Abstract
Cancer is a complex disease and it is now clear that not only epithelial tumor cells play a role in carcinogenesis. The tumor microenvironment is composed of non-stromal cells, including endothelial cells, adipocytes, immune and nerve cells, and a stromal compartment composed of extracellular matrix, cancer-associated fibroblasts and mesenchymal cells. Tumorigenesis is a dynamic process with constant interactions occurring between the tumor cells and their surroundings. Even though all connections have not yet been discovered, it is now known that crosstalk between actors of the microenvironment drives cancer progression. Taking into account this complexity, it is important to develop relevant models to study carcinogenesis. Conventional 2D culture models fail to represent the entire tumor microenvironment properly and the use of animal models should be decreased with respect to the 3Rs rule. To this aim, in vitro organotypic models have been significantly developed these past few years. These models have different levels of complexity and allow the study of tumor cells alone or in interaction with the microenvironment actors during the multiple stages of carcinogenesis. This review depicts recent insights into organotypic modeling of the tumor and its microenvironment all throughout cancer progression. It offers an overview of the crosstalk between epithelial cancer cells and their microenvironment during the different phases of carcinogenesis, from the early cell autonomous events to the late metastatic stages. The advantages of 3D over classical 2D or in vivo models are presented as well as the most promising organotypic models. A particular focus is made on organotypic models used for studying cancer progression, from the less complex spheroids to the more sophisticated body-on-a-chip. Last but not least, we address the potential benefits of these models in personalized medicine which is undoubtedly a domain paving the path to new hopes in terms of cancer care and cure.
Highlights
Carcinogenesis is a complex multistep process, often described as somatic evolution
Carcinogenesis is the fruit of the interplay between multiple cell autonomous and nonautonomous processes, defined as “Hallmarks of cancer,” that include genomic instability, proliferative abnormality, stromal reprogramming, angiogenesis, immune suppression and tumor sustaining inflammation
We summarize the recently described interactions between the tumor microenvironment (TME) actors and the tumor cells in the cancer progression cascade
Summary
Carcinogenesis is a complex multistep process, often described as somatic evolution. Typically, cancer progression involves the accumulation of genetic and/or epigenetic somatic modifications and exposition to environmental factors. Understanding the key aspects of tumoral progression is of utmost importance for the development of novel successful anticancer strategies Organotypic modeling of these aspects alongside the interactions between the different actors of the TME would allow a better comprehension of the mechanisms that mediate tumoral progression and a first solid step toward preclinical drug screening in physiologically relevant situations. Tumor Growth in situ—Interactions of Cancer Cells With the TME Elements Many in vitro organotypic models have been used to study tumor initiation and growth and to identify how parenchymal cells (endothelial, epithelial, immune, nerve and stromal cells) and components (ECM, secreted factors) of the TME influence the growth in situ of different cancer types. Invasion Breast cancer (Avgustinova et al, 2016) Colon cancer (Nam et al, 2018) Colorectal cancer (Libanje et al, 2019)
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