Abstract
3D tumor models clearly outperform 2D cell cultures in recapitulating tissue architecture and drug response. However, their potential in understanding treatment efficacy and resistance development should be better exploited if also long-term effects of treatment could be assessed in vitro. The main disadvantages of the matrices commonly used for in vitro culture are their limited cultivation time and the low comparability with patient-specific matrix properties. Extended cultivation periods are feasible when primary human cells produce the extracellular matrix in situ. Herein, we adapted the hyalograft-3D approach from reconstructed human skin to normal and tumor oral mucosa models and compared the results to bovine collagen-based models. The hyalograft models showed similar morphology and cell proliferation after 7 weeks compared to collagen-based models after 2 weeks of cultivation. Tumor thickness and VEGF expression increased in hyalograft-based tumor models, whereas expression of laminin-332, tenascin C, and hypoxia-inducible factor 1α was lower than in collagen-based models. Taken together, the in situ produced extracellular matrix better confined tumor invasion in the first part of the cultivation period, with continuous tumor proliferation and increasing invasion later on. This proof-of-concept study showed the successful transfer of the hyalograft approach to tumor oral mucosa models and lays the foundation for the assessment of long-term drug treatment effects. Moreover, the use of an animal-derived extracellular matrix is avoided.
Highlights
Stromal, endothelial, and immune cells create a unique environment for each individual tumor with altered paracrine signaling compared to the normal tissue (Zheng and Gao, 2019)
We extended the culture period from 2 weeks of collagen-based normal oral mucosa models (c-NOM) and tumor oral mucosa models (c-TOM) to 7 weeks in hyalograft-based h-NOM and h-TOM models
The epithelium of c-NOM models consisted of a basal layer with rounded cells and multiple layers of spinous cells, as found in non-keratinized oral mucosa (Figure 1B)
Summary
Endothelial, and immune cells create a unique environment for each individual tumor with altered paracrine signaling compared to the normal tissue (Zheng and Gao, 2019). This cellular tumor microenvironment can promote tumor growth, invasion, and dissemination (Varol, 2019) as well as treatment resistance (Jo et al, 2018). Non-human matrices like cellulose are used as scaffolds for ex vivo tumor models (Nath and Devi, 2016) Major drawbacks of these approaches include poor stability, limited lifespan, and underrepresentation of patient-specific tumor microenvironment components. Thereby, hyalograft-based skin models extended the life by six times, compared to collagen-based skin models (Stark et al, 2006)
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