Abstract
Simple SummaryColorectal cancer is an increasingly prevalent disease that accounts for substantial mortality and morbidity and is responsible for an impaired quality of life. This scenario highlights the urgent need to better understand the biological mechanisms underlying colorectal cancer onset, progression and spread to improve diagnosis and establish tailored therapeutic strategies. Therefore, understanding tumor microenvironment dynamics could be crucial, since it is where the tumorigenic process begins and evolves under the heavy influence of the complex crosstalk between all elements: the cellular component (cancer cells and the non-malignant stromal cells), the non-cellular component (extracellular matrix) and the interstitial fluids. Bioengineered models that can accurately mimic the tumor microenvironment are the golden key to comprehending disease biology. Therefore, the focus of this review addresses the advanced 3D-based models of the decellularized extracellular matrix as high-throughput strategies in colorectal cancer research that potentially fill some of the gaps between in vitro two-dimensional and in vivo models.More than a physical structure providing support to tissues, the extracellular matrix (ECM) is a complex and dynamic network of macromolecules that modulates the behavior of both cancer cells and associated stromal cells of the tumor microenvironment (TME). Over the last few years, several efforts have been made to develop new models that accurately mimic the interconnections within the TME and specifically the biomechanical and biomolecular complexity of the tumor ECM. Particularly in colorectal cancer, the ECM is highly remodeled and disorganized and constitutes a key component that affects cancer hallmarks, such as cell differentiation, proliferation, angiogenesis, invasion and metastasis. Therefore, several scaffolds produced from natural and/or synthetic polymers and ceramics have been used in 3D biomimetic strategies for colorectal cancer research. Nevertheless, decellularized ECM from colorectal tumors is a unique model that offers the maintenance of native ECM architecture and molecular composition. This review will focus on innovative and advanced 3D-based models of decellularized ECM as high-throughput strategies in colorectal cancer research that potentially fill some of the gaps between in vitro 2D and in vivo models. Our aim is to highlight the need for strategies that accurately mimic the TME for precision medicine and for studying the pathophysiology of the disease.
Highlights
Colorectal cancer (CRC) is an increasingly prevalent disease that accounts for substantial mortality and morbidity and is responsible for an impaired quality of life and high financial resource consumption [1]
The extracellular matrix (ECM) is known to modulate distinct biological processes associated with cancer progression, namely increased cell proliferation, apoptosis and hypoxia resistance, invasion, metastasis, angiogenesis, cancer cell immune evasion, and stemness (Figure 1) [44,45,46,47,48]
Type 1 collagen overexpression in tumor tissues has been implicated in the promotion of tumor growth, epithelial to mesenchymal transition (EMT), distant metastasis and increased stemness properties of CRC cells, through integrin α2β1 and the activation of
Summary
Colorectal cancer (CRC) is an increasingly prevalent disease that accounts for substantial mortality and morbidity and is responsible for an impaired quality of life and high financial resource consumption [1]. Immunotherapy has a limited application in CRC, being only recommended to patients with high microsatellite instable (MSI) tumors, which correspond to less than 15% of all CRC cases [4] This scenario highlights the urgent need to better understand the biological mechanisms underlying CRC onset, progression and spread to improve CRC diagnosis and establish tailored therapeutic strategies. The ECM is significantly altered, both structurally and in terms of composition, usually enabling cellular transformation, angiogenesis, inflammation, invasion and metastasis [8,9] These tumor ECM alterations translate into dysfunctional biomechanical tissue properties with increased stiffness activating several cellular pathways, such as YAP/TAZ [10], TXNIP [11], Rho/Rock-PTEN [12], PI3K-AKT [13], GSK3β [14] and AMPK [15,16]. The focus of this review is to summarize the innovative and advanced 3Dbased models of CRC, with a special highlight on the decellularization-based models, which offer the intrinsic native properties of the ECM to accurately resemble and reconstruct the TME to study CRC biology and drug discovery
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