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.

中文翻译：

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乳腺癌-成纤维细胞相互作用的三维模型。

肿瘤微环境是一个复杂的生态位，由细胞外基质蛋白和各种可溶性因子组成的网络中的癌细胞和基质细胞组成。肿瘤微环境的细胞和非细胞成分之间的动态相互作用调节肿瘤的发生和发展。成纤维细胞是最丰富的基质细胞类型，在原发性肿瘤和转移中都与癌细胞动态相互作用。癌细胞激活驻留的成纤维细胞以产生并分泌可溶的信号分子，从而支持癌细胞的增殖，迁移，基质侵袭以及耐药性和肿瘤血管生成。近年来，已经开发出各种形式的三维肿瘤模型来研究肿瘤与基质之间的相互作用，并确定阻断这些相互作用的抗癌药物。当前在肿瘤模型的开发中存在与生理相关，可扩展并且允许方便，按需添加肿瘤微环境的期望成分的技术缺口。在这篇综述中，我们讨论了我们小组的三项研究，这些研究专注于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日益增加的复杂性介绍这些研究。我们将讨论实体肿瘤中活化的成纤维细胞和乳腺癌细胞之间存在的CXCL12-CXCR4趋化因子受体信号转导对模型的验证，突出模型的优点和缺点，并以我们对它们的应用的观点作为结论。按需添加肿瘤微环境的所需成分。在这篇综述中，我们讨论了我们小组的三项研究，这些研究专注于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日益增加的复杂性介绍这些研究。我们将讨论使用实体肿瘤中活化的成纤维细胞和乳腺癌细胞中存在的CXCL12-CXCR4趋化因子-受体信号转导对模型的验证，突出模型的优点和缺点，并以我们对它们的应用的观点作为结论。按需添加肿瘤微环境的所需成分。在这篇综述中，我们讨论了我们小组的三项研究，这些研究专注于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日益增加的复杂性介绍这些研究。我们将讨论使用实体肿瘤中活化的成纤维细胞和乳腺癌细胞中存在的CXCL12-CXCR4趋化因子-受体信号转导对模型的验证，突出模型的优点和缺点，并以我们对它们的应用的观点作为结论。

影响陈述

肿瘤基质在癌症发展为致命的转移性疾病中起着重要作用。现代治疗策略正在考虑针对肿瘤基质以改善癌症患者的预后。开发靶向基质的疗法的当前挑战是缺乏临床前生理肿瘤模型。在癌症研究中广泛使用的动物模型缺乏人类基质，因此不适合用于癌症药物发现的化学化合物筛选。在这篇评论中，我们概述了体外我们已经开发出的三维肿瘤模型来研究癌细胞与基质细胞之间的相互作用。我们以模块化的方式描述从球形模型到复杂的器官型模型的肿瘤模型的发展，并讨论使用正确的生理模型来概括肿瘤基质信号传导的重要性。这些仿生肿瘤模型将有助于理解肿瘤基质信号传导生物学，并提供可扩展的方法来测试和发现抗癌药物。