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Open AccessArticle

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

1
Mimetas BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands
2
Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4647; https://doi.org/10.3390/ijms20184647
Received: 31 August 2019 / Revised: 13 September 2019 / Accepted: 17 September 2019 / Published: 19 September 2019
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D in vitro models. Here, we demonstrated a 3D microfluidic interstitial flow model to mimic the intratumoral pressure in PDAC. We found that subjecting the S2-028 PDAC cell line to interstitial flow inhibits the proliferation, while maintaining a high viability. We observed increased gemcitabine chemoresistance, with an almost nine-fold higher EC50 as compared to a monolayer culture (31 nM versus 277 nM), and an alleviated expression and function of the multidrug resistance protein (MRP) family. In conclusion, we developed a 3D cell culture modality for studying intratissue pressure and flow that exhibits more predictive capabilities than conventional 2D cell culture and is less time-consuming, and more scalable and accessible than animal models. This increase in microphysiological relevance might support improved efficiency in the drug development pipeline. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; microfluidics; interstitial flow; gemcitabine; chemoresistance; cancer; modeling pancreatic ductal adenocarcinoma; microfluidics; interstitial flow; gemcitabine; chemoresistance; cancer; modeling
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MDPI and ACS Style

Kramer, B.; Haan, L.d.; Vermeer, M.; Olivier, T.; Hankemeier, T.; Vulto, P.; Joore, J.; Lanz, H.L. Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins. Int. J. Mol. Sci. 2019, 20, 4647. https://doi.org/10.3390/ijms20184647

AMA Style

Kramer B, Haan Ld, Vermeer M, Olivier T, Hankemeier T, Vulto P, Joore J, Lanz HL. Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins. International Journal of Molecular Sciences. 2019; 20(18):4647. https://doi.org/10.3390/ijms20184647

Chicago/Turabian Style

Kramer, Bart; Haan, Luuk d.; Vermeer, Marjolein; Olivier, Thomas; Hankemeier, Thomas; Vulto, Paul; Joore, Jos; Lanz, Henriëtte L. 2019. "Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins" Int. J. Mol. Sci. 20, no. 18: 4647. https://doi.org/10.3390/ijms20184647

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