Cancer Research in Rat Models

Szpirer, Claude

doi:10.1007/978-1-60327-389-3_30

Cited by 23 publications

(8 citation statements)

References 108 publications

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“…Rat models offer some distinct advantages and disadvantages compared to mouse models of human disease. Compared to other disease host species, rats have relatively complex and modifiable behaviors as well as numerous differences in immune function [ 64 – 67 ]. In addition, the size of rat brain offers the opportunity for close stereotactic localization of tumor initiation site to study differences related to brain location.…”

Section: Discussionmentioning

confidence: 99%

Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

et al. 2017

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Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor-associated microglia- and bone marrow-derived macrophages, and the formation of stem-like cell niches within the tumor. This transgenic rat model may enable detailed interspecies comparisons of fundamental cancer pathways and clinically relevant experimental imaging procedures and interventions that are limited by the smaller size of the mouse brain.

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Section: Discussionmentioning

confidence: 99%

Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

et al. 2017

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“…Less is known about the MaSC population in the mammary gland of rats, although these animals have been used intensively for studies on the hormonal regulation of mammogenesis and lactation . Moreover, rats develop mammary cancer spontaneously or when treated with carcinogenic compounds such as 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) and 7,12‐Dimethylbenz[a]anthracene (DMBA), and are therefore frequently used as animals models for breast cancer studies . A putative stem cell niche was identified in the rat mammary gland based on its unique ultrastructural features with residing SLC, suggesting a stem cell niche similar to those found in other mammalian mammary tissues .…”

Section: Characterization Of Mammary Stem Cellsmentioning

confidence: 99%

Conserved and variable: Understanding mammary stem cells across species

2017

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Postnatal mammary gland development requires the presence of mammary stem and progenitor cells (MaSC), which give rise to functional milk-secreting cells and regenerate the mammary epithelium with each cycle of lactation. These long-lived, tissue-resident MaSC are also targets for malignant transformation and may be cancer cells-oforigin. Consequently, MaSC are extensively researched in relation to their role and function in development, tissue regeneration, lactation, and breast cancer. The basic structure and function of the mammary gland are conserved among all mammalian species, from the most primitive to the most evolved. However, species vary greatly in their lactation strategies and mammary cancer incidence, making MaSC an interesting focus for comparative research. MaSC have been characterized in mice, to a lesser degree in humans, and to an even lesser degree in few additional mammals. They remain uncharacterized in most mammalian species, including "ancient" monotremes, marsupials, wild, and rare species, as well as in common and domestic species such as cats. Identification and comparison of MaSC across a large variety of species, particularly those with extreme lactational adaptations or low mammary cancer incidence, is expected to deepen our understanding of development and malignancy in the mammary gland. Here, we review the current status of MaSC characterization across species, and underline species variations in lactation and mammary cancer through which we may learn about the role of MaSC in these processes. V C 2017 International Society for Advancement of Cytometry

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“…The rat has also long been a common choice for pharmacology and toxicology studies because it shares a similar pathway with humans for eradicating toxins [ 8 ]. With respect to cancer research [ 9 , 10 ], and more precisely mammary cancer research, it is noteworthy that rat and human carcinomas show similar development and histopathological features [ 11 , 12 ]; furthermore, rat mammary tumors are strongly hormone dependent for both induction and growth, thus resembling human breast tumors and no virus appears to be involved in rat and human mammary carcinogenesis, unlike mouse mammary carcinogenesis the etiological agent of which is the mouse mammary tumor virus. As stated by Russo “The rat mammary tumor model is well suited for studying in situ and invasive lesions […].…”

Section: Introductionmentioning

confidence: 99%

Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes

Szpirer

2020

J Biomed Sci

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The laboratory rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and diseases. Rat genome mapping and genomics was considerably developed in the last decades. The availability of these resources has stimulated numerous studies aimed at discovering causal disease genes by positional identification. Numerous rat genes have now been identified that underlie monogenic or complex diseases and remarkably, these results have been translated to the human in a significant proportion of cases, leading to the identification of novel human disease susceptibility genes, helping in studying the mechanisms underlying the pathological abnormalities and also suggesting new therapeutic approaches. In addition, reverse genetic tools have been developed. Several genome-editing methods were introduced to generate targeted mutations in genes the function of which could be clarified in this manner [generally these are knockout mutations]. Furthermore, even when the human gene causing a disease had been identified without resorting to a rat model, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, over 350 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases, thereby providing a rich resource of disease models. This article is an update of the progress made in this research and provides the reader with an inventory of these disease genes, a significant number of which have similar effects in rat and humans.

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Cancer Research in Rat Models

Cited by 23 publications

References 108 publications

Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

Conserved and variable: Understanding mammary stem cells across species

Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes

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