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 Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

2020 ◽  
Vol 7 (2) ◽  
pp. 36 ◽  
Author(s):  
João P. Cotovio ◽  
Tiago G. Fernandes
Keyword(s):  
Cell Types ◽  
In Vitro Models ◽  
Hepatic Cell ◽  
Current Status ◽  
Organ Shortage ◽  
Cell Lineages ◽  
Potential Applications ◽  
Liver Organoids

Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

scholarly journals The MEMIC: An ex vivo system to model the complexity of the tumor microenvironment

2021 ◽  
Author(s):  
Libuše Janská ◽  
Libi Anandi ◽  
Nell C. Kirchberger ◽  
Zoran S. Marinkovic ◽  
Logan T. Schachtner ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Tumor Stroma ◽  
Stem Cell Differentiation ◽  
Blood Stream ◽  
Direct Access ◽  
Ex Vivo Model

There is an urgent need for accurate, scalable, and cost-efficient experimental systems to model the complexity of the tumor microenvironment. Here, we detail how to fabricate and use the Metabolic Microenvironment Chamber (MEMIC) – a 3D-printed ex vivo model of intratumoral heterogeneity. A major driver of the cellular and molecular diversity in tumors is the accessibility to the blood stream that provides key resources such as oxygen and nutrients. While some tumor cells have direct access to these resources, many others must survive under progressively more ischemic environments as they reside further from the vasculature. The MEMIC is designed to simulate the differential access to nutrients and allows co-culturing different cell types, such as tumor and immune cells. This system is optimized for live imaging and other microscopy-based approaches, and it is a powerful tool to study tumor features such as the effect of nutrient scarcity on tumor-stroma interactions. Due to its adaptable design and full experimental control, the MEMIC provide insights into the tumor microenvironment that would be difficult to obtain via other methods. As a proof of principle, we show that cells sense gradual changes in metabolite concentration resulting in multicellular spatial patterns of signal activation and cell proliferation. To illustrate the ease of studying cell-cell interactions in the MEMIC, we show that ischemic macrophages reduce epithelial features in neighboring tumor cells. We propose the MEMIC as a complement to standard in vitro and in vivo experiments, diversifying the tools available to accurately model, perturb, and monitor the tumor microenvironment, as well as to understand how extracellular metabolites affect other processes such as wound healing and stem cell differentiation.

scholarly journals Bioreactors as physiologicallike in vitro models

2020 ◽  
Author(s):  
Sara Mantero ◽  
Federica Boschetti
Keyword(s):  
Culture Conditions ◽  
In Vitro Models ◽  
In Vivo Models ◽  
In Vitro Development ◽  
Culture Cells ◽  
Vitro Development ◽  
Tissue Models ◽  
Mechanical Stretching

Bioreactors are powerful tools for in vitro development of engineered substitutes through controlled biological, physical, and mechanical culture conditions: bioreactor technology allows a closer in vitro replication of native tissues. One of bioreactors applications is the design of in vitro 3D tissue models as a bridge between 2D and in vivo models, allowing the application of 3R (replacement, reduction, refinement) principle. To this aim, bioreactors can be used to culture cells seeded on engineered scaffolds under in vivo-like conditions. Another key use of bioreactors is for perfusion decellularization of tissues and organs to be used as scaffolds. This contribution describes a dynamic stretching. bioreactor, imposing a mechanical stretching to the cultured constructs, allowing the development of skeletal muscle engineered constructs, and a decellularization bioreactor, designed for decellularization of blood vessels.

scholarly journals Development of Preclinical Models to Understand and Treat Colorectal Cancer

2018 ◽  
Vol 31 (03) ◽  
pp. 199-204 ◽  
Author(s):  
Judith Sebolt-Leopold
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Tumors ◽  
Human Colorectal Cancer ◽  
Preclinical Models ◽  
In Vivo Models ◽  
Molecular Determinants ◽  
Experimental Therapies ◽  
Molecular Aberrations

AbstractThe establishment and validation of preclinical models that faithfully recapitulate the pathogenesis and treatment response of human colorectal cancer (CRC) is critical to expedient therapeutic advances in the clinical management of this disease. Integral to the application of precision medicine for patients diagnosed with metastatic CRC is the need to understand the molecular determinants of response for a given therapy. Preclinical models of CRC have proven invaluable in answering many of our basic questions relating to the molecular aberrations that drive colorectal tumor progression. This review will address the comparative merits and limitations of the broad spectrum of in vitro and in vivo models available for study of colorectal tumors and their response to experimental therapies.

scholarly journals Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2078
Author(s):  
Luca Gelsomino ◽  
Giuseppina Daniela Naimo ◽  
Rocco Malivindi ◽  
Giuseppina Augimeri ◽  
Salvatore Panza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Leptin Receptor ◽  
Macrophage Phenotype ◽  
In Vivo Models ◽  
Monocyte Chemoattractant Protein 1 ◽  
Arginase 1 ◽  
The Impact

Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.

scholarly journals Experimental Models in Rheumatoid Arthritis:

2020 ◽  
Vol 8 (1) ◽  
pp. 119-134
Author(s):  
Verônica Assalin Zorgetto-Pinheiro ◽  
Alexandre Meira de Vasconcelos ◽  
Rafael Sanaiotte Pinheiro ◽  
Danielle Bogo ◽  
Iandara Schettert Silva
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Testing ◽  
Pathological Condition ◽  
In Vitro Models ◽  
Experimental Models ◽  
In Vivo Models ◽  
Methodological Tool ◽  
Class 1

Rheumatoid arthritis is an autoimmune and chronic pathological condition characterized by an inflammatory process of the joints It is a complex and multifactorial, involving genetic, epigenetic and environmental factors and the use of experimental models is required to better understand its pathology and for drug testing. The aim of this study was to perform a systematic literature review on experimental models in rheumatoid arthritis using IRAMUTEQ, a software that analysis, qualitatively and quantitatively, text fragments, as a methodological tool. After searching for articles published in the last five years on Scopus database and applying the exclusion criteria, we ended with 84 articles. The most commonly employed experimental models was the arthritis induction by inoculation of the Complete Freund's Adjuvant (CFA), followed by the use of combined methodologies and the collagen-induced arthritis (CIA). The analyses of abstracts by the IRAMUTEQ software provided a classification according to their textual elements in four classes, which were grouped into three main themes: in vivo models (class 1), clinical practice and traditional medicine (classes 2 and 3) and in vitro models (class 4) and it was also possible to build a similarity tree of the terms present in the abstracts and a word cloud with the most cited terms. Thus, the use of the IRAMUTEQ software as a methodological tool has been satisfactory, since it was possible to identify the main experimental models used, keywords, pathological processes and molecules involved in the pathogenesis of rheumatoid arthritis free of the researchers’ bias, in addition to being a tool for visual and intuitive results.

scholarly journals CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches

2021 ◽  
Author(s):  
Arianna Manini ◽  
Leonardo Pantoni
Keyword(s):  
Therapeutic Option ◽  
In Vitro Models ◽  
Monogenic Disease ◽  
Therapeutic Approaches ◽  
In Vivo Models ◽  
Human Phenotype ◽  
Knock Out ◽  
Novel Therapeutic

AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

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.

IN VITRO MODELS OF MYCOBACTERIUM TUBERCULOSIS DORMANCY, AND IN VIVO MODELS OF LATENT TUBERCULOSIS INFECTION

2019 ◽  
Vol 64 (5) ◽  
pp. 299-307
Author(s):  
M. V. Fursov ◽  
I. A. Dyatlov ◽  
V. D. Potapov
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
In Vitro Models ◽  
Tuberculosis Infection ◽  
Published Data ◽  
In Vivo Models ◽  
Dormant State

Modeling of tuberculosis infection is carried out in order to clarify various aspects of the tuberculosis pathogenesis, as well as the testing of new anti-tuberculosis drugs. The characteristic of in vitro models (n = 16) for Mycobacterium tuberculosis dormant state and in vivo models (n = 14) for the latent tuberculosis infection involving several animal species published to date are presented in this review. A brief description of the models and the results obtained by the authors are presented. The analysis of the published data reflects the list of methodological procedures that allow researchers to study the mechanism of the transition of M. tuberculosis cells to a dormant state and reverse to metabolically active state, as well as the process of conversion of active tuberculosis infection to a latent tuberculosis and reactivation.

Imaging Microphysiological Systems: A Review

2020 ◽  
Author(s):  
Samantha Peel ◽  
Mark Jackman
Keyword(s):  
Drug Discovery ◽  
Animal Studies ◽  
Imaging Techniques ◽  
Quantitative Information ◽  
In Vitro Models ◽  
Microscopy Imaging ◽  
In Vivo Models ◽  
Microphysiological Systems

Microphysiological Systems (MPS), often referred to as 'organ-on-chips' are microfluidic-based in vitro models that aim to recapitulate the dynamic chemical and mechanical microenvironment of living organs. MPS promise to bridge the gap between in vitro and in vivo models, and ultimately improve the translation from pre-clinical animal studies to clinical trials. However, despite the explosion of interest in recent years, and the obvious rewards for such models which could improve R&D efficiency and reduce drug attrition in the clinic, the pharmaceutical industry has been slow to fully adopt this technology. The ability to extract robust, quantitative information from MPS at scale is a key requirement if these models are to impact drug discovery and the subsequent drug development process. Microscopy imaging remains a core technology that enables the capture of information at the single cell level and with subcellular resolution. Furthermore, such imaging techniques can be automated, increasing throughput, enabling compound screening. In this review we discuss a range of imaging techniques that have been applied to MPS of varying focus, such as organoids and organ-chip-type models. We outline the opportunities these technologies can bring in terms of understanding mechanistic biology, but also how they could be used in higher-throughput screens, widening the scope of their impact in drug discovery. We discuss the associated challenges of imaging these complex models and the steps required to enable full exploitation. Finally, we discuss the requirements for MPS, if they are to be applied at a scale necessary to support drug discovery projects.

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