胞介导的肿瘤细胞募集。方法:通过流式细胞术对照射后的小鼠乳腺组织中浸润巨噬细胞的表型进行表征。然后,我们利用体内巨噬细胞浸润结果,用原代成纤维细胞、巨噬细胞和4T1小鼠乳腺癌细胞构建了辐射损伤的球体模型,为我们的模型提供信息。我们分析了4T1与促愈合M2:促炎M1巨噬细胞的生物学相关比例共同培养时对球体的浸润。最后,我们量化了与有利于肿瘤细胞浸润的条件相关的白细胞介素6(IL-6)分泌,并在体外和体内直接评估了IL-6对肿瘤细胞侵袭性的影响。结果:在我们的体内模型中,我们观察到照射后10天小鼠乳腺中M2巨噬细胞显著增加。我们确定,在M2:M1巨噬细胞比例为2:1的情况下,肿瘤细胞向辐照球体的运动性增强。我们还测量了体内和模型中照射后IL-6分泌的显著增加。这种分泌增加了肿瘤细胞的侵袭性,并且通过中和IL-6减轻了肿瘤细胞侵袭和募集。结论:我们的工作表明,浸润性巨噬细胞和受损基质细胞之间的相互作用通过IL-6信号促进了乳腺癌症的复发。补充信息:在线版本包含补充材料,请访问10.1007/s12195-023-00775-x。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Irradiated Mammary Spheroids Elucidate Mechanisms of Macrophage-Mediated Breast Cancer Recurrence.

Introduction: While most patients with triple negative breast cancer receive radiation therapy to improve outcomes, a significant subset of patients continue to experience recurrence. Macrophage infiltration into radiation-damaged sites has been shown to promote breast cancer recurrence in pre-clinical models. However, the mechanisms that drive recurrence are unknown. Here, we developed a novel spheroid model to evaluate macrophage-mediated tumor cell recruitment.

Methods: We characterized infiltrating macrophage phenotypes into irradiated mouse mammary tissue via flow cytometry. We then engineered a spheroid model of radiation damage with primary fibroblasts, macrophages, and 4T1 mouse mammary carcinoma cells using in vivo macrophage infiltration results to inform our model. We analyzed 4T1 infiltration into spheroids when co-cultured with biologically relevant ratios of pro-healing M2:pro-inflammatory M1 macrophages. Finally, we quantified interleukin 6 (IL-6) secretion associated with conditions favorable to tumor cell infiltration, and we directly evaluated the impact of IL-6 on tumor cell invasiveness in vitro and in vivo.

Results: In our in vivo model, we observed a significant increase in M2 macrophages in mouse mammary glands 10 days post-irradiation. We determined that tumor cell motility toward irradiated spheroids was enhanced in the presence of a 2:1 ratio of M2:M1 macrophages. We also measured a significant increase in IL-6 secretion after irradiation both in vivo and in our model. This secretion increased tumor cell invasiveness, and tumor cell invasion and recruitment were mitigated by neutralizing IL-6.

Conclusions: Our work suggests that interactions between infiltrating macrophages and damaged stromal cells facilitate breast cancer recurrence through IL-6 signaling.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-023-00775-x.

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来源期刊
CiteScore
5.60
自引率
3.60%
发文量
30
审稿时长
>12 weeks
期刊介绍: The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.
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