New Experimental Model Of Brain Tumors In Brains Of Adult Immunocompetent Rats (original) (raw)
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Development of a Large-Animal Human Brain Tumor Xenograft Model In Immunosuppressed Cats
Cancer research, 1991
A large-animal model was developed to facilitate the noninvasive investigation of the effect on the human glioma-derived D-54 MG (glioblastoma multiforme) continuous cell line of a variety of therapeutic regimens. Twenty random-bred male cats were inoculated intracerebrally with I x 10" D-54 MG tumor cells after being initiated on one of three preparatory regimens of cyclosporin A p.o. Reproducible success of D-54 MG xenotransplantation (100%, 6 of 6 cats) was achieved only after pretreatment with 120 mg cyclosporin A p.o. (24-30 mg/kg) daily for •Id days prior to tumor implantation. High-performance liquid chromatography-derived whole blood cyclosporin A 12-h trough levels of >640 ng/ml were seen in successful implants. Lesions ranging from 2 to 20 mm in diameter were seen in cats sacrificed 27-44 days after implan tation with no growth seen in control animals. Histopathological examination revealed the tumors to be well-circum scribed anaplastic intracerebral tumors with some invasion into surround ing host parenchyma. Perivascular lymphocytic cuffing was observed, but intratumoral lymphocytic infiltration was minimal. Gadolinium-EDTAenhanced nuclear magnetic resonance imaging provided accurate tumor localization in TVweighted images ('/'/ 26 ms; /'« 600 ms). Biochemical tests of kidney, liver, and hematological function were within normal limits, although 10% (2 of 20) of the animals developed gingival hyperplasia, and 5% (1 of 20) developed intussusception. The reproducible growth of the D-54 MG human glioblastoma cell line in a large-animal model eliminates many of the limitations associated with the standard nude mouse/rat model, thereby providing a novel test bed for a variety of imaging modalities as well as for drug immunoconjugate localization and toxicity studies.
A Xenotransplant Model of Human Brain Tumors in Wild-Type Mice
iScience
The development of adequate model systems to study human malignancies is crucial for basic and preclinical research. Here, we exploit the ''immune-privileged'' developmental time window to achieve orthotopic xenotransplantation of human brain tumor cells in wild-type (WT) mice. We find that, when transplanted in utero, human glioblastoma (GBM) cells readily integrate in the embryonic mouse brain mirroring key tumor-associated pathological features such as infiltration, vascularization, and complex tumor microenvironment including reactive astrocytes and host immune cell infiltration. Remarkably, activation of the host IBA1 tumor-associated microglia/macrophages depends on the type of glioma cell transplanted, suggesting our approach allows one to study human GBM interactions with the immune system of WT host mice. The embryonic engraftment model complements existing ones, providing a rapid and valuable alternative to study fundamental biology of human brain tumors in immune competent mice.
Induction of human glioma tumor in sprague-dawley rat with intact immune system
Turkish Neurosurgery, 2016
it provides the possibility to investigate the histological and genetic characteristics of neoplasms (11). Commonly applied models that generate brain neoplasms in animals include: a) Chemical mutagen-induced models (36) b) Genetic modification-induced models (2) c) Xenograft induced models (20, 30). These models have led to better understanding of the mechanisms related to tumor progression. However, these models are not comprehensive, and each of the models has its own issues (18, 31). The major drawbacks of chemically induced brain tumors include their histological characteristics █ INTRODUCTION G lioblastoma (GBM) is a common and aggressive type of brain tumor in humans. Despite improvement in therapy techniques, patients have a short life expectancy (12-15 months) and GBM is an incurable disease (7, 32). The inefficacy of current treatment methods stimulates the researchers to seek novel therapeutic agents and strategies. So, development of laboratory and animal model is a substantial step for the advances in the treatment of GBM (19, 23). An animal model is an important tool for the understanding of complex phenomena involved in glioma generation; and AIm: Glioblastoma (GBM) is an aggressive brain tumor in humans. The median survival rate of patients is one year after the diagnosis. So, development of an animal model is necessary for the advances in the research treatment of GBM. The aim of this study was to investigate the capability of human glioma cells in inducing glioma tumors in rats with intact immune system. mATERIAl and mEThODS: U87 cells were implanted in the frontal lobe of rats without suppressing the immune system. We used magnetic resonance imaging (MRI), Hematoxylin-Eosin (H&E) and Immunohistochemical (IHC) staining to assess characteristics of tumor. RESUlTS: At the 10 th and 14 th days of tumor inoculation, MRI images contained the tumor areas in the brain. All tumor-bearing rats developed tumors. The rats retained the morphology and histological characteristics of human glioma. Animals mimic GBM characteristics, such as mitotic activity, invasion, neovascularization, necrosis and pseudopalisading cells. IHC staining revealed tumor growth and progression in the tumor-bearing rats. CONClUSION: This model is a standard system for studying the tumor phenotype, genotype, and for evaluating the efficacy of anti-cancer agents. It is a reliable, simple, inexpensive, and easily reproducible model, which may be a way for pre-clinical studies.
Journal of Neuro-Oncology, 2009
In this review we will describe eight commonly used rat brain tumor models and their application for the development of novel therapeutic and diagnostic modalities. The C6, 9L and T9 gliomas were induced by repeated injections of methylnitrosourea (MNU) to adult rats. The C6 glioma has been used extensively for a variety of studies, but since it arose in an outbred Wistar rat, it is not syngeneic to any inbred strain, and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma has been used widely and has provided important information relating to brain tumor biology and therapy. The T9 glioma, although not generally recognized, was and probably still is the same as the 9L. Both of these tumors arose in Fischer rats and can be immunogenic in syngeneic hosts, a fact that must be taken into consideration when used in therapy studies, especially if survival is the endpoint. The RG2 and F98 gliomas were both chemically induced by administering ethylnitrosourea (ENU) to pregnant rats, the progeny of which developed brain tumors that subsequently were propagated in vitro and cloned. They are either weakly or non-immunogenic and have an invasive pattern of growth and uniform lethality, which make them particularly attractive models to test new therapeutic modalities. The CNS-1 glioma was induced by administering MNU to a Lewis rat. It has an infiltrative pattern of growth and is weakly immunogenic, which should make it useful in experimental neuro-oncology. Finally, the BT4C glioma was induced by administering ENU to a BD IX rat, following which brain cells were propagated in vitro until a tumorigenic clone was isolated. This tumor has been used for a variety of studies to evaluate new therapeutic modalities. The Avian Sarcoma Virus (ASV) induced tumors, and a continuous cell line derived from one of them designated RT-2, have been useful for studies in which de novo tumor induction is an important requirement. These tumors also are immunogenic and this limits their usefulness for therapy studies. It is essential to recognize the limitations of each of the models that have been described, and depending upon the nature of the study to be conducted, it is important that the appropriate model be selected.
Immunological considerations of modern animal models of malignant primary brain tumors
Journal of Translational Medicine, 2009
Recent advances in animal models of glioma have facilitated a better understanding of biological mechanisms underlying gliomagenesis and glioma progression. The limitations of existing therapy, including surgery, chemotherapy, and radiotherapy, have prompted numerous investigators to search for new therapeutic approaches to improve quantity and quality of survival from these aggressive lesions. One of these approaches involves triggering a tumor specific immune response. However, a difficulty in this approach is the the scarcity of animal models of primary CNS neoplasms which faithfully recapitulate these tumors and their interaction with the host's immune system. In this article, we review the existing methods utilized to date for modeling gliomas in rodents, with a focus on the known as well as potential immunological aspects of these models. As this review demonstrates, many of these models have inherent immune system limitations, and the impact of these limitations on studies on the influence of pre-clinical therapeutics testing warrants further attention.
Neuropathology and Applied Neurobiology, 2011
A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients Aims: Brain metastasis is a common cause of mortality in cancer patients, and associated with poor prognosis. Our objective was to develop a clinically relevant animal model by transplanting human biopsy spheroids derived from metastatic lesions into brains of immunodeficient rats. Methods: Nine different patient brain metastases from four different primary cancers were implanted into brains of immunodeficient rats. The xenografts were compared with patient tumours by magnetic resonance imaging, histochemistry, immunohistochemistry and DNA copy number analysis. Results: After transplantation, tumour growth was achieved in seven out of nine human brain metastases. Spheroids derived from four of the metastases initiated in the rat brains were further serially transplanted into new animals and a 100% tumour take was observed during second passage. Three of the biopsies were implanted subcutaneously, where no tumour take was observed. The animal brain metastases exhibited similar radiological features as observed clinically. Histological comparisons between the primary tumours from the patients, the patient brain metastases and the derived xenografts showed striking similarities in histology and growth patterns. Also, immunohistochemistry showed a strong marker expression similarity between the patient tumours and the corresponding xenografts. DNA copy number analysis between the brain metastases, and the corresponding xenografts revealed strong similarities in gains and losses of chromosomal content. Conclusion: We have developed a representative in vivo model for studying the growth of human metastatic brain cancers. The model described represents an important tool to assess responses to new treatment modalities and for studying mechanisms behind metastatic growth in the central nervous system. biomed.uib.no † †These authors have contributed equally to this publication.
A model for xenotransplantation of human malignant astrocytomas into the brain of normal adult rats
Acta Neurochirurgica, 1982
Transplantation of human brain tumours into the brain of normal laboratory animals is still considered to be unsatisfactory by many researchers, despite the fact that the brain is considered an immunologically privileged site. We present in this paper a model of xenotransplantation fo human astrocytomas grade Ill-IV into the brain of normal, adult Sprague-Dawley rats with good take rates, i.e. takes in two thirds of the animals, half of these with large, infiltrating turnouts. The transplants are placed using a microsurgical technique in the vessel-rich choroidal fissure in the host brain from where rapid vascularization occurs. The technique has previously been used for CNS-regeneration studies. This model should provide an excellent opportunity to study human malignant astrocytomas in a milieu as natural as possible.
Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?
Frontiers in oncology, 2016
Immunotherapy is now advancing at remarkable pace for tumors located in various tissues, including the brain. Strategies launched decades ago, such as tumor antigen-specific therapeutic vaccines and adoptive transfer of tumor-infiltrating lymphocytes are being complemented by molecular engineering approaches allowing the development of tumor-specific TCR transgenic and chimeric antigen receptor T cells. In addition, the spectacular results obtained in the last years with immune checkpoint inhibitors are transfiguring immunotherapy, these agents being used both as single molecules, but also in combination with other immunotherapeutic modalities. Implementation of these various strategies is ongoing for more and more malignancies, including tumors located in the brain, raising the question of the immunological particularities of this site. This may necessitate cautious selection of tumor antigens, minimizing the immunosuppressive environment and promoting efficient T cell trafficking ...