Three-dimensional models of breast cancer–fibroblasts interactions
Three-dimensional models of breast cancer–fibroblasts interactions
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DOI：
10.1177/1535370220917366
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发表时间：
2020-04
影响因子：
3.2
通讯作者：
Sunil Singh;Sydnie Tran;Justin Putman;Hossein Tavana
中科院分区：
文献类型：
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作者：
Sunil Singh;Sydnie Tran;Justin Putman;Hossein Tavana
肿瘤微环境是由癌细胞和基质细胞组成的细胞外基质蛋白和多种可溶性因子网络的复杂生态位。肿瘤微环境中细胞和非细胞组分之间的动态相互作用调节着肿瘤的发生和发展。成纤维细胞是最丰富的间质细胞类型，在原发性肿瘤和转移性肿瘤中与癌细胞动态相互作用。癌细胞激活常驻成纤维细胞产生和分泌可溶性信号分子，支持癌细胞增殖、迁移、基质侵袭、耐药和肿瘤血管生成。近年来，各种形式的三维肿瘤模型已经被开发出来，以研究肿瘤-基质相互作用，并确定阻断这些相互作用的抗癌药物。目前，在开发与生理相关、可扩展并允许方便、按需添加肿瘤微环境所需成分的肿瘤模型方面存在技术差距。在这篇综述中，我们讨论了我们小组的三个研究，重点是开发生物工程模型来研究肿瘤基质信号传导。我们将按时间顺序并根据其日益增加的复杂性来介绍这些研究。我们将讨论使用CXCL12-CXCR4趋化因子受体信号在实体瘤中活化的成纤维细胞和乳腺癌细胞中存在的模型的验证，强调模型的优点和缺点，并总结我们对其应用的看法。肿瘤间质在癌症发展为致命的转移性疾病中起重要作用。现代治疗策略正在考虑靶向肿瘤基质以改善癌症患者的预后。目前开发基质靶向治疗的一个挑战是缺乏临床前生理性肿瘤模型。癌症研究中广泛使用的动物模型缺乏人类基质，不适合用于癌症药物发现的化合物筛选。在这篇综述中，我们概述了我们开发的体外三维肿瘤模型，用于研究癌细胞和基质细胞之间的相互作用。我们以模块化的方式描述了肿瘤模型的发展，从球体模型到复杂的器官型模型，并讨论了使用正确的生理模型来概括肿瘤间质信号传导的重要性。这些仿生肿瘤模型将促进对肿瘤间质信号生物学的理解，并为癌症药物的测试和发现提供可扩展的方法。
Tumor microenvironment is a complex niche consisting of cancer cells and stromal cells in a network of extracellular matrix proteins and various soluble factors. Dynamic interactions among cellular and non-cellular components of the tumor microenvironment regulate tumor initiation and progression. Fibroblasts are the most abundant stromal cell type and dynamically interact with cancer cells both in primary tumors and in metastases. Cancer cells activate resident fibroblasts to produce and secrete soluble signaling molecules that support proliferation, migration, matrix invasion, and drug resistance of cancer cell and tumor angiogenesis. In recent years, various forms of three-dimensional tumor models have been developed to study tumor–stromal interactions and to identify anti-cancer drugs that block these interactions. There is currently a technological gap in development of tumor models that are physiologically relevant, scalable, and allow convenient, on-demand addition of desired components of the tumor microenvironment. In this review, we discuss three studies from our group that focus on developing bioengineered models to study tumor-stromal signaling. We will present these studies chronologically and based on their increasing complexity. We will discuss the validation of the models using a CXCL12-CXCR4 chemokine-receptor signaling present among activated fibroblasts and breast cancer cells in solid tumors, highlight the advantages and shortcomings of the models, and conclude with our perspectives on their applications. Impact statement Tumor stroma plays an important role in progression of cancers to a fatal metastatic disease. Modern treatment strategies are considering targeting tumor stroma to improve outcomes for cancer patients. A current challenge to develop stroma-targeting therapeutics is the lack of preclinical physiologic tumor models. Animal models widely used in cancer research lack human stroma and are not amenable to screening of chemical compounds for cancer drug discovery. In this review, we outline in vitro three-dimensional tumor models that we have developed to study the interactions among cancer cells and stromal cells. We describe development of the tumor models in a modular fashion, from a spheroid model to a sophisticated organotypic model, and discuss the importance of using correct physiologic models to recapitulate tumor-stromal signaling. These biomimetic tumor models will facilitate understanding of tumor-stromal signaling biology and provide a scalable approach for testing and discovery of cancer drugs.