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Cancers
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Designification & Intelligentsia of Humanized Rodent Models in Cancer Research
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Designification & Intelligentsia of Humanized Rodent Models in Cancer Research

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 29560

Special Issue Editor

Prof. Dr. Dietmar W. Hutmacher

E-Mail Website
Guest Editor
Faculty of Engineering, School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, QLD 4000, Australia
Interests: biomaterials; tissue engineering; regenerative medicine; preclinical animal models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Humanized animal models, particularly new model types created in the past decade, have reformed cancer research. Comparative cancer medicine is founded on the ability of animal models to mimic human physiology, for example by reacting similarly to a particular cancer disease. Historically a constraint on research has been the limited means by which researchers could modify potential cancer animal models. Techniques for genetic manipulation such as CRISPR became available in the  radically changed the decision-making process for the selection of an animal model. In many cases it became possible to manipulate the biology of the mouse and make it into a viable model for a specific cancer disease, where previously it would have been unsuitable. Generally, such manipulations are some kind of humanization recreating a more human-like physiology in the mouse and rats to further the understanding of basic, human-specific biology or to enable the investigation of a human disease, its progression and related treatment possibilities. In order to recapitulate relevant parts of human conditions two main, conceptually distinct yet overlapping humanization pathways are commonly utilized in today’s cancer  research models. (A) Transferring/engrafting of cells or (B) Engineering of human genetic tissues of human origin (xenografts) features in an animal host genome into an immunodeficient host. The special issue will feature articles related to basic and translational cancer research in humanized rodents.

Prof. Dr. Dietmar Hutmacher
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Humanized animal models
  • human origin
  • xenografts
  • humanized rodents

Published Papers (6 papers)

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Research

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19 pages, 4777 KiB  
Article
A Biobank of Colorectal Cancer Patient-Derived Xenografts
by Suad M. Abdirahman, Michael Christie, Adele Preaudet, Marie C. U. Burstroem, Dmitri Mouradov, Belinda Lee, Oliver M. Sieber and Tracy L. Putoczki
Cancers 2020, 12(9), 2340; https://doi.org/10.3390/cancers12092340 - 19 Aug 2020
Cited by 12 | Viewed by 4023
Abstract
Colorectal cancer (CRC) is a challenging disease, with a high mortality rate and limited effective treatment options, particularly for late-stage disease. Patient-derived xenografts (PDXs) have emerged as an informative, renewable experimental resource to model CRC architecture and biology. Here, we describe the generation [...] Read more.
Colorectal cancer (CRC) is a challenging disease, with a high mortality rate and limited effective treatment options, particularly for late-stage disease. Patient-derived xenografts (PDXs) have emerged as an informative, renewable experimental resource to model CRC architecture and biology. Here, we describe the generation of a biobank of CRC PDXs from stage I to stage IV patients. We demonstrate that PDXs within our biobank recapitulate the histopathological and mutation features of the original patient tumor. In addition, we demonstrate the utility of this resource in pre-clinical chemotherapy and targeted treatment studies, highlighting the translational potential of PDX models in the identification of new therapies that will improve the overall survival of CRC patients. Full article
(This article belongs to the Special Issue Designification & Intelligentsia of Humanized Rodent Models in Cancer Research)
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23 pages, 10758 KiB  
Article
Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer
by Alvaro Sanchez-Herrero, Isabel A. Calvo, Maria Flandes-Iparraguirre, Marietta Landgraf, Christoph A. Lahr, Abbas Shafiee, Froilán Granero-Molto, Borja Saez, Manuel M. Mazo, Bruno Paiva, Elena de Juan Pardo, Andrew Nicol, Felipe Prosper, Laura J. Bray and Jacqui A. McGovern
Cancers 2020, 12(8), 2205; https://doi.org/10.3390/cancers12082205 - 06 Aug 2020
Cited by 4 | Viewed by 2870
Abstract
Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the [...] Read more.
Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour–microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform. Full article
(This article belongs to the Special Issue Designification & Intelligentsia of Humanized Rodent Models in Cancer Research)
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16 pages, 8464 KiB  
Article
Development of a MEL Cell-Derived Allograft Mouse Model for Cancer Research
by Min Young Kim, Sungwoo Choi, Seol Eui Lee, Ji Sook Kim, Seung Han Son, Young Soo Lim, Bang-Jin Kim, Buom-Yong Ryu, Vladimir N. Uversky, Young Jin Lee and Chul Geun Kim
Cancers 2019, 11(11), 1707; https://doi.org/10.3390/cancers11111707 - 01 Nov 2019
Cited by 1 | Viewed by 4558
Abstract
Murine erythroleukemia (MEL) cells are often employed as a model to dissect mechanisms of erythropoiesis and erythroleukemia in vitro. Here, an allograft model using MEL cells resulting in splenomegaly was established to develop a diagnostic model for isolation/quantification of metastatic cells, anti-cancer drug [...] Read more.
Murine erythroleukemia (MEL) cells are often employed as a model to dissect mechanisms of erythropoiesis and erythroleukemia in vitro. Here, an allograft model using MEL cells resulting in splenomegaly was established to develop a diagnostic model for isolation/quantification of metastatic cells, anti-cancer drug screening, and evaluation of the tumorigenic or metastatic potentials of molecules in vivo. In this animal model, circulating MEL cells from the blood stream were successfully isolated and quantified with an additional in vitro cultivation step. In terms of the molecular-pathological analysis, we were able to successfully evaluate the functional discrimination between methyl-CpG-binding domain 2 (Mbd2) and p66α in erythroid differentiation, and tumorigenic potential in spleen and blood stream of allograft model mice. In addition, we found that the number of circulating MEL cells in anti-cancer drug-treated mice was dose-dependently decreased. Our data demonstrate that the newly established allograft model is useful to dissect erythroleukemia pathologies and non-invasively provides valuable means for isolation of metastatic cells, screening of anti-cancer drugs, and evaluation of the tumorigenic potentials. Full article
(This article belongs to the Special Issue Designification & Intelligentsia of Humanized Rodent Models in Cancer Research)
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Review

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25 pages, 1290 KiB  
Review
The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance
by Anjali Balakrishnan, Sabrina Roy, Taylor Fleming, Hon S. Leong and Carol Schuurmans
Cancers 2020, 12(7), 1964; https://doi.org/10.3390/cancers12071964 - 19 Jul 2020
Cited by 20 | Viewed by 3557
Abstract
Gliomas are a diverse group of brain tumors comprised of malignant cells (‘tumor’ cells) and non-malignant ‘normal’ cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both ‘tumor’ and ‘normal’ cells [...] Read more.
Gliomas are a diverse group of brain tumors comprised of malignant cells (‘tumor’ cells) and non-malignant ‘normal’ cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both ‘tumor’ and ‘normal’ cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell–cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that ‘vesiculome’ data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response. Full article
(This article belongs to the Special Issue Designification & Intelligentsia of Humanized Rodent Models in Cancer Research)
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22 pages, 2244 KiB  
Review
Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies
by Rana Mhaidly and Els Verhoeyen
Cancers 2020, 12(7), 1915; https://doi.org/10.3390/cancers12071915 - 15 Jul 2020
Cited by 30 | Viewed by 11550
Abstract
Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for hematological malignancies. However, improvements in CAR T-cell therapies are urgently needed since CAR T cell application is associated with toxicities, exhaustion, immune suppression, lack of long-term persistence, and low CAR T-cell tumor [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for hematological malignancies. However, improvements in CAR T-cell therapies are urgently needed since CAR T cell application is associated with toxicities, exhaustion, immune suppression, lack of long-term persistence, and low CAR T-cell tumor infiltration. Major efforts to overcome these hurdles are currently on the way. Incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system and tumor tissue, represent an important fundamental and preclinical research tool. We will focus here on several CAR T and CAR NK therapies that have benefited from evaluation in humanized mice. These models are of great value for the cancer therapy field as they provide a more reliable understanding of sometimes complicated therapeutic interventions. Additionally, they are considered the gold standard with regard to assessment of new CAR technologies in vivo for safety, efficacy, immune response, design, combination therapies, exhaustion, persistence, and mechanism of action prior to starting a clinical trial. They help to expedite the critical translation from proof-of-concept to clinical CAR T-cell application. In this review, we discuss innovative developments in the CAR T-cell therapy field that benefited from evaluation in humanized mice, illustrated by multiple examples. Full article
(This article belongs to the Special Issue Designification & Intelligentsia of Humanized Rodent Models in Cancer Research)
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18 pages, 333 KiB  
Review
Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development
by Tiina E. Kähkönen, Jussi M. Halleen and Jenni Bernoulli
Cancers 2020, 12(6), 1615; https://doi.org/10.3390/cancers12061615 - 18 Jun 2020
Cited by 6 | Viewed by 2466
Abstract
Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of [...] Read more.
Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in. Preclinical immuno-oncology models for studying metastases have long been limited to syngeneic or carcinogenesis-inducible models that have murine cancer and immune cells. However, the translational power of these models has been questioned. Interactions between tumor and immune cells are often species-specific and regulated by different cytokines in mice and humans. For increased translational power, mice engrafted with functional parts of human immune system have been developed. These humanized mice are utilized to advance understanding the role of immune cells in the metastatic process, but increasingly also to study the efficacy and safety of novel immunotherapies. From these aspects, this review will discuss the role of immune cells in the metastatic process and the utility of humanized mouse models in immuno-oncology research for metastatic cancers, covering several models from the perspective of efficacy and safety of immunotherapies. Full article
(This article belongs to the Special Issue Designification & Intelligentsia of Humanized Rodent Models in Cancer Research)
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