3D printed in vitro tumor tissue model of colorectal cancer

Abstract

Rationale: The tumor microenvironment (TME) determines tumor progression and affects clinical therapy. Its basic components include cancer-associated fibroblasts (CAFs) and tumor-associated endothelial cells (TECs), both of which constitute the tumor matrix and microvascular network. The ability to simulate interactions between cells and extracellular matrix in a TME in vitro can assist the elucidation of cancer growth and evaluate the efficiency of therapies. Methods: In the present study, an in vitro 3D model of tumor tissue that mimicked in vivo cell physiological function was developed using tumor-associated stromal cells. Colorectal cancer cells, CAFs, and TECs were co-cultured on 3D-printed scaffolds so as to constitute an extracellular matrix (ECM) that allowed cell processes such as adhesion, stemness, proliferation, and vascularization to take place. Normal stromal cells were activated and reprogrammed into tumor-related stromal cells to construct a TME of tumor tissues. Results: The activated stromal cells overexpressed a variety of tumor-related markers and remodeled the ECM. Furthermore, the metabolic signals and malignant transformation of the in vitro 3D tumor tissue was substantially similar to that observed in tumors in vivo . Conclusions: The 3D tumor tissue exhibited physiological activity with high drug resistance. The model is suitable for research studies of tumor biology and the development of personalized treatments for cancer.

A Colorectal Cancer 3D Bioprinting Workflow as a Platform for Disease Modeling and Chemotherapeutic Screening

“…The focus on malignancies, however, has been almost exclusively on breast, ovarian, and brain cancers ( Satpathy et al, 2018 ; Datta et al, 2020 ; Augustine et al, 2021 ). Besides a vast spectrum of 3D cell culturing methods (including various spheroid techniques ( Reidy et al, 2021 )), the closest work done in the context of CRC prior to this study included the following: the use of alginate (micro)beads enclosing HCT-116 cells to assess viability, tumor markers ( Rios de la Rosa et al, 2018 ), and drug response ( Shakibaei et al, 2015 ); printing of collagen-based scaffolds on which HCT-116 cells could be grown (together with stromal cells) ( Chen et al, 2020 ); bioprinting of bovine colon cells (in GelMa bioink) ( Töpfer et al, 2019 ); and the biofabrication of a human small intestine model (again for drug penetration and toxicity studies) ( Madden et al, 2018 ). Furthermore, the literature on bioprinting of primary cancer patient samples is scarce, with one recent proof-of-concept work including two hepatocellular carcinoma samples and one sarcoma sample ( Maloney et al, 2020 ).…”

Cancer Cell Direct Bioprinting: A Focused Review

“…For urinary bladder cancer, the research is mainly focused on bladder replacement, for example, using collagen and polyglycolide scaffolds cultured with autologous bladder urothelial and muscle cells [ 189 ], or generation of organoids using transurethral or xenograft resections [ 190 ]. In colorectal cancer, the main research is focused on the establishment of an in vitro 3D model, using colorectal cancer cells (HCT 116) with collagen and polycaprolactone scaffolds combined with animal experimentation [ 191 ] or employing an encapsulator machine for alginate microbead casting [ 192 ]. The large contribution of breast cancer research may be explained as a result of being the second main cause of death in women [ 12 ].…”

Decellularized Colorectal Cancer Matrices as Bioactive Scaffolds for Studying Tumor-Stroma Interactions

“…This technique is based on the computer-assisted deposition of bioinks, which can include cells, hydrogels and decellularized matrices into specified 3D conformations [ 129 ]. Chen and colleagues developed a bionatural and slow-degrading collagen-polycaprolactone (PCL) bioprinted 3D CRC model, by co-culturing not only CAFs but also CRC cells and tumor-associated endothelial cells, mimicking the in vivo TME regarding proliferation, vascularization and adhesion [ 130 ]. The bioprinting scaffold-based 3D systems provide successful platforms for studying cell–cell interactions in CRC, but most of them still lack native components and fail to reproduce inter-patient ECM heterogenicity [ 118 ].…”