A 3D View of Colorectal Cancer Models in Predicting Therapeutic Responses and Resistance

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.

Section: Spheroidsmentioning

confidence: 99%

3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment

Franchi-Mendes

Eduardo

Domenici

et al. 2021

“…The stroma or tumor microenvironment (TME) is largely responsible for tumor heterogeneity and plasticity and may contribute to CRC progression by means of reciprocal interactions with carcinoma cells [ 147 ]. Now, heterotypic structures that are more complex than PDOs rely on the transient co-culture of PDOs with stromal cell types that increase cell−cell interactions, or the use of short-lived tissue or tumor explants, which cannot be considered PDOs [ 148 , 149 , 150 ]. Therefore, many studies are trying to develop a new generation of heterotypic PDOs via co-culture with non-epithelial stromal cells such as cancer-associated fibroblasts (CAF), enteric nervous system, endothelial and immune cells.…”

Section: Organoid Limitations and New 3d Modelsmentioning

confidence: 99%

Organoids and Colorectal Cancer

Barbáchano

Fernández‐Barral

Bustamante-Madrid

et al. 2021

Organoids were first established as a three-dimensional cell culture system from mouse small intestine. Subsequent development has made organoids a key system to study many human physiological and pathological processes that affect a variety of tissues and organs. In particular, organoids are becoming very useful tools to dissect colorectal cancer (CRC) by allowing the circumvention of classical problems and limitations, such as the impossibility of long-term culture of normal intestinal epithelial cells and the lack of good animal models for CRC. In this review, we describe the features and current knowledge of intestinal organoids and how they are largely contributing to our better understanding of intestinal cell biology and CRC genetics. Moreover, recent data show that organoids are appropriate systems for antitumoral drug testing and for the personalized treatment of CRC patients.

“…Several reports have considered CRC spheroids as a good tool to study in a 3D system the features of tumor cells and their interactions with immune cells [ 125 , 126 , 127 , 136 , 137 , 138 ]. The interest on CRC is related to the strong clinical relevance of this tumor and the impact of immune infiltration on patient prognosis [ 139 , 140 , 141 ].…”

Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning

confidence: 99%

Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

Poggi

Villa

Fernadez

et al. 2021

Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.