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

2019 ◽  
Vol 20 (18) ◽  
pp. 4647 ◽  
Author(s):  
Bart Kramer ◽  
Luuk de Haan ◽  
Marjolein Vermeer ◽  
Thomas Olivier ◽  
Thomas Hankemeier ◽  
...  
Keyword(s):  
Cell Culture ◽  
Multidrug Resistance ◽  
Pancreatic Ductal Adenocarcinoma ◽  
3D Cell Culture ◽  
In Vitro Models ◽  
Ductal Adenocarcinoma ◽  
Interstitial Flow ◽  
Multidrug Resistance Proteins ◽  
And Function

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.

scholarly journals Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Beate Gündel ◽  
Xinyuan Liu ◽  
Matthias Löhr ◽  
Rainer Heuchel
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Treatment Options ◽  
3D Cell Culture ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
The Past ◽  
Slow Progress

Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.

scholarly journals Tailoring 3D cell culture templates with common hydrogels

2018 ◽  
Author(s):  
Aurélien Pasturel ◽  
Pierre-Olivier Strale ◽  
Vincent Studer
Keyword(s):  
Cell Culture ◽  
3D Cell Culture ◽  
In Vitro Models ◽  
Manufacturing Method ◽  
Biologically Relevant ◽  
Physiological Conditions ◽  
Subtractive Manufacturing ◽  
User Friendly

3D cell culture aims at reconciliating the simplicity of in vitro models with the human like properties encountered in vivo. Soft permeable hydrogels have emerged as user-friendly materials to grow cells in more physiological conditions. With the intent on turning these homogeneous substrates into biomimetic templates, we introduce a generic solution compatible with the most biologically relevant and often frail materials. Here we take control of the chemical environment driving generic radical reactions to craft common gels with patterned light. In a simple microreactor, we harness the well-known inhibition of radicals by oxygen to enable topographical photopolymerization. Strikingly, by sustaining an oxygen rich environment, we can also induce hydrogel photo-scission which turns out to be a powerful and generic subtractive manufacturing method. We finally introduce a flexible patterned functionalization protocol based on available photo-linkers. Using these common tools on the most popular hydrogels, we tailored soft templates where cells grow or self-organize into standardized structures. The platform we describe has the potential to set a standard in future 3D cell culture experiments.

scholarly journals 3D Modeling of Epithelial Tumors—The Synergy between Materials Engineering, 3D Bioprinting, High-Content Imaging, and Nanotechnology

2021 ◽  
Vol 22 (12) ◽  
pp. 6225
Author(s):  
Poonam Trivedi ◽  
Rui Liu ◽  
Hongjie Bi ◽  
Chunlin Xu ◽  
Jessica M. Rosenholm ◽  
...  
Keyword(s):  
Cell Culture ◽  
Treatment Strategies ◽  
3D Cell Culture ◽  
Drug Efficacy ◽  
In Vitro Models ◽  
Experimental Models ◽  
Epithelial Cancer ◽  
High Content Imaging ◽  
Novel Technologies

The current statistics on cancer show that 90% of all human cancers originate from epithelial cells. Breast and prostate cancer are examples of common tumors of epithelial origin that would benefit from improved drug treatment strategies. About 90% of preclinically approved drugs fail in clinical trials, partially due to the use of too simplified in vitro models and a lack of mimicking the tumor microenvironment in drug efficacy testing. This review focuses on the origin and mechanism of epithelial cancers, followed by experimental models designed to recapitulate the epithelial cancer structure and microenvironment, such as 2D and 3D cell culture models and animal models. A specific focus is put on novel technologies for cell culture of spheroids, organoids, and 3D-printed tissue-like models utilizing biomaterials of natural or synthetic origins. Further emphasis is laid on high-content imaging technologies that are used in the field to visualize in vitro models and their morphology. The associated technological advancements and challenges are also discussed. Finally, the review gives an insight into the potential of exploiting nanotechnological approaches in epithelial cancer research both as tools in tumor modeling and how they can be utilized for the development of nanotherapeutics.

scholarly journals Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2473
Author(s):  
Owen Hoare ◽  
Nicolas Fraunhoffer ◽  
Abdessamad Elkaoutari ◽  
Odile Gayet ◽  
Martin Bigonnet ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Drug Sensitivity ◽  
In Vitro Models ◽  
Ductal Adenocarcinoma ◽  
Preclinical Model ◽  
Preclinical Models ◽  
Clinical Reality ◽  
First Time

Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models—patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)—were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions: Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.

scholarly journals Application of Cell Culture Models in Studying Viral Diseases (SARS, H1N1 Flu, MERS, COVID-19): A Review

2021 ◽  
pp. 1-7
Author(s):  
Afra Hadjizadeh ◽  
Minoo Alavi ◽  
Samira Tajvar ◽  
Afra Hadjizadeh
Keyword(s):  
Cell Culture ◽  
Influenza A ◽  
Ethical Issues ◽  
3D Cell Culture ◽  
In Vitro Models ◽  
Viral Diseases ◽  
Emerging Viruses ◽  
Culture Models ◽  
Cell Culture Models

The emergence of recent viral outbreaks, especially the COVID-19 pandemic, and the resulting global mortality and damage has created an urgent need to accelerate the identification, prevention, and treatment of these viral diseases. Due to the limitations in the use of humans, and animal models in terms of time, costs, metabolism differences and ethical issues, in vitro models have become essential in virology research. In the present review, we collected the application of several used cell culture models in studies on four pathogenic viruses - severe acute respiratory syndrome coronavirus (SARS-CoV), influenza A virus (H1N1), middle east respiratory syndrome coronavirus (MERS-CoV), and 2019 novel coronavirus (SARS-CoV-2). These models included, 2D and 3D cell culture (organoids, microfluidic-chips, and bioprinted models). A collection of existing research on these viruses can help fight against the SARS-CoV-2 virus and speed it up against future emerging viruses. Moreover, it can show the shortcomings of in vitro models in virology studies that have been performed to date and provide researchers with new ideas for developing models that are more efficient to deal with similar viral outbreaks.

scholarly journals Mammary gland 3D cell culture systems in farm animals

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Laurence Finot ◽  
Eric Chanat ◽  
Frederic Dessauge
Keyword(s):  
Cell Culture ◽  
Mammary Gland ◽  
Bacterial Infections ◽  
Three Dimensional ◽  
3D Cell Culture ◽  
Farm Animals ◽  
Culture Systems ◽  
Cell Culture Systems

AbstractIn vivo study of tissue or organ biology in mammals is very complex and progress is slowed by poor accessibility of samples and ethical concerns. Fortunately, however, advances in stem cell identification and culture have made it possible to derive in vitro 3D “tissues” called organoids, these three-dimensional structures partly or fully mimicking the in vivo functioning of organs. The mammary gland produces milk, the source of nutrition for newborn mammals. Milk is synthesized and secreted by the differentiated polarized mammary epithelial cells of the gland. Reconstructing in vitro a mammary-like structure mimicking the functional tissue represents a major challenge in mammary gland biology, especially for farm animals for which specific agronomic questions arise. This would greatly facilitate the study of mammary gland development, milk secretion processes and pathological effects of viral or bacterial infections at the cellular level, all with the objective of improving milk production at the animal level. With this aim, various 3D cell culture models have been developed such as mammospheres and, more recently, efforts to develop organoids in vitro have been considerable. Researchers are now starting to draw inspiration from other fields, such as bioengineering, to generate organoids that would be more physiologically relevant. In this chapter, we will discuss 3D cell culture systems as organoids and their relevance for agronomic research.

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