Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms22084289
Keywords
pancreatic cancer; desmoplasia; hyaluronic acid; chemoresistance; 3D tumour models
Funding
- EPSRC
- United Kingdom's National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre
- NIHR Invention for Innovation (i4i) programme
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The study utilized a biomimetic model including artificial cancer mass and fibrotic stromal compartment to mimic pancreatic cancer. The results showed varying drug sensitivity across different tumor models, with significantly reduced drug penetration in the complex tumor model.
Pancreatic cancer is a unique cancer in that up to 90% of its tumour mass is composed of a hypovascular and fibrotic stroma. This makes it extremely difficult for chemotherapies to be delivered into the core of the cancer mass. We tissue-engineered a biomimetic 3D pancreatic cancer (tumouroid) model comprised of a central artificial cancer mass (ACM), containing MIA Paca-2 cells, surrounded by a fibrotic stromal compartment. This stromal compartment had a higher concentration of collagen type I, fibronectin, laminin, and hyaluronic acid (HA) than the ACM. The incorporation of HA was validated with alcian blue staining. Response to paclitaxel was determined in 2D MIA Paca-2 cell cultures, the ACMs alone, and in simple and complex tumouroids, in order to demonstrate drug sensitivity within pancreatic tumouroids of increasing complexity. The results showed that MIA Paca-2 cells grew into the complex stroma and invaded as cell clusters with a maximum distance of 363.7 mu m by day 21. In terms of drug response, the IC50 for paclitaxel for MIA Paca-2 cells increased from 0.819 nM in 2D to 3.02 nM in ACMs and to 5.87 nM and 3.803 nM in simple and complex tumouroids respectively, indicating that drug penetration may be significantly reduced in the latter. The results demonstrate the need for biomimetic models during initial drug testing and evaluation.
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