Despite advances in breast cancer therapy,effective targeting of cancer stem cells(CSCs)remains a challenge.CSCs,which have self-renewal,tumorigenic and metastatic properties,are often quiescent and located in hypoxic...Despite advances in breast cancer therapy,effective targeting of cancer stem cells(CSCs)remains a challenge.CSCs,which have self-renewal,tumorigenic and metastatic properties,are often quiescent and located in hypoxic regions of tumors[1],making them resistant to conventional chemoand radiotherapies[2].These characteristics allow CSCs to survive,leading to relapse and metastasis.Studying CSCs under conditions similar to their hypoxic niche is essential for evaluating therapies that target these cells.We show that CSCs can be targeted via binding to externalized phosphatidylserine(PS).PS,a negatively charged lipid,is typically confined to the inner leaflet of cell membranes[3].However,its externalization occurs on dying and diseased cells,and as we demonstrated,on stem cells[4].PS-targeting agents like Annexin V(AnnV)[5]and the monoclonal antibody bavituxumab(Bavi)[6]are under investigation for cancer therapy,but these are limited in their use as they remain surface bound and do not deliver payloads into cells.展开更多
Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,ad...Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,adverse immune responses to these composites can occur,which have been attributed to size and morphology of HA particles.Approaches to effectively modulate these adverse immune responses have not been described.PLA degradation products have been shown to alter immune cell metabolism(immunometabolism),which drives the inflammatory response.Accordingly,to modulate the inflammatory response to composite biomaterials,inhibitors were incorporated into composites comprised of amorphous PLA(aPLA)and HA(aPLA+HA)to regulate glycolytic flux.Inhibition at specific steps in glycolysis reduced proinflammatory(CD86+CD206-)and increased pro-regenerative(CD206+)immune cell populations around implanted aPLA+HA.Notably,neutrophil and dendritic cell(DC)numbers along with proinflammatory monocyte and macrophage populations were decreased,and Arginase 1 expression among DCs was increased.Targeting immunometabolism to control the proinflammatory response to biomaterial composites,thereby creating a pro-regenerative microenvironment,is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis,which could lead to improved bone regeneration.展开更多
基金supported in part by GLAdiator Biosciences and The James and Kathleen Cornelius Endowment(to Christopher Contag)This work is partially supported by NIH/NCI R01CA245699American Cancer Society ACS0137006(to Huiping Liu).
文摘Despite advances in breast cancer therapy,effective targeting of cancer stem cells(CSCs)remains a challenge.CSCs,which have self-renewal,tumorigenic and metastatic properties,are often quiescent and located in hypoxic regions of tumors[1],making them resistant to conventional chemoand radiotherapies[2].These characteristics allow CSCs to survive,leading to relapse and metastasis.Studying CSCs under conditions similar to their hypoxic niche is essential for evaluating therapies that target these cells.We show that CSCs can be targeted via binding to externalized phosphatidylserine(PS).PS,a negatively charged lipid,is typically confined to the inner leaflet of cell membranes[3].However,its externalization occurs on dying and diseased cells,and as we demonstrated,on stem cells[4].PS-targeting agents like Annexin V(AnnV)[5]and the monoclonal antibody bavituxumab(Bavi)[6]are under investigation for cancer therapy,but these are limited in their use as they remain surface bound and do not deliver payloads into cells.
基金Funding for this work was provided in part by the James and Kathleen Cornelius Endowment at MSU.The Mass Spectrometry core at MSU,especially A.J.Schilmiller and J.O’Keefe,helped to analyze releasates.
文摘Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,adverse immune responses to these composites can occur,which have been attributed to size and morphology of HA particles.Approaches to effectively modulate these adverse immune responses have not been described.PLA degradation products have been shown to alter immune cell metabolism(immunometabolism),which drives the inflammatory response.Accordingly,to modulate the inflammatory response to composite biomaterials,inhibitors were incorporated into composites comprised of amorphous PLA(aPLA)and HA(aPLA+HA)to regulate glycolytic flux.Inhibition at specific steps in glycolysis reduced proinflammatory(CD86+CD206-)and increased pro-regenerative(CD206+)immune cell populations around implanted aPLA+HA.Notably,neutrophil and dendritic cell(DC)numbers along with proinflammatory monocyte and macrophage populations were decreased,and Arginase 1 expression among DCs was increased.Targeting immunometabolism to control the proinflammatory response to biomaterial composites,thereby creating a pro-regenerative microenvironment,is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis,which could lead to improved bone regeneration.
