Modeling Cancer with Tissue Engineering

Advances in tumor cell biology, 3D cell culture, and tissue engineering have enabled the rapid development of comprehensive in vitro tumor models with an accurate understanding of their multi-dimensional structure and organization. Moreover, these models allow to study the complex relationships in the tumor microenvironment (TME), which has a significant role in cancer progression and metastasis [1,2,3].

The tissue engineering field is enabling the development of tissue models which mimic the TME with high fidelity. These 3D biomimetic models are able to guide tumor tissue formation in vitro with controlled and tunable architectural complexity [4,5].

Fischbach et al. created a hydrogel system to examine the role of the transition from 2D to 3D culture on cancer cell angiogenic capability. The 3D culture recreated tumor microenvironmental cues and led to enhanced interleukin 8 (IL-8) secretion and regulated cancer cell angiogenic signaling. Moreover, the tridimensional culture controlled local and systemic blockade of both IL-8 and VEGF signaling, indicating that this can improve antiangiogenic therapies [6].


Several 3D platforms mimic the complexity of the tumor microenvironment. An example of these platforms is the natural matrices, derived from the extracellular matrix, which can support essential cancer cell-ECM interactions, such as integrin binding, growth factor signaling and 3D cell migration and invasion. Another approach to obtain these 3D platforms is using synthetic matrices, such as traditional fully synthetic materials - polyesters poly(lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL), for instance [7].


Previous studies [8,9] have proved the feasibility of using poly ε-caprolactone (PCL), a semi-crystalline polymer, on modeling cancer. Malakpour et al. developed highly porous 3D PCL fiber meshes to mimic the collagen fibers on the extracellular matrix soft tissue. This fabrication aimed to speed up the development and optimization of 3D tumor models as physiologically relevant systems that can contribute to therapeutic studies. The cell proliferation was assessed in the 3D meshes after seeding different numbers of JIMT-1 or MCF-7 breast cancer cells, MCF-10A normal-like breast epithelial cells, or adult human dermal fibroblasts. The results obtained indicate that these models are efficient options to mimic the TME [10].



Figure 1: Cryosectioned samples showing infiltration of human breast cancer and normal human cells into the 3D PCL fiber mesh after one week of incubation. (A) MCF-7 cells, (B) JIMT-1cells, (C) MCF-10A cells, and (D) human adult dermal fibroblasts. The cell nuclei were stained with DAPI (blue) for visualization [10]. To illustrate what is newest in the development of technologies for modeling cancer, it is worth analyzing a research from the University of Texas Southwestern Medical Center, which used CRISPR-Cas9. This powerful technology relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. The study reported a methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells of various tissues, including muscle, brain, liver, and lungs, and enables the creation of organ-specific cancer models in mice’s livers and lungs. This strategy opens the path for new approaches to improve cancer therapy and tumor biology studies [11].



Figure 2: CRISPR-Cas9 RNPs for tissue-specific genome editing [11].



REFERENCES

1. Roy, V. et al. Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors. Biomed Res. Int. 2020, 6051210 (2020).

2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

3. Bregenzer, M. E. et al. Integrated cancer tissue engineering models for precision medicine. PLoS One 14, e0216564 (2019).

4. Fong, E. L. S. et al. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. Proceedings of the National Academy of Sciences vol. 110 6500–6505 (2013).

5. Fong, E. L., Santoro, M., Farach-Carson, M. C., Kasper, F. K. & Mikos, A. G. Tissue engineering perfusable cancer models. Current Opinion in Chemical Engineering vol. 3 112–117 (2014).

6. Fischbach, C. et al. Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement. Proc. Natl. Acad. Sci. U. S. A. 106, 399–404 (2009).

7. Fong, E. L. S., Harrington, D. A., Farach-Carson, M. C. & Yu, H. Heralding a new paradigm in 3D tumor modeling. Biomaterials 108, 197–213 (2016).

8. Hartman, O. et al. Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model. Biomaterials 31, 5700–5718 (2010).

9. Amirabadi, H. E. et al. A novel method to understand tumor cell invasion: integrating extracellular matrix mimicking layers in microfluidic chips by ‘selective curing’. Biomedical Microdevices vol. 19 (2017).

10. Permlid, A. M. et al. Unique animal friendly 3D culturing of human cancer and normal cells. Toxicology in Vitro vol. 60 51–60 (2019).

11. Wei, T., Cheng, Q., Min, Y.-L., Olson, E. N. & Siegwart, D. J. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat. Commun. 11, 3232 (2020).


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