Humanized Mouse Xenograft Models: Narrowing the Tumor–Microenvironment Gap

Morton, J. Jason; Bird, Gregory; Refaeli, Yosef; Jimeno, Antonio

doi:10.1158/0008-5472.can-16-1260

Cited by 200 publications

(166 citation statements)

References 48 publications

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“…If speciesspecific factors are subject of research, one possible bypass is the use of humanized mouse acceptors. Humanized substrains of NSG and NOG expressing species-specific human cytokines, growth factors, receptors, histocompatibility antigens or adhesion molecules, or harboring even functional human hematopoietic stem cells or tissues such as bone marrow, liver, and thymus are under development to address questions related to human immune cells and stem cells within their niche (39,41) as well as virus (EBV and HCV)-related aspects of cancer (42). In contrast, syngeneic, immune-compatible transplanted cells are not rejected by the host organism.…”

Section: Cell-based Transplantation Modelsmentioning

confidence: 99%

Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

et al. 2017

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The devastating diseases of human cancer are mimicked in basic and translational cancer research by a steadily increasing number of tumor models, a situation requiring a platform with standardized reports to share model data. Models in Translational Oncology (MiTO) database was developed as a unique Web platform aiming for a comprehensive overview of preclinical models covering genetically engineered organisms, models of transplantation, chemical/physical induction, or spontaneous development, reviewed here. MiTO serves data entry for metastasis profiles and interventions. Moreover, cell lines and animal lines including tool strains can be recorded. Hyperlinks for connection with other databases and file uploads as supplementary information are supported. Several communication tools are offered to facilitate exchange of information. Notably, intellectual property can be protected prior to publication by inventordefined accessibility of any given model. Data recall is via a highly configurable keyword search. Genome editing is expected to result in changes of the spectrum of model organisms, a reason to open MiTO for species-independent data. Registered users may deposit own model fact sheets (FS). MiTO experts check them for plausibility. Independently, manually curated FS are provided to principle investigators for revision and publication. Importantly, noneditable versions of reviewed FS can be cited in peer-reviewed journals.

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Section: Cell-based Transplantation Modelsmentioning

confidence: 99%

Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

et al. 2017

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“…In particular, the authors observed that the stroma surrounding the tumors had human T and B cell infiltration, the stromal microenvironment was reprogrammed, with alteration of gene expressions governing the extracellular matrix, the immune response, and the epithelial-mesenchymal transition. 44 Importantly, humanized mice may be useful not only for studying human diseases but also for discovering more effective anticancer therapies. Even though we are still in the early stages of this type of technology, there are several recently published studies showing the utility of humanized mice in the development of immunomodulatory anticancer agents.…”

Section: Mouse Species Advantages Limitationsmentioning

confidence: 99%

“…44 In this review, one of the main key points raised was in regard to the eventual presence of mature xenoreactive T cells in humanized mice created by the injection of purified CD34+ cells. In this case, T cells could recognize tumor cells as a foreign body and possibly kill them as it was observed that tumors implanted in humanized mice grow more slowly than tumors implanted on the same non-humanized mice strain.…”

Section: Mouse Species Advantages Limitationsmentioning

confidence: 99%

“…In this case, T cells could recognize tumor cells as a foreign body and possibly kill them as it was observed that tumors implanted in humanized mice grow more slowly than tumors implanted on the same non-humanized mice strain. 44 This causes concern when antitumor efficacy of new compounds is evaluated; therefore, future studies should aim to create humanized mice in which HSPCs and the tumor are derived from the same patient.…”

Section: Mouse Species Advantages Limitationsmentioning

confidence: 99%

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The role of mouse models in translational cancer research: present and future directions

Porru

Leonetti

2017

Transl Med Rep

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A major issue in the research for new anticancer therapeutics is represented by the low number of new compounds approved for clinical use in comparison to the good success rate reported in preclinical studies. This high attrition rate could be attributed to many factors including the unsatisfactory predictive value of experiments performed in animals. To this purpose, general opinions suggest that classical models as murine tumors and xenografts do not mimic the complexity of human cancer diseases and that the use and integration of different relevant mouse models could improve the efficiency of the drug development process. In this review, we overview the present state of research in the field of mouse models for cancer and describe the advantages and limitations of the different models. Finally, strategies for improving the predictive value of animal experiments will be also discussed.

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“…Humanized mouse models have been extensively used to study human diseases and virus pathogenesis (21)(22)(23)(24)(25)(26)(27)(28). These models reconstitute the microenvironment of the human lung to evaluate the host response during virus infection in the human lung.…”

mentioning

confidence: 99%

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

Escaffre

Saito

Juelich

et al. 2017

J Virol

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Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/␥ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune systemreconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh strain induced cytopathic lesions in lung grafts similar to those described in patients irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltration in the small airways and alveolar area, induced oxidative stress, and triggered the production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.

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Humanized Mouse Xenograft Models: Narrowing the Tumor–Microenvironment Gap

Cited by 200 publications

References 48 publications

Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

The role of mouse models in translational cancer research: present and future directions

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

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