Engineering the tumor microenvironment : novel 3d in vitro models to study cellular interactions & therapeutics

2022 ◽  
Author(s):  
Marcel Heinrich
Keyword(s):  
Tumor Microenvironment ◽  
In Vitro Models ◽  
Cellular Interactions

scholarly journals Characterizing the Role of Biologically Relevant Fluid Dynamics on Silver Nanoparticle Dependent Oxidative Stress in Adherent and Suspension In Vitro Models

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 832
Author(s):  
Katherine E. Burns ◽  
Robert F. Uhrig ◽  
Maggie E. Jewett ◽  
Madison F. Bourbon ◽  
Kristen A. Krupa
Keyword(s):  
Oxidative Stress ◽  
Fluid Dynamics ◽  
In Vitro Models ◽  
Poor Correlation ◽  
Cellular Interactions ◽  
Dynamic Flow ◽  
In Vivo Models ◽  
And Oxidative Stress

Silver nanoparticles (AgNPs) are being employed in numerous consumer goods and applications; however, they are renowned for inducing negative cellular consequences including toxicity, oxidative stress, and an inflammatory response. Nanotoxicological outcomes are dependent on numerous factors, including physicochemical, biological, and environmental influences. Currently, NP safety evaluations are carried out in both cell-based in vitro and animal in vivo models, with poor correlation between these mechanisms. These discrepancies highlight the need for enhanced exposure environments, which retain the advantages of in vitro models but incorporate critical in vivo influences, such as fluid dynamics. This study characterized the effects of dynamic flow on AgNP behavior, cellular interactions, and oxidative stress within both adherent alveolar (A549) and suspension monocyte (U937) models. This study determined that the presence of physiologically relevant flow resulted in substantial modifications to AgNP cellular interactions and subsequent oxidative stress, as assessed via reactive oxygen species (ROS), glutathione levels, p53, NFκB, and secretion of pro-inflammatory cytokines. Within the adherent model, dynamic flow reduced AgNP deposition and oxidative stress markers by roughly 20%. However, due to increased frequency of contact, the suspension U937 cells were associated with higher NP interactions and intracellular stress under fluid flow exposure conditions. For example, the increased AgNP association resulted in a 50% increase in intracellular ROS and p53 levels. This work highlights the potential of modified in vitro systems to improve analysis of AgNP dosimetry and safety evaluations, including oxidative stress assessments.

Abstract PO004: Reverse-engineering the tumor microenvironment through microfluidics and bioengineered in vitro models

2021 ◽  
Author(s):  
Jose M. Ayuso ◽  
Mehtab Farooqui ◽  
Maria Virumbrales-Munoz ◽  
Shujah Rehman ◽  
Melissa C. Skala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Reverse Engineering ◽  
In Vitro Models

scholarly journals Controlled activation of morphogenesis to generate a functional human microvasculature in a synthetic matrix

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 804-815 ◽  
Author(s):  
Donny Hanjaya-Putra ◽  
Vivek Bose ◽  
Yu-I Shen ◽  
Jane Yee ◽  
Sudhir Khetan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
In Vitro Models ◽  
Cellular Interactions ◽  
Vascular Networks ◽  
3 Dimensional ◽  
Endothelial Colony Forming Cells ◽  
Vascular Morphogenesis ◽  
Synthetic Matrix ◽  
Synthetic Matrices

Abstract Understanding the role of the extracellular matrix (ECM) in vascular morphogenesis has been possible using natural ECMs as in vitro models to study the underlying molecular mechanisms. However, little is known about vascular morphogenesis in synthetic matrices where properties can be tuned toward both the basic understanding of tubulogenesis in modular environments and as a clinically relevant alternative to natural materials for regenerative medicine. We investigated synthetic, tunable hyaluronic acid (HA) hydrogels and determined both the adhesion and degradation parameters that enable human endothelial colony-forming cells (ECFCs) to form efficient vascular networks. Entrapped ECFCs underwent tubulogenesis dependent on the cellular interactions with the HA hydrogel during each stage of vascular morphogenesis. Vacuole and lumen formed through integrins α5β1 and αVβ3, while branching and sprouting were enabled by HA hydrogel degradation. Vascular networks formed within HA hydrogels containing ECFCs anastomosed with the host's circulation and supported blood flow in the hydrogel after transplantation. Collectively, we show that the signaling pathways of vascular morphogenesis of ECFCs can be precisely regulated in a synthetic matrix, resulting in a functional microvasculature useful for the study of 3-dimensional vascular biology and toward a range of vascular disorders and approaches in tissue regeneration.

scholarly journals Advanced co-culture 3D breast cancer model for investigation of fibrosis induced by external stimuli: optimization study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ilya Yakavets ◽  
Aurelie Francois ◽  
Alice Benoit ◽  
Jean-Louis Merlin ◽  
Lina Bezdetnaya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Culture Media ◽  
Luminal Breast Cancer ◽  
Radiation Toxicity ◽  
Cellular Interactions ◽  
Breast Cancer Patients ◽  
Vitro Model

AbstractRadiation-induced fibrosis (RIF) is the main late radiation toxicity in breast cancer patients. Most of the current 3D in vitro breast cancer models are composed by cancer cells only and are unable to reproduce the complex cellular homeostasis within the tumor microenvironment to study RIF mechanisms. In order to account complex cellular interactions within the tumor microenvironment, an advanced 3D spheroid model, consisting of the luminal breast cancer MCF-7 cells and MRC-5 fibroblasts, was developed. The spheroids were generated using the liquid overlay technique in culture media into 96-well plates previously coated with 1% agarose (m/v, in water). In total, 21 experimental setups were tested during the optimization of the model. The generated spheroids were characterized using fluorescence imaging, immunohistology and immunohistochemistry. The expression of ECM components was confirmed in co-culture spheroids. Using α-SMA staining, we confirmed the differentiation of healthy fibroblasts into myofibroblasts upon the co-culturing with cancer cells. The induction of fibrosis was studied in spheroids treated 24 h with 10 ng/mL TGF-β and/or 2 Gy irradiation. Overall, the developed advanced 3D stroma-rich in vitro model of breast cancer provides a possibility to study fibrosis mechanisms taking into account 3D arrangement of the complex tumor microenvironment.

scholarly journals Potentiality, Limitations, and Consequences of Different Experimental Models to Improve Photodynamic Therapy for Cancer Treatment in Relation to Antiangiogenic Mechanism

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2118
Author(s):  
Martin Majerník ◽  
Rastislav Jendželovský ◽  
Peter Fedoročko
Keyword(s):  
Photodynamic Therapy ◽  
In Vitro Models ◽  
Experimental Models ◽  
Cellular Interactions ◽  
Wide Range ◽  
Therapy Effect ◽  
Complex Features ◽  
Complex Phenomena

The relevance of experimentally gained information represents a long-term debating issue in the field of molecular biology research. The loss of original conditions in the in vitro environment affects various biological mechanisms and cellular interactions. Consequently, some biochemical mechanisms are lost or critically altered. Analyses in these modified conditions could, therefore, distort the relevancy of experimentally gained information. In some cases, the similarities with original conditions are so small that utilization of simpler in vitro models seems impossible, or could occur in a very limited way. To conclude, the study of more complex phenomena places higher demands on the complexity of the experimental model. The latest information highlights the fact that the tumor angiogenesis mechanism has very complex features. This complexity can be associated with a wide range of angiogenic factors expressed by a variety of malignant and non-malignant cells. Our article summarizes the results from various experimental models that were utilized to analyze a photodynamic therapy effect on tumor angiogenic mechanisms. Additionally, based on the latest information, we present the most important attributes and limitations of utilized experimental models. We also evaluate the essential problems associated with angiogenic mechanism induction after photodynamic therapy application.

scholarly journals A computational diffusion model to study antibody transport within reconstructed tumor microenvironments

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ana Luísa Cartaxo ◽  
Jaime Almeida ◽  
Emilio J. Gualda ◽  
Maria Marsal ◽  
Pablo Loza-Alvarez ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Fluorescent Antibody ◽  
Light Sheet ◽  
In Vitro Models ◽  
Experimental Models ◽  
Computational Framework ◽  
Heterogeneous Distribution ◽  
Alginate Capsules

Abstract Background Antibodies revolutionized cancer treatment over the past decades. Despite their successfully application, there are still challenges to overcome to improve efficacy, such as the heterogeneous distribution of antibodies within tumors. Tumor microenvironment features, such as the distribution of tumor and other cell types and the composition of the extracellular matrix may work together to hinder antibodies from reaching the target tumor cells. To understand these interactions, we propose a framework combining in vitro and in silico models. We took advantage of in vitro cancer models previously developed by our group, consisting of tumor cells and fibroblasts co-cultured in 3D within alginate capsules, for reconstruction of tumor microenvironment features. Results In this work, an experimental-computational framework of antibody transport within alginate capsules was established, assuming a purely diffusive transport, combined with an exponential saturation effect that mimics the saturation of binding sites on the cell surface. Our tumor microenvironment in vitro models were challenged with a fluorescent antibody and its transport recorded using light sheet fluorescence microscopy. Diffusion and saturation parameters of the computational model were adjusted to reproduce the experimental antibody distribution, with root mean square error under 5%. This computational framework is flexible and can simulate different random distributions of tumor microenvironment elements (fibroblasts, cancer cells and collagen fibers) within the capsule. The random distribution algorithm can be tuned to follow the general patterns observed in the experimental models. Conclusions We present a computational and microscopy framework to track and simulate antibody transport within the tumor microenvironment that complements the previously established in vitro models platform. This framework paves the way to the development of a valuable tool to study the influence of different components of the tumor microenvironment on antibody transport.

scholarly journals Developing preclinical models of neuroblastoma: driving therapeutic testing

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Kimberly J. Ornell ◽  
Jeannine M. Coburn
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Therapeutics ◽  
Tumor Stroma ◽  
In Vitro Models ◽  
Preclinical Models ◽  
In Vivo Models ◽  
Therapeutic Development ◽  
Potential Applications

AbstractDespite advances in cancer therapeutics, particularly in the area of immuno-oncology, successful treatment of neuroblastoma (NB) remains a challenge. NB is the most common cancer in infants under 1 year of age, and accounts for approximately 10% of all pediatric cancers. Currently, children with high-risk NB exhibit a survival rate of 40–50%. The heterogeneous nature of NB makes development of effective therapeutic strategies challenging. Many preclinical models attempt to mimic the tumor phenotype and tumor microenvironment. In vivo mouse models, in the form of genetic, syngeneic, and xenograft mice, are advantageous as they replicated the complex tumor-stroma interactions and represent the gold standard for preclinical therapeutic testing. Traditional in vitro models, while high throughput, exhibit many limitations. The emergence of new tissue engineered models has the potential to bridge the gap between in vitro and in vivo models for therapeutic testing. Therapeutics continue to evolve from traditional cytotoxic chemotherapies to biologically targeted therapies. These therapeutics act on both the tumor cells and other cells within the tumor microenvironment, making development of preclinical models that accurately reflect tumor heterogeneity more important than ever. In this review, we will discuss current in vitro and in vivo preclinical testing models, and their potential applications to therapeutic development.

scholarly journals Chemoresistance of Cancer Cells: Requirements of Tumor Microenvironment-mimicking In Vitro Models in Anti-Cancer Drug Development

Theranostics ◽  
2018 ◽  
Vol 8 (19) ◽  
pp. 5259-5275 ◽  
Author(s):  
Yeonho Jo ◽  
Nakwon Choi ◽  
Kyobum Kim ◽  
Hyung-Jun Koo ◽  
Jonghoon Choi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Drug Development ◽  
Cancer Cells ◽  
In Vitro Models ◽  
Cancer Drug ◽  
Anti Cancer

scholarly journals 3D bioprinting of hepatocytes: core–shell structured co-cultures with fibroblasts for enhanced functionality

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rania Taymour ◽  
David Kilian ◽  
Tilman Ahlfeld ◽  
Michael Gelinsky ◽  
Anja Lode
Keyword(s):  
Cell Types ◽  
In Vitro Models ◽  
Core Shell ◽  
Specific Cell ◽  
Cellular Interactions ◽  
Culture Models ◽  
Vitro Model ◽  
And Function ◽  
Different Cell Types

AbstractWith the aim of understanding and recapitulating cellular interactions of hepatocytes in their physiological microenvironment and to generate an artificial 3D in vitro model, a co-culture system using 3D extrusion bioprinting was developed. A bioink based on alginate and methylcellulose (algMC) was first shown to be suitable for bioprinting of hepatocytes; the addition of Matrigel to algMC enhanced proliferation and morphology of them in monophasic scaffolds. Towards a more complex system that allows studying cellular interactions, we applied core–shell bioprinting to establish tailored 3D co-culture models for hepatocytes. The bioinks were specifically functionalized with natural matrix components (based on human plasma, fibrin or Matrigel) and used to co-print fibroblasts and hepatocytes in a spatially defined, coaxial manner. Fibroblasts acted as supportive cells for co-cultured hepatocytes, stimulating the expression of certain biomarkers of hepatocytes like albumin. Furthermore, matrix functionalization positively influenced both cell types in their respective compartments by enhancing their adhesion, viability, proliferation and function. In conclusion, we established a functional co-culture model with independently tunable compartments for different cell types via core–shell bioprinting. This provides the basis for more complex in vitro models allowing co-cultivation of hepatocytes with other liver-specific cell types to closely resemble the liver microenvironment.

3D in vitro Models to Mimic the Tumor Microenvironment

2021 ◽  
pp. 359-411
Author(s):  
Marcel Alexander ◽  
Ngoc Tien Huynh ◽  
Yu Shrike Zhang ◽  
Jai Prakash
Keyword(s):  
Tumor Microenvironment ◽  
In Vitro Models
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