Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors

Abstract

Cancer research has considerably progressed with the improvement of in vitro study models, helping to understand the key role of the tumor microenvironment in cancer development and progression. Over the last few years, complex 3D human cell culture systems have gained much popularity over in vivo models, as they accurately mimic the tumor microenvironment and allow high-throughput drug screening. Of particular interest, in vitrohuman 3D tissue constructs, produced by the self-assembly method of tissue engineering, have been successfully used to model the tumor microenvironment and now represent a very promising approach to further develop diverse cancer models. In this review, we describe the importance of the tumor microenvironment and present the existing in vitro cancer models generated through the self-assembly method of tissue engineering. Lastly, we highlight the relevance of this approach to mimic various and complex tumors, including basal cell carcinoma, cutaneous neurofibroma, skin melanoma, bladder cancer, and uveal melanoma.

Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing

“…When cultured in vitro under optimal conditions, cells can produce and deposit their matrix components to form an ECM similar to the one found in vivo. The scaffold-free methods rely on this ability to generate a specific tissue from the self-aggregation of cells producing their 3D matrix [ 96 , 110 , 249 ].…”

“…Switzer and G.K. Summer showed that ascorbate, an enzymatic cofactor of lysyl- and prolyl-hydroxylase, stimulates the production of collagen type I by human dermal fibroblasts when added into the culture media [ 274 ]. Indeed, ascorbic acid facilitates the proline’s hydroxylation, which is crucial for collagen fibrils stability and their deposition [ 96 ]. This was followed by a groundbreaking experiment done by R. Hata and H. Senoo in 1989.…”

“…After a week in culture to allow a full cover of the apical region by the epithelial cells, the cellular sheets are maintained for 21 days at an air/liquid interface to induce the maturation of the epithelium cells. Thereby, engineered cellular assembly mimicking the native tissues is obtained and can be used as models for research or as grafts for autologous transplants [ 96 , 108 ].…”

“…Lack of vasculature: The absence of vascularization in engineered tissue is a disadvantage for tissue transplants since it is a significant reason for poor graft take [ 93 ]. The development of endothelial capillaries within 3D engineered tissues could improve graft take [ 94 , 95 ] and contribute to creating a more relevant tumour microenvironment for cancer study models or studying angiogenic functions [ 78 , 96 , 97 ].…”

“…Lack of interaction with the immune system: A significant drawback of all in vitro models is that the created microenvironment does not include immunologic components, thus contributing to the gap between in vitro and in vivo models. The incorporation of immune cells and lymphatic capillaries to make cancer models more relevant is still a challenge but seems like a reachable objective [ 78 , 96 ].…”