Abstract
Simple SummaryThe tumour microenvironment is composed of multiple non-cancerous cells that communicate with the tumour cells, influencing their behaviour and impacting the progression of the disease and the response to therapy. To better understand the disease and try to predict the response of patients to therapy, there has been an effort to develop experimental strategies that could represent this complex human tumour microenvironment in a dish (in vitro). In this review, we describe the importance of each cell type and review the in vitro approaches recently developed for cultivating together the different cell types (co-culture) in a three-dimensional configuration to better represent the architecture of the tumour and cell interactions (3D models). We describe and compare the different studies and outline perspectives on the 3D modelling strategies and their potential impact in cancer research and anticancer drug discovery.The tumour microenvironment plays a critical role in tumour progression and drug resistance processes. Non-malignant cell players, such as fibroblasts, endothelial cells, immune cells and others, interact with each other and with the tumour cells, shaping the disease. Though the role of each cell type and cell communication mechanisms have been progressively studied, the complexity of this cellular network and its role in disease mechanism and therapeutic response are still being unveiled. Animal models have been mainly used, as they can represent systemic interactions and conditions, though they face recognized limitations in translational potential due to interspecies differences. In vitro 3D cancer models can surpass these limitations, by incorporating human cells, including patient-derived ones, and allowing a range of experimental designs with precise control of each tumour microenvironment element. We summarize the role of each tumour microenvironment component and review studies proposing 3D co-culture strategies of tumour cells and non-malignant cell components. Moreover, we discuss the potential of these modelling approaches to uncover potential therapeutic targets in the tumour microenvironment and assess therapeutic efficacy, current bottlenecks and perspectives.
Highlights
Recapitulative disease models are important experimental tools, in the oncology field in which new drugs fail in clinical trials more than in any other area [1]
This disruptive effect was mostly abrogated with inhibitors of matrix metalloproteinase (MMP) or hepatocyte growth factor (HGF) receptor (c-MET), in accordance with other studies reporting the contribution of cancerassociated fibroblasts (CAF)-derived mediators to tumour progression [130,131]
In vitro models based on 3D co-culture of tumour cells and CAF lead, in general, to a more invasive tumour cell phenotype, signs of epithelial to mesenchymal transition (EMT) and higher drug resistance, which are features that can resemble the tumour progression in vivo
Summary
Recapitulative disease models are important experimental tools, in the oncology field in which new drugs fail in clinical trials more than in any other area [1]. The cellular elements of the TME may vary within different cancers and the ECM and other non-cellular components. In addition to direct cell–cell contacts between tumour cells and the different TME cell types and amongst the latter, the main TME mediators are soluble factors (such as cytokines, chemokines, proteases, and other enzymes involved in remodelling the ECM) and exosomes. MMP are proteolytic enzymes that mediate matrix degradation, facilitate migration and invasion, promote angiogenesis and release ECM trapped growth factors [27,28,29]. LOX enzymes are responsible for collagen crosslinking, increasing matrix stiffness and are associated with enhanced tumour growth and progression [30]. We address the strategies developed to model the TME, with an emphasis on in vitro 3D co-culture approaches and their relevance for oncology research and anticancer drug discovery. Advantages and caveats of 3D TME models will be discussed, as well as current needs and future perspectives
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