Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour

Kovalchuk, Anna; Mychasiuk, Richelle; Muhammad, Arif; Hossain, Shakhawat; Ilnytskyy, Slava; Ghose, A.M.; Kirkby, Charles; Ghasroddashti, E; Kovalchuk, Olga; Kolb, Bryan

doi:10.18632/oncotarget.6596

Cited by 31 publications

(29 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The BE has been observed in several species, suggesting it provides a beneficial effect that has been conserved through evolution (72)(73)(74). One consequence of BE is an adaptive response which renders bystander cells more resistant to future stressors (52).…”

Section: Cisplatin Evs Can Cause Bystander Effect and An Adaptive Resmentioning

confidence: 99%

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

105

View full text Add to dashboard Cite

Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

show abstract

Section: Cisplatin Evs Can Cause Bystander Effect and An Adaptive Resmentioning

confidence: 99%

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

105

View full text Add to dashboard Cite

show abstract

“…It is sensitive to a wide array of stimuli, including hormones, drugs, toxic chemicals, stress, and social experiences (Kolb et al, 2012 ). In our previous study, we showed that direct and bystander irradiation led to altered dendritic morphology and aberrant gene expression in the PFC tissues of exposed female rats (Kovalchuk et al, 2016 ). Here, for the first time, we show that very low, clinically, and occupationally relevant doses of radiation affect gene expression in the PFC in a sex-specific manner.…”

Section: Discussionmentioning

confidence: 95%

“…Mancuso et al ( 2008 , 2011 ) reported the presence of bystander effects in the cerebellums of mutant mouse strains following irradiation of the animals' bodies. Recently, we showed that directly irradiating a rat liver while shielding the rest of the animal caused distal systemic effects—molecular and neuroanatomical changes in brain and affected animal behavior (Kovalchuk et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Profound and Sexually Dimorphic Effects of Clinically-Relevant Low Dose Scatter Irradiation on the Brain and Behavior

Kovalchuk

Mychasiuk

Muhammad

et al. 2016

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

Irradiated cells can signal damage and distress to both close and distant neighbors that have not been directly exposed to the radiation (naïve bystanders). While studies have shown that such bystander effects occur in the shielded brain of animals upon body irradiation, their mechanism remains unexplored. Observed effects may be caused by some blood-borne factors; however they may also be explained, at least in part, by very small direct doses received by the brain that result from scatter or leakage. In order to establish the roles of low doses of scatter irradiation in the brain response, we developed a new model for scatter irradiation analysis whereby one rat was irradiated directly at the liver and the second rat was placed adjacent to the first and received a scatter dose to its body and brain. This work focuses specifically on the response of the latter rat brain to the low scatter irradiation dose. Here, we provide the first experimental evidence that very low, clinically relevant doses of scatter irradiation alter gene expression, induce changes in dendritic morphology, and lead to behavioral deficits in exposed animals. The results showed that exposure to radiation doses as low as 0.115 cGy caused changes in gene expression and reduced spine density, dendritic complexity, and dendritic length in the prefrontal cortex tissues of females, but not males. In the hippocampus, radiation altered neuroanatomical organization in males, but not in females. Moreover, low dose radiation caused behavioral deficits in the exposed animals. This is the first study to show that low dose scatter irradiation influences the brain and behavior in a sex-specific way.

show abstract

“…Our recent study published in the Oncotarget (2016) was the first to conduct a large-scale analysis of the molecular, neuroanatomical, and behavioral consequences of direct and bystander low-dose irradiation on the rodent brain. 41 The key findings were that: (i) direct head exposure to radiation doses as low as 24.5 cGy induced persistent, albeit small, increases in DNA damage, as measured by levels of gH2AX and effects on gene expression in the PFCs of exposed animals; (ii) bystander effects exist in the brain following liver irradiation and manifest as small increases in DNA damage, as measured by levels of gH2AX and alterations to gene and protein expressions; (iii) both head and liver irradiation reduce dendritic space (and, thus, synapse numbers) in measures of spine density, dendritic complexity, and dendritic length; (iv) the neuroanatomical effects are brain region-specific and are more pronounced in females; and (v) both head and liver irradiation alter behavior. 41 These intriguing bystander effects may be caused by certain blood-derived factors or by very small, scattered irradiation doses received by the brain.…”

Section: Direct Bystander and Scatter Low-dose Radiation Effects Onmentioning

confidence: 99%

Low dose radiation effects on the brain – from mechanisms and behavioral outcomes to mitigation strategies

Kovalchuk

Kolb

2017

Cell Cycle

Self Cite

View full text Add to dashboard Cite

Based on the most recent estimates by the Canadian Cancer Society, 2 in 5 Canadians will develop cancer in their lifetimes. More than half of all cancer patients receive some type of radiation therapy, and all patients undergo radiation-based diagnostics. While radiation is one of the most important diagnostic and treatments modalities, high-dose cranial radiation therapy causes numerous central nervous system side-effects, including declines in cognitive function, memory, and attention. While the mechanisms of these effects have been studies, they still need to be further elucidated. On the other hand, the effects of low dose radiation as well as indirect radiation bystander effects on the brain remain elusive. We pioneered analysis of the molecular and cellular effects of low dose direct, bystander and scatter radiation on the brain. Using a rat model, we showed that low dose radiation exposures cause molecular and cellular changes in the brain and impacts animal behavior. Here we reflect upon our recent findings and current state of knowledge in the field, and suggest novel radiation effect biomarkers and means of prevention. We propose strategies and interventions to prevent and mitigate radiation effects on the brain.

show abstract

Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour

Cited by 31 publications

References 46 publications

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Profound and Sexually Dimorphic Effects of Clinically-Relevant Low Dose Scatter Irradiation on the Brain and Behavior

Low dose radiation effects on the brain – from mechanisms and behavioral outcomes to mitigation strategies

Contact Info

Product

Resources

About