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具有血管再循环的免疫浸润癌球体模型揭示了时间依赖性和组织特异性巨噬细胞募集。

Immune-Infiltrated Cancer Spheroid Model with Vascular Recirculation Reveals Temporally Dependent and Tissue-Specific Macrophage Recruitment.

作者信息

Zhang Feng, Jozani Kimia Asadi, Chakravarty Anushree, Lin Dawn, Hollinger Andrew, Rajasekar Shravanthi, Zhang Boyang

机构信息

School of Biomedical Engineering, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.

Department of Chemical Engineering, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.

出版信息

Adv Healthc Mater. 2025 Apr;14(9):e2402946. doi: 10.1002/adhm.202402946. Epub 2025 Feb 17.

Abstract

Immune cell infiltration in tumors has been reported to influence tumor progression and clinical outcomes. Considerable efforts have been made to understand interactions between tumors and the immune system. However, current models are either not comprehensive or limited to short-term studies. Recognizing thedynamic and long-term nature of tumor-immune interactions, an immune-infiltrated cancer spheroid model is developed by continuously perfusing and recirculating immune cells with gravity-driven flow through a tubular blood vessel adjacent to a cancer spheroid. Fibroblasts and pericytes are embedded in the gel matrix to support endothelial cells and enhance the vascular barrier. With continuous monocyte recirculation, monocyte adhesion, transendothelium migration, differentiation, and macrophage recruitment into breast carcinoma and hepatoma spheroids is successfully demonstrated over a week. The macrophage recruitment process is temporally dependent and tissue-specific, leading to the formation of cancer-macrophage heterospheroids. Elevated secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), which regulates monocyte recruitment and macrophage activation, is observed in the breast carcinoma model. Increased levels of Interleukin 6 (IL-6) and Interleukin 8 (IL-8) are detected, indicating a pro-inflammatory environment associated with tumor progression and metastasis. This platform provides a valuable framework for investigating immune cell infiltration and differentiation within the tumor microenvironment, supporting the advancement of cancer immunotherapies.

摘要

据报道,肿瘤中的免疫细胞浸润会影响肿瘤进展和临床结果。人们已经付出了巨大努力来了解肿瘤与免疫系统之间的相互作用。然而,目前的模型要么不够全面,要么仅限于短期研究。认识到肿瘤-免疫相互作用的动态性和长期性,通过重力驱动的流动使免疫细胞持续灌注和循环,流经与癌球相邻的管状血管,从而建立了免疫浸润癌球模型。成纤维细胞和周细胞嵌入凝胶基质中,以支持内皮细胞并增强血管屏障。通过持续的单核细胞再循环,成功地证明了单核细胞在一周内对乳腺癌和肝癌球的黏附、跨内皮迁移、分化以及巨噬细胞募集。巨噬细胞募集过程具有时间依赖性和组织特异性,导致癌-巨噬细胞异质球的形成。在乳腺癌模型中观察到调节单核细胞募集和巨噬细胞激活的粒细胞-巨噬细胞集落刺激因子(GM-CSF)分泌增加。检测到白细胞介素6(IL-6)和白细胞介素8(IL-8)水平升高,表明存在与肿瘤进展和转移相关的促炎环境。该平台为研究肿瘤微环境中的免疫细胞浸润和分化提供了一个有价值的框架,有助于癌症免疫疗法的发展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d2f/11973944/2c5335891f92/ADHM-14-0-g001.jpg

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