Ionizing Radiation-Induced Extracellular Vesicle Release Promotes AKT-Associated Survival Response in SH-SY5Y Neuroblastoma Cells

Tortolici, Flavia; Vumbaca, Simone; Incocciati, Bernadette; Dayal, Renu; Aquilano, Katia; Giovanetti, Anna; Rufini, Stefano

doi:10.3390/cells10010107

Cited by 19 publications

(22 citation statements)

References 50 publications

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“…In the same cancer type a promigratory role of radiation-related EVs was reported (Arscot et al 2013 ). Likewise, EVs from irradiated head and neck cancer and neuroblastoma cells stimulate survival, migration and invasiveness in in vitro approaches (Mutschelknaus et al 2016 , 2017 ; Tortolici et al 2021 ). However, there are also studies reporting the induction of harmful effects of EVs from irradiated cancer cells in recipient cells, like increased chromosomal damage and increased ROS levels induced by EVs from irradiated MCF-7 breast cancer cells (Al-Mayah et al 2012 ; Nakaoka et al 2021 ).…”

Section: Out-of-field Effects: Model Systems and Mechanismsmentioning

confidence: 99%

Out-of-field effects: lessons learned from partial body exposure

Pazzaglia

Eidemüller

Lumniczky³

et al. 2022

Radiat Environ Biophys

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Partial body exposure and inhomogeneous dose delivery are features of the majority of medical and occupational exposure situations. However, mounting evidence indicates that the effects of partial body exposure are not limited to the irradiated area but also have systemic effects that are propagated outside the irradiated field. It was the aim of the “Partial body exposure” session within the MELODI workshop 2020 to discuss recent developments and insights into this field by covering clinical, epidemiological, dosimetric as well as mechanistic aspects. Especially the impact of out-of-field effects on dysfunctions of immune cells, cardiovascular diseases and effects on the brain were debated. The presentations at the workshop acknowledged the relevance of out-of-field effects as components of the cellular and organismal radiation response. Furthermore, their importance for the understanding of radiation-induced pathologies, for the discovery of early disease biomarkers and for the identification of high-risk organs after inhomogeneous exposure was emphasized. With the rapid advancement of clinical treatment modalities, including new dose rates and distributions a better understanding of individual health risk is urgently needed. To achieve this, a deeper mechanistic understanding of out-of-field effects in close connection to improved modelling was suggested as priorities for future research. This will support the amelioration of risk models and the personalization of risk assessments for cancer and non-cancer effects after partial body irradiation.

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Section: Out-of-field Effects: Model Systems and Mechanismsmentioning

confidence: 99%

Out-of-field effects: lessons learned from partial body exposure

Pazzaglia

Eidemüller

Lumniczky³

et al. 2022

Radiat Environ Biophys

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“…Generally, physical stimulation stresses cells to produce more EVs [ 172 ]. Ionizing radiation has been reported to increase the number of EVs produced by cancer cells in a dose- and time-dependent manner [ 18 , 113 , 114 , 115 ]. The upregulation of EV production by cancer cells upon exposure to ionizing radiation has been linked with the DNA-damaged activated p53 signaling pathway [ 173 , 174 ].…”

Section: Strategies To Increase Production Of Extracellular Vesiclesmentioning

confidence: 99%

“…EVs produced by cancer cells can also be employed as diagnostic cancer biomarkers, since they contain cargo that reflects the tumor’s genetic and mutational status [ 16 , 17 ]. Understanding of the impact of tumor microenvironments, e.g., pH, extracellular matrix (ECM) stiffness, oxidative stress, hypoxia, and nutrient deprivation, as well as of treatment modalities, e.g., irradiation, chemotherapy, and photodynamic therapy, on the EV secretion of cancer cells has been instrumental in enhancing the EV production by cancer cells in vitro [ 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Scalable Production of Extracellular Vesicles and Its Therapeutic Values: A Review

Kee

Al-Masawa

et al. 2022

IJMS

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Extracellular vesicles (EVs) are minute vesicles with lipid bilayer membranes. EVs are secreted by cells for intercellular communication. Recently, EVs have received much attention, as they are rich in biological components such as nucleic acids, lipids, and proteins that play essential roles in tissue regeneration and disease modification. In addition, EVs can be developed as vaccines against cancer and infectious diseases, as the vesicle membrane has an abundance of antigenic determinants and virulent factors. EVs for therapeutic applications are typically collected from conditioned media of cultured cells. However, the number of EVs secreted by the cells is limited. Thus, it is critical to devise new strategies for the large-scale production of EVs. Here, we discussed the strategies utilized by researchers for the scalable production of EVs. Techniques such as bioreactors, mechanical stimulation, electrical stimulation, thermal stimulation, magnetic field stimulation, topographic clue, hypoxia, serum deprivation, pH modification, exposure to small molecules, exposure to nanoparticles, increasing the intracellular calcium concentration, and genetic modification have been used to improve the secretion of EVs by cultured cells. In addition, nitrogen cavitation, porous membrane extrusion, and sonication have been utilized to prepare EV-mimetic nanovesicles that share many characteristics with naturally secreted EVs. Apart from inducing EV production, these upscaling interventions have also been reported to modify the EVs’ cargo and thus their functionality and therapeutic potential. In summary, it is imperative to identify a reliable upscaling technique that can produce large quantities of EVs consistently. Ideally, the produced EVs should also possess cargo with improved therapeutic potential.

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“…552 EVs secreted by irradiated cancer cells mediate bystander effects on other tumour cells, contributing to stress signalling, DNA repair and migration. [552][553][554][555] As BCL6 appeared to upregulate stress response signalling proteins in response to acute IR (Chapter 3), its export to surrounding GBM cells could help to induce stress responses in these cells.…”

Section: 444: Exocytosis and Caveolaementioning

confidence: 99%

“…552 In GBM and other cancers, IRinduced EVs are taken up by surrounding cancer cells, where they induce bystander effects such as activation of DNA repair pathways, stress signalling and migration. [552][553][554][555] Therefore, it is possible that BCL6 is secreted in EVs in response to acute IR treatment to transmit stress responses important for cell survival to surrounding GBM cells. It is also possible that BCL6 has another function at the plasma membrane, such as regulation of the exo-or endocytosis of signalling receptors.…”

Section: 33: Bcl6 Associates With Plasma Membrane Proteins After Irra...mentioning

confidence: 99%

BCL6 is a context-dependent mediator of the glioblastoma therapy response

Tribe¹

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<p>Glioblastoma is a rapidly fatal brain cancer with no cure. The resistance of glioblastoma tumours to available therapies means that more effective treatments are desperately needed. Previous research showed that the transcriptional repressor protein BCL6 is upregulated by chemo- and radiotherapy in glioblastoma and that inhibition of BCL6 enhances the effectiveness of these therapies. Therefore, BCL6 is a promising target to improve the efficacy of available treatments for glioblastoma. BCL6 is known as a transcriptional repressor in germinal centre B cells and an oncogene in lymphoma, as well as in other cancers. However, previous research indicated that BCL6 induced by therapy in glioblastoma may not act as a transcriptional repressor. This thesis aimed to clarify the role of BCL6 in the therapy response of glioblastoma. The effect of BCL6 inhibition on the whole proteome response of glioblastoma cells to DNA-damaging treatments was investigated. This confirmed that BCL6 was involved in the therapy response of glioblastoma and that acute irradiation appeared to cause BCL6 to switch from a repressor of the DNA damage response to a promoter of stress response signalling. Rapid immunoprecipitation mass spectrometry of endogenous proteins enabled identification of proteins associated with BCL6 in untreated and irradiated glioblastoma cells. BCL6 appeared to be a transcriptional regulator in untreated glioblastoma and its association with the corepressor NCOR2 was validated using proximity ligation assays. However, association with nuclear proteins was lost in response to acute irradiation. This was accompanied by the irradiation-induced association of BCL6 with plasma membrane proteins. Targeted long-read transcript sequencing did not reveal differential alternative splicing of BCL6 in response to acute irradiation. This indicated that the canonical BCL6 protein was expressed in irradiated glioblastoma cells and that the change in BCL6 function must be mediated by mechanisms other than the production of splice variants, such as through post-translational modification. Overall, these results support the hypothesis that BCL6 is involved in the therapy resistance of glioblastoma cells but reveal that its activity is context-dependent and may be mediated by the intensity of cellular stress.</p>

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Ionizing Radiation-Induced Extracellular Vesicle Release Promotes AKT-Associated Survival Response in SH-SY5Y Neuroblastoma Cells

Cited by 19 publications

References 50 publications

Out-of-field effects: lessons learned from partial body exposure

Out-of-field effects: lessons learned from partial body exposure

Scalable Production of Extracellular Vesicles and Its Therapeutic Values: A Review

BCL6 is a context-dependent mediator of the glioblastoma therapy response

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