Radiation-Induced Changes in Tumor Vessels and Microenvironment Contribute to Therapeutic Resistance in Glioblastoma

Seo, Yun‐Soo; Ko, In Ok; Park, Hyejin; Jeong, Ye Ji; Park, Ji Ae; Kim, Kwang Seok; Park, Jong Bae; Lee, Hae June

doi:10.3389/fonc.2019.01259

Cited by 40 publications

(32 citation statements)

References 37 publications

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“…When cells are stimulated, the microenvironment around the cells has a buffer effect, which may lead to the degradation of CD3d. There is an inhibitory effect on its increase, so the increase in CD3d in the brain is not as large as it is in cells (Seo et al, ). Apoptosis is an autonomous procedure of cell death that is of great significance to the development of the nervous system and to maintaining cellular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

et al. 2020

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Introduction Methamphetamine (METH) is a psychostimulant drug with complicated neurotoxicity, and abuse of METH is very common. Studies have shown that METH exposure causes alpha‐synuclein (α‐syn) accumulation. However, the mechanism of α‐syn accumulation has not been determined. Methods In this study, we established cell and animal models of METH intoxication to evaluate how METH affects α‐syn expression. In addition, to explore METH‐induced neurotoxicity, we measured the level of Parkin and the phosphorylation levels of α‐syn, Polo‐like kinase 2 (PLK2), the proteasome activity marker CD3δ, and the apoptosis‐related proteins Caspase‐3 and PARP. Parkin is a key enzyme in the ubiquitin–proteasome system. In addition, the effect of Parkin on METH‐induced neurotoxicity was investigated by overexpressing it in vitro and in vivo. Results METH exposure increased polyubiquitin and α‐syn expression, as did MG132. Furthermore, the level of Parkin and the interaction between Parkin and α‐syn decreased after METH exposure. Importantly, the increases in α‐syn expression and neurotoxicity were relieved by Parkin overexpression. Conclusions By establishing stable cell lines and animal models that overexpress Parkin, we confirmed Parkin as an important factor in METH‐induced α‐syn degradation dysfunction in vitro and in vivo. Parkin may be a promising target for the treatment of METH‐induced neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

et al. 2020

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“…While ADSCs are widely applied in pre-clinical and clinical applications, they might not attain their full efficacy, even when applied in autologous or allogenic settings. This efficacy might be related to the route of administration being mostly realized through intravenous injection [148].…”

Section: Adscs Issues Between Hopes and Limitsmentioning

confidence: 99%

Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing

Mazini

Rochette

Admou

et al. 2020

IJMS

341

255

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Adipose tissue derived stem cells (ADSCs) are mesenchymal stem cells identified within subcutaneous tissue at the base of the hair follicle (dermal papilla cells), in the dermal sheets (dermal sheet cells), in interfollicular dermis, and in the hypodermis tissue. These cells are expected to play a major role in regulating skin regeneration and aging-associated morphologic disgraces and structural deficits. ADSCs are known to proliferate and differentiate into skin cells to repair damaged or dead cells, but also act by an autocrine and paracrine pathway to activate cell regeneration and the healing process. During wound healing, ADSCs have a great ability in migration to be recruited rapidly into wounded sites added to their differentiation towards dermal fibroblasts (DF), endothelial cells, and keratinocytes. Additionally, ADSCs and DFs are the major sources of the extracellular matrix (ECM) proteins involved in maintaining skin structure and function. Their interactions with skin cells are involved in regulating skin homeostasis and during healing. The evidence suggests that their secretomes ensure: (i) The change in macrophages inflammatory phenotype implicated in the inflammatory phase, (ii) the formation of new blood vessels, thus promoting angiogenesis by increasing endothelial cell differentiation and cell migration, and (iii) the formation of granulation tissues, skin cells, and ECM production, whereby proliferation and remodeling phases occur. These characteristics would be beneficial to therapeutic strategies in wound healing and skin aging and have driven more insights in many clinical investigations. Additionally, it was recently presented as the tool key in the new free-cell therapy in regenerative medicine. Nevertheless, ADSCs fulfill the general accepted criteria for cell-based therapies, but still need further investigations into their efficiency, taking into consideration the host-environment and patient-associated factors.

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“…Female athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected PDX GBM cell lines (GBM 6,10,12, 39, 46, 76, 123, 164, 196; per group, per line). GBM 6 cells were additionally implanted 6 months after completion of fractionated radiation (4Gy x 10 fractions or 2Gy x 30 fractions) vs sham radiation.…”

Section: Methodsmentioning

confidence: 99%

“…A panel of well characterized PDX GBM cell lines ( GBM 6,10,12,39,46,76,123,143,164,196) were obtained from flank tumors and cultured in vitro (1-3 weeks). Detailed cell line information can be found in Table 1.…”

Section: Pdx Gbm Cell Linesmentioning

confidence: 99%

“…A growing body of literature has elucidated the substantial impacts of radiotherapy on non-tumor cells present in the tumor microenvironment and surrounding CNS parenchyma [10,11]. Although radiation remains standard of care and despite the nearly uniform GBM recurrence rates, we and others have made the concerning observation that the radiated microenvironment actually increases the aggressiveness of GBM cells implanted into an irradiated brain [12,13,14]. To date, studies reporting this phenomena have each evaluated a single cell line, leaving open the question of how widespread this susceptibility to increased aggressiveness may be across the clinical and moleulular spectrum of human GBM.…”

Section: Introductionmentioning

confidence: 99%

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Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts

Zhang

Olson

Carlstrom

et al. 2020

Preprint

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ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected PDX GBM cell lines (GBM 6,10,12, 39, 46, 76, 123, 164, 196; per group, per line). GBM 6 cells were additionally implanted 6 months after completion of fractionated radiation (4Gy x 10 fractions or 2Gy x 30 fractions) vs sham radiation.Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. ResultOf nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196); similar to previous observations with GBM 143. GBM 6 was also evaluated 6 months after fractionated radiation yielding similar results. However, two lines yielded prolonged survival in the 4 pre-radiated brain (GBM 10, 12); GBM12 and 10 demonstrated the fastest baseline growth in the non-radiated brain; GBM 39, 123 whose rate of growth was not impacted by the radiated brain, demonstrated a an intermediate baseline growth rate between that of those positively and negatively impacted by the radiated brain microenvironment. No other clinical or molecular phenotype was found to consistently correlate with response to the radiated microenvironment. ConclusionAmong a total of 10 total human GBM lines evaluated to date, 60% induce faster mortality in a radiated microenvironment, and 20% induce slower mortality. These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.

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Radiation-Induced Changes in Tumor Vessels and Microenvironment Contribute to Therapeutic Resistance in Glioblastoma

Cited by 40 publications

References 37 publications

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts

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