Abstract
With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumor niche. Advancements in the field of tissue engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, polyurethane (PU) scaffold-based, long-term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells, and stellate cells. Recognizing the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumor compartment consisting of cancer cells [fibronectin (FN)-coated] and a surrounding stromal compartment consisting of stellate and endothelial cells [collagen I (COL)-coated]. Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported timeframe in vitro. Furthermore, the hybrid model showed extensive COL production by the cells, mimicking desmoplasia, one of PDAC’s hallmark features. Fibril alignment of the stellate cells was observed, which attested to their activated state. All three cell types expressed various cell-specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low-cost tool for in vitro studies of PDAC, as well as for treatment screening.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths worldwide and accounts for about 7% of all cancer-related deaths (Siegel et al, 2018)
We have previously reported that PANC-1 pancreatic cancer cells are able to grow on PU scaffolds for over 28 days (4 weeks), forming dense cell clusters and secreting substantial amounts of collagen I (COL) in FN coated scaffolds (Totti et al, 2018)
In this work, mono-cultures of human microvascular endothelial cells (HMECs) endothelial cells and PS-1 stellate cells were established on PU scaffolds both uncoated and coated with either FN or COL for 28 days
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths worldwide and accounts for about 7% of all cancer-related deaths (Siegel et al, 2018). The 5-year survival rate is about 9% and has barely improved over the last decades (Cancer.Net, 2019). These dismal figures for PDAC are due to its late-stage diagnosis, early and rapid metastasis, along with a high resistance to currently available treatment options (mainly, chemotherapy and radiotherapy) (Kleeff et al, 2016). The latter is attributed to the complex tumor microenvironment (TME) of PDAC. Fibrosis/desmoplasia contributes to the high resistance of PDAC to treatment (Seicean et al, 2015; Chand et al, 2016; Totti et al, 2017; Ansari et al, 2018; Totti et al, 2018)
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