在早期药物发现中解决肿瘤微环境问题：克服耐药性和确定癌症治疗新靶点的策略。

Addressing the tumour microenvironment in early drug discovery: a strategy to overcome drug resistance and identify novel targets for cancer therapy.

机构信息

Discovery Biology, Griffith University, Nathan, QLD, Australia; Cancer Therapeutics CRC, Griffith University, Nathan, QLD, Australia.

Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of Chemical Engineering and Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Melbourne, VIC, Australia; Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.

出版信息

Drug Discov Today. 2021 Mar;26(3):663-676. doi: 10.1016/j.drudis.2020.11.030. Epub 2020 Dec 2.

DOI:10.1016/j.drudis.2020.11.030

PMID:33278601

Abstract

The tumour microenvironment (TME) comprises not only malignant and non-malignant cells, but also the extracellular matrix (ECM), secreted factors, and regulators of cellular functions. In addition to genetic alterations, changes of the biochemical/biophysical properties or cellular composition of the TME have been implicated in drug resistance. Here, we review the composition of the ECM and different elements of the TME contributing to drug resistance, including soluble factors, hypoxia, extracellular acidity, and cell adhesion properties. We discuss selected approaches for modelling the TME, current progress, and their use in low-and high-throughput assays for preclinical studies. Lastly, we summarise the status quo of advanced 3D cancer models compatible with high-throughput screening (HTS), the technical practicalities and challenges.

摘要

肿瘤微环境（TME）不仅包括恶性和非恶性细胞，还包括细胞外基质（ECM）、分泌因子以及细胞功能的调节剂。除了遗传改变外，TME 的生化/生物物理特性或细胞组成的变化也与耐药性有关。在这里，我们回顾了 ECM 的组成以及导致耐药性的 TME 的不同元素，包括可溶性因子、缺氧、细胞外酸度和细胞黏附特性。我们讨论了用于模拟 TME 的选定方法、当前的进展及其在用于临床前研究的高通量筛选（HTS）中的应用。最后，我们总结了与高通量筛选（HTS）兼容的先进 3D 癌症模型的现状，包括技术的实际情况和挑战。