Mouse Models For Cancer Research Research Articles

A Method to Study Migration and Invasion of Mouse Intestinal Organoids

Colorectal cancer (CRC) is the third most common cancer worldwide and it is the second leading cause of cancer death. In CRC, as in most cancers, the formation of metastasis through the migration and invasion of cancer cells to distant organs is associated with a dismal prognosis. The study of the mechanisms associated with cancer, and, in particular, CRC, changed in the last decade due to the introduction of organoids. These represent a step forward in terms of complexity from cell lines and allowed the use of mouse models in cancer research to be limited. Although organoids faithfully model the cellular complexity of CRC, current protocols do not allow for the use of organoids in some crucial processes of metastasis, such as migration and invasion. In this study, a method to study migration and invasion using mouse intestinal organoids in vitro is presented. This protocol provides researchers with the opportunity to investigate the migratory behavior of organoid lines and study the impact of distinct mutations on the migratory and invasive capacity of cancer cells.

Mouse models for cancer research - current state and the perspective.

Cancer is one of the leading causes of death worldwide. We still do not understand all the details of carcinogenesis, and effective treatment is lacking for many oncological diseases. Animal models provide an irreplaceable tool to observe the growth and spreading of neoplastic cells in an environment of living organisms, to test the efficacy of cancer treatment, side effects, and toxicity, and to study the tumor microenvironment. Mice are the most often used model organisms because of their easy handling, short reproductive period, multiple strains, and complete DNA sequencing. An ideal model should accurately recapitulate each step of tumor development. Recent techniques have established models that enable the study of different aspects of cancer, but choosing a particular model depends on the application of output data. This article aimed to review induced, transplantable, and engineered mice and highlight their significance for recent and future cancer research.

How CRISPR Is Revolutionizing the Generation of New Models for Cancer Research.

Cancers arise through acquisition of mutations in genes that regulate core biological processes like cell proliferation and cell death. Decades of cancer research have led to the identification of genes and mutations causally involved in disease development and evolution, yet defining their precise function across different cancer types and how they influence therapy responses has been challenging. Mouse models have helped define the in vivo function of cancer-associated alterations, and genome-editing approaches using CRISPR have dramatically accelerated the pace at which these models are developed and studied. Here, we highlight how CRISPR technologies have impacted the development and use of mouse models for cancer research and discuss the many ways in which these rapidly evolving platforms will continue to transform our understanding of this disease.

Improving Osteosarcoma Treatment: Comparative Oncology in Action.

Osteosarcoma (OSA) is the most common pediatric malignant bone tumor. Although surgery together with neoadjuvant/adjuvant chemotherapy has improved survival for localized OSA, most patients develop recurrent/metastatic disease with a dismally poor outcome. Therapeutic options have not improved for these OSA patients in recent decades. As OSA is a rare and "orphan" tumor, with no distinct targetable driver antigens, the development of new efficient therapies is still an unmet and challenging clinical need. Appropriate animal models are therefore critical for advancement in the field. Despite the undoubted relevance of pre-clinical mouse models in cancer research, they present some intrinsic limitations that may be responsible for the low translational success of novel therapies from the pre-clinical setting to the clinic. From this context emerges the concept of comparative oncology, which has spurred the study of pet dogs as a uniquely valuable model of spontaneous OSA that develops in an immune-competent system with high biological and clinical similarities to corresponding human tumors, including in its metastatic behavior and resistance to conventional therapies. For these reasons, the translational power of studies conducted on OSA-bearing dogs has seen increasing recognition. The most recent and relevant veterinary investigations of novel combinatorial approaches, with a focus on immune-based strategies, that can most likely benefit both canine and human OSA patients have been summarized in this commentary.

Transgenic Mouse Models in Cancer Research.

The use of existing mouse models in cancer research is of utmost importance as they aim to explore the casual link between candidate cancer genes and carcinogenesis as well as to provide models to develop and test new therapies. However, faster progress in translating mouse cancer model research into the clinic has been hampered due to the limitations of these models to better reflect the complexities of human tumors. Traditionally, immunocompetent and immunodeficient mice with syngeneic and xenografted tumors transplanted subcutaneously or orthotopically have been used. These models are still being widely employed for many different types of studies, in part due to their widespread availability and low cost. Other types of mouse models used in cancer research comprise transgenic mice in which oncogenes can be constitutively or conditionally expressed and tumor-suppressor genes silenced using conventional methods, such as retroviral infection, microinjection of DNA constructs, and the so-called “gene-targeted transgene” approach. These traditional transgenic models have been very important in studies of carcinogenesis and tumor pathogenesis, as well as in studies evaluating the development of resistance to therapy. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing approach has revolutionized the field of mouse cancer models and has had a profound and rapid impact on the development of more effective systems to study human cancers. The CRISPR/Cas9-based transgenic models have the capacity to engineer a wide spectrum of mutations found in human cancers and provide solutions to problems that were previously unsolvable. Recently, humanized mouse xenograft models that accept patient-derived xenografts and CD34+ cells were developed to better mimic tumor heterogeneity, the tumor microenvironment, and cross-talk between the tumor and stromal/immune cells. These features make them extremely valuable models for the evaluation of investigational cancer therapies, specifically new immunotherapies. Taken together, improvements in both the CRISPR/Cas9 system producing more valid mouse models and in the humanized mouse xenograft models resembling complex interactions between the tumor and its environment might represent one of the successful pathways to precise individualized cancer therapy, leading to improved cancer patient survival and quality of life.

Abstract 2816: The Jackson Laboratory Repository: Mouse models for cancer research

Abstract The mouse is a well-established model organism for research of the biology, prevention, diagnosis, and treatment of cancer. Among the advantages of this valuable biomedical research tool are a relatively short reproductive cycle, an accelerated lifespan, and the ease of genetic manipulation and modification. Serving as a resource to the scientific community, the JAX Repository collection encompasses over 10,000 mouse strains and acquires hundreds of new models each year. Some of these new models are highlighted in this poster. Many of these strains have applications for modeling human cancer, including genetically engineered mouse models for specific cancers and xenograft models. Research tool strains, such as cas9-expressing (CRISPR) lines, a suite of immunodeficient mice, and recombinase expressing strains, are available to investigators to generate customized mutant lines for specialized purposes. JAX offers supplementary research tools that include specialized strain platforms and other useful resources. The JAX patient-derived xenograft (PDX) cancer model resource leverages the immunodeficient NSG strain for tumor engraftment. The Repository maintains a searchable online resource to find mice (www.jaxmice.jax.org) and an Oncology Therapeutic Area page (www.jax.org/jax-mice-and-services/solutions-by-therapeutic-area/oncology) as a launch pad to featured JAX strains and resources related to oncology research. The Repository has a rigorous quality control program that inspects and confirms expected mutation identity and genetic background. JAX mouse lines are also screened for alleles (GFP, cre, lacZ, etc.) that may contaminate strains in mouse lines shared between labs—an underappreciated problem that may contribute to inconsistencies of reproducibility. In addition, the Reproductive Sciences group at JAX safeguards each strain by cryopreservation, and can create cohorts for studies rapidly using IVF technology. Researchers can submit their strains to be considered for inclusion in the Repository by using the on-line form available at The Jackson Laboratory website: www.jax.org/donate-a-mouse. The Jackson Laboratory Repository is supported by the NIH, The Howard Hughes Medical Institute, and other private charitable foundations. Citation Format: Deborah Boswell, Stephen Rockwood, Michael Sasner, The JAX Repository Team. The Jackson Laboratory Repository: Mouse models for cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2816. doi:10.1158/1538-7445.AM2017-2816

Applying humanized mouse models to immune therapy research

Mouse models have been a mainstay in biomedical research for decades. As these models have become more sophisticated, their application has grown and now includes a wide variety of immunodeficient strains that can be used to examine the in vivo growth of human tumors and to test new cancer treatments. One of the most popular models is the immunodeficient nonobese diabetic severe combined immunodeficiency (NOD scid) gamma (NSG) transgenic mouse line, which can be endowed with a humanized immune system using CD34+ hematopoietic stem cells. Next-generation NSG models that support human myeloid cell proliferation, such as the NSG-SGM3 mouse, can now provide in vivo conditions that better mimic the natural tumor environment. Human tumor tissue or cell lines can be coengrafted into these mouse models, providing a powerful tool for studying the interactions between human immune cells and human cancers. In this webinar we will discuss the latest advances in mouse models for cancer research and how they are being applied to help us understand the pathways and mechanisms involved in new immune therapies.

Abstract IA21: Impact of thermoregulatory metabolism on immunosuppression and therapeutic responsiveness of tumors

Abstract An important, but underappreciated, aspect of using mouse models in cancer research concerns the impact of basic housing conditions on mouse physiology and how this influences what we have come to consider “baseline” responses. In fact, we recently published data (Kokolus et al., PNAS, 2013; Kokolus et al., Front. Imm. 2014) demonstrating the surprising influence of mild cold stress (resulting from standard, IACUC-enforced housing temperatures) on tumor growth rates, CD8+T cell and dendritic cell function, and the degree of immunosuppressive cell activity which together show that the anti-tumor immune response in control mice is significantly suppressed. Newer data (N. Leigh/K. Kokolus et al., see separate abstract at this meeting) has revealed that mild cold stress also significantly influences the severity of graft vs. host disease (GVHD) in major mouse models of bone marrow transplantation, a condition which also depends upon the balance between effector T cell function and immunosuppressive activity which apparently can be easily shifted by thermoregulatory stress. These and other data, including our observations that intrinsic therapeutic sensitivity of tumor cells is significantly influenced by housing temperature (J. Eng et al., submitted; see separate abstract at this meeting), are disconcerting in terms of revealing the degree to which the outcomes of mouse experimentation can be influenced by these variables which are rarely recognized. However, it has also been fortuitous as we have begun to appreciate intriguing relationships between thermoregulatory metabolism and immune cell activity which, if understood more completely, could be exploited to improve immunotherapy for cancer or other diseases. Mild cold stress stimulates the production of norepinephrine by the sympathetic nervous system which in turn stimulates metabolic heat production via thermogenesis in brown fat and other tissues. This talk will focus on our recognition that increased β-adrenergic signaling by norepinephrine in mildly cold-stressed mice is a key event, driving not only changes in anti-tumor immunity, but also but therapeutic responsiveness in mouse tumor models, as well as the observed differences in GVHD. Excitingly, treatment of mice with common β−blockers largely reverses the phenotypes associated with mild cold stress in each of these models. Overall, these data support the idea that systemic stress is a significant variable that should be considered when evaluating therapies in mouse tumor models or for evaluating the impact of metabolism on the immune response. Alleviating this stress may identify novel targets for improving cancer therapies, and in particular, immunotherapies, in patients. Citation Format: Elizabeth A. Repasky. Impact of thermoregulatory metabolism on immunosuppression and therapeutic responsiveness of tumors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA21.

Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review.

Carcinogenesis is a multistep and also a multifactorial process that involves agents like genetic and environmental factors. Matrix metalloproteinases (MMPs) are major proteolytic enzymes which are involved in cancer cell migration, invasion, and metastasis. Genetic variations in genes encoding the MMPs were shown in human studies to influence cancer risk and phenotypic features of a tumor. The complex role of MMPs seems to be important in the mechanism of carcinogenesis, but it is not well recognized. Rodent studies concentrated particularly on the better understanding of the biological functions of the MMPs and their impact on the pathological process, also through the modification of Mmp genes. This review presents current knowledge and the existing evidence on the importance of selected MMPs in genetic mouse models of cancer and human genetic association studies. Further, this work can be useful for scientists studying the role of the genetic impact of MMPs in carcinogenesis.

Antiangiogenic cancer drug using the zebrafish model.

The process of de novo vessel formation, called angiogenesis, is essential for tumor progression and spreading. Targeting of molecular pathways involved in such tumor angiogenetic processes by using specific drugs or inhibitors is important for developing new anticancer therapies. Drug discovery remains to be the main focus for biomedical research and represents the essence of antiangiogenesis cancer research. To pursue these molecular and pharmacological goals, researchers need to use animal models that facilitate the elucidation of tumor angiogenesis mechanisms and the testing of antiangiogenic therapies. The past few years have seen the zebrafish system emerge as a valid model organism to study developmental angiogenesis and, more recently, as an alternative vertebrate model for cancer research. In this review, we will discuss why the zebrafish model system has the advantage of being a vertebrate model equipped with easy and powerful transgenesis as well as imaging tools to investigate not only physiological angiogenesis but also tumor angiogenesis. We will also highlight the potential of zebrafish for identifying antitumor angiogenesis drugs to block tumor development and progression. We foresee the zebrafish model as an important system that can possibly complement well-established mouse models in cancer research to generate novel insights into the molecular mechanism of the tumor angiogenesis.

Mouse models for cancer research

Mouse models of cancer enable researchers to learn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Journal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue.

Modeling INK4/ARF Tumor Suppression in the Mouse

The INK4/ARF locus encodes the p15(INK4B), p16(INK4A) and p14(ARF) tumor suppressor proteins whose loss of function is associated with the pathogenesis of many human cancers. Dissecting the relative contribution of these genes to growth control in vivo is complicated by their physical contiguity and the frequency of homozygous deletions that inactivate all three components of this locus. While genetically engineered mouse models provide a rigorous system for elucidating cancer gene function, there is some evidence to suggest there are cross-species differences in regulating tumor biology. Given the prevalence of mouse models in cancer research and the potential contribution of such models to preclinical studies, it is important determine to what degree the function of these critical tumor suppressors is conserved between organisms. In this review, we assess the relative biological roles of INK4A, INK4B and ARF in mice and humans with the aim of determining the faithfulness of mouse models and also of obtaining insights into the pattern of specific tumor types that are associated with germline and somatic mutations at components of this locus. We will discuss 1) the contribution of INK4A, INK4B and ARF to growth control in vitro in a series of cell types, 2) the in vivo phenotypes associated with germline loss of function of this locus and 3) the study of Ink4a and Arf in different cancer-specific mouse models.