Backgrounds:Breast cancer metastasis remains the leading cause of mortality and frequently targets the bone.Breast cancer cells release soluble factors and extracellular vesicles that disrupt bone marrow(BM)/bone home...Backgrounds:Breast cancer metastasis remains the leading cause of mortality and frequently targets the bone.Breast cancer cells release soluble factors and extracellular vesicles that disrupt bone marrow(BM)/bone homeostasis,promoting osteoclastogenesis and the accumulation of senescent cells.In line with updated cancer hallmarks,senescent mesenchymal stem/stromal cells(MSCs),osteoblasts,and osteocytes contribute to remodeling of the BM microenvironment,thereby favoring pre-metastatic niche(PMN)formation and subsequent bone metastasis.We previously demonstrated that untreated stage III-B breast cancer patients(BCPs)exhibit increased oxidative stress and elevated reactive oxygen species(ROS)levels,accompanied by senescent and functionally impaired BM-MSCs—key regulators of BM/bone homeostasis.In the present study,we sought to identify the molecular targets affected by oxidative stress that drive MSC senescence in these patients.Methods:BM-MSCs were isolated from untreated stage III-B BCPs and healthy volunteers(HVs).Oxidative stress responses were evaluated by quantitative real-time PCR(qRT-PCR)analysis of stress-and antioxidant-related genes.Oxidative damage to DNA,proteins,and lipids was assessed using alkaline comet assay,chromosomal aberration(CAs)analysis,micronuclei(MN)and nuclear blebs(NBs)quantification,protein carbonyl content,and detection of 4-hydroxynonenal(4-HNE)adducts.The MSC secretome was analyzed by label-free quantitative proteomics followed by Gene Ontology enrichment analysis.Results:Our results show that elevated oxidative stress in BCPs induces the overexpression of oxidative stress-related and antioxidant response genes in BM-MSCs;however,this response is insufficient to prevent extensive ROS-induced damage to deoxyribonucleic acid(DNA),proteins,and lipids.In addition,proteomic analysis of the BM-MSC secretome revealed a distinct protein expression profile in BCPs compared with HVs.Conclusions:Together,these findings highlight oxidative stress-induced MSC damage as a key mechanism contributing to PMN formation and suggest potential therapeutic targets to mitigate bone metastasis in advanced breast cancer.展开更多
Several authors have addressed the importance of mitochondrial function in inflammatory syn-dromes,as it may play a role in the genesis of tissue injury.Sepsis and exposition to environmental particles are examples of...Several authors have addressed the importance of mitochondrial function in inflammatory syn-dromes,as it may play a role in the genesis of tissue injury.Sepsis and exposition to environmental particles are examples of inflammatory conditions.Sepsis occurs with an exacerbated inflammatory response that damages tissue mitochondria and impairs bioenergetic processes.One of the current hypotheses for the molecular mech-anisms underlying the complex condition of sepsis is that enhanced NO production and oxidative stress lead to mitochondrial dysfunction,bioenergetic derangement and organ failure.The mechanism of particulate mat-terhealth effects are believed to involve inflammation and oxidative stress.Components in particles that elicit inflammation have been poorly investigated,although recent research points out to the contribution of composi-tional elements and particle size.Oxygen metabolism and mitochondrial function appear to be important areas of study in inflammatory conditions for clarifying molecular mechanisms involved.展开更多
基金supported by the FONCYT,PICT 2016-#1093,Argentina.CONICET,PIP2014-#300,Argentina.Florencio Fiorini Foundation(#2021-2022),Argentina.
文摘Backgrounds:Breast cancer metastasis remains the leading cause of mortality and frequently targets the bone.Breast cancer cells release soluble factors and extracellular vesicles that disrupt bone marrow(BM)/bone homeostasis,promoting osteoclastogenesis and the accumulation of senescent cells.In line with updated cancer hallmarks,senescent mesenchymal stem/stromal cells(MSCs),osteoblasts,and osteocytes contribute to remodeling of the BM microenvironment,thereby favoring pre-metastatic niche(PMN)formation and subsequent bone metastasis.We previously demonstrated that untreated stage III-B breast cancer patients(BCPs)exhibit increased oxidative stress and elevated reactive oxygen species(ROS)levels,accompanied by senescent and functionally impaired BM-MSCs—key regulators of BM/bone homeostasis.In the present study,we sought to identify the molecular targets affected by oxidative stress that drive MSC senescence in these patients.Methods:BM-MSCs were isolated from untreated stage III-B BCPs and healthy volunteers(HVs).Oxidative stress responses were evaluated by quantitative real-time PCR(qRT-PCR)analysis of stress-and antioxidant-related genes.Oxidative damage to DNA,proteins,and lipids was assessed using alkaline comet assay,chromosomal aberration(CAs)analysis,micronuclei(MN)and nuclear blebs(NBs)quantification,protein carbonyl content,and detection of 4-hydroxynonenal(4-HNE)adducts.The MSC secretome was analyzed by label-free quantitative proteomics followed by Gene Ontology enrichment analysis.Results:Our results show that elevated oxidative stress in BCPs induces the overexpression of oxidative stress-related and antioxidant response genes in BM-MSCs;however,this response is insufficient to prevent extensive ROS-induced damage to deoxyribonucleic acid(DNA),proteins,and lipids.In addition,proteomic analysis of the BM-MSC secretome revealed a distinct protein expression profile in BCPs compared with HVs.Conclusions:Together,these findings highlight oxidative stress-induced MSC damage as a key mechanism contributing to PMN formation and suggest potential therapeutic targets to mitigate bone metastasis in advanced breast cancer.
文摘Several authors have addressed the importance of mitochondrial function in inflammatory syn-dromes,as it may play a role in the genesis of tissue injury.Sepsis and exposition to environmental particles are examples of inflammatory conditions.Sepsis occurs with an exacerbated inflammatory response that damages tissue mitochondria and impairs bioenergetic processes.One of the current hypotheses for the molecular mech-anisms underlying the complex condition of sepsis is that enhanced NO production and oxidative stress lead to mitochondrial dysfunction,bioenergetic derangement and organ failure.The mechanism of particulate mat-terhealth effects are believed to involve inflammation and oxidative stress.Components in particles that elicit inflammation have been poorly investigated,although recent research points out to the contribution of composi-tional elements and particle size.Oxygen metabolism and mitochondrial function appear to be important areas of study in inflammatory conditions for clarifying molecular mechanisms involved.
