The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model

García, Celina; Dubois, Luiz Gustavo; Xavier, Anna L.R.; Geraldo, Luiz Henrique Medeiros; Fonseca, Anna Carolina Carvalho da; Correia, Ana Helena Pereira; Meirelles, Fernanda; Ventura, G.; Romão, Luciana; Canêdo, Nathalie Henriques Silva; Souza, Jorge Marcondes de; Menezes, João R.L.; Moura‐Neto, Vivaldo; Tovar‐Moll, Fernanda; Lima, Flávia Regina Souza

doi:10.1186/1471-2407-14-923

Cited by 33 publications

(27 citation statements)

References 59 publications

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“…1D ), probably because these tumor stem-like cells have been selected through the previous TMZ treatment. GBM11 cells could also grow in an in vivo animal model (data not shown), as described by Garcia et al ( 36 ). This suggests that the glioma stem-like cells are able to contribute to the tumor growing in vivo and that the previous treatment with TMZ may have contributed to the recurrence of a tumor endowed with a higher number of cancer stem-like cells.…”

Section: Discussionsupporting

confidence: 72%

Glioblastoma entities express subtle differences in molecular composition and response to treatment

et al. 2017

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Glioblastoma (GBM) is a grade IV astrocytoma. GBM patients show resistance to chemotherapy such as temozolomide (TMZ), the gold standard treatment. In order to simulate the molecular mechanisms behind the different chemotherapeutic responses in GBM patients we compared the cellular heterogeneity and chemotherapeutic resistance mechanisms in different GBM cell lines. We isolated and characterized a human GBM cell line obtained from a GBM patient, named GBM11. We studied the GBM11 behaviour when treated with Tamoxifen (TMX) that, among other functions, is a protein kinase C (PKC) inhibitor, alone and in combination with TMZ in comparison with the responses of U87 and U118 human GBM cell lines. We evaluated the cell death, cell cycle arrest and cell proliferation, mainly through PKC expression, by flow cytometry and western blot analysis and, ultimately, cell migration capability and F-actin filament disorganization by fluorescence microscopy. We demonstrated that the constitutive activation of p-PKC seems to be one of the main metabolic implicated on GBM malignancy. Despite of its higher resistance, possibly due to the overexpression of P-glycoprotein and stem-like cell markers, GBM11 cells presented a subtle different chemotherapeutic response compared to U87 and U118 cells. The GBM11, U87, U118 cell lines show subtle molecular differences, which clearly indicate the characterization of GBM heterogeneity, one of the main reasons for tumor resistance. The adding of cellular heterogeneity in molecular behaviour constitutes a step closer in the understanding of resistant molecular mechanisms in GBM, and can circumvents the eventual impaired therapy.

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Section: Discussionsupporting

confidence: 72%

Glioblastoma entities express subtle differences in molecular composition and response to treatment

et al. 2017

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“…However, during pathological conditions such as infections, trauma, or cerebral ischemia, microglia rapidly change their morphology from branched cells to reactive cells with thickened and retracted processes, acquiring a more rounded shape, referred to as amoeboid [55,56]. Chronic microglial activation is an important feature of many neurodegenerative diseases contributing significantly to disease progression [10].…”

Section: Discussionmentioning

confidence: 99%

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion

Leardini-Tristão

Andrade

García

et al. 2020

J Neuroinflammation

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Background: Brain circulation disorders such as chronic cerebral hypoperfusion have been associated with a decline in cognitive function during the development of dementia. Astrocytes together with microglia participate in the immune response in the CNS and make them potential sentinels in the brain parenchyma. In addition, astrocytes coverage integrity has been related to brain homeostasis. Currently, physical exercise has been proposed as an effective intervention to promote brain function improvement. However, the neuroprotective effects of early physical exercise on the astrocyte communication with the microcirculation and the microglial activation in a chronic cerebral hypoperfusion model are still unclear. The aim of this study was to investigate the impact of early intervention with physical exercise on cognition, brain microcirculatory, and inflammatory parameters in an experimental model of chronic cerebral hypoperfusion induced by permanent bilateral occlusion of the common carotid arteries (2VO). Methods: Wistar rats aged 12 weeks were randomly divided into four groups: Sham-sedentary group (Sham-Sed), Sham-exercised group (Sham-Ex), 2VO-sedentary group (2VO-Sed), and 2VO-exercised group (2VO-Ex). The early intervention with physical exercise started 3 days after 2VO or Sham surgery during 12 weeks. Then, the brain functional capillary density and endothelial-leukocyte interactions were evaluated by intravital microscopy; cognitive function was evaluated by open-field test; hippocampus postsynaptic density protein 95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the capillaries, microglial activation, and structural capillary density were evaluated by immunohistochemistry.Results: Early moderate physical exercise was able to normalize functional capillary density and reduce leukocyte rolling in the brain of animals with chronic cerebral hypoperfusion. These effects were accompanied by restore synaptic protein and the improvement of cognitive function. In addition, early moderate exercise improves astrocytes coverage in blood vessels of the cerebral cortex and hippocampus, decreases microglial activation in the hippocampus, and improves structural capillaries in the hippocampus.(Continued on next page) (Continued from previous page)Conclusions: Microcirculatory and inflammatory changes in the brain appear to be involved in triggering a cognitive decline in animals with chronic cerebral ischemia. Therefore, early intervention with physical exercise may represent a preventive approach to neurodegeneration caused by chronic cerebral hypoperfusion.

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“…While humanized mice are undeniably useful for testing human-specific immunotherapeutics, that system is complex, costly and precludes the use of existing genetically modified immunocompetent mice. There has been one previously reported observation of spontaneous immune tolerance against an adherently grown human GBM cell line in adult SWR/J mice [ 21 ]. However, the authors did not provide reasons for the absence of the species-dependent host vs. graft rejection in their model and their experiments were terminated at day 14.…”

Section: Discussionmentioning

confidence: 99%

An immunocompetent mouse model of human glioblastoma

Semenkow

Kahlert

et al. 2017

Oncotarget

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Orthotopic xenotransplantation studies represent the final stage in preclinical cancer research and could facilitate the implementation of precision medicine. To date, these xenografts have been tested in immunodeficient animals, but complete elimination of the adaptive immunity is a significant drawback. We present a method of efficient human glioblastoma (GBM) cell engraftment in adult mice with intact immune systems, mediated by a transient blockade of T-cell co-stimulation. Compared to transplants grown in immunodeficient hosts, the resulting tumors more accurately resemble the clinical pathophysiology of patient GBMs, which are characterized by blood-brain-barrier leakage and strong neo-vascularization. We expect our method to have great utility for studying human tumor cell biology, particularly in the field of cancer immunotherapy and in studies on microenvironmental interactions. Given the straightforward approach, the method may also be applicable to other tumor types and additional model organisms.

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The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model

Cited by 33 publications

References 59 publications

Glioblastoma entities express subtle differences in molecular composition and response to treatment

Glioblastoma entities express subtle differences in molecular composition and response to treatment

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion

An immunocompetent mouse model of human glioblastoma

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