Bone destruction induced by breast cancer metastasis causes severe complications,including death,in breast cancer patients.Communication between cancer cells and skeletal cells in metastatic bone microenvironments is ...Bone destruction induced by breast cancer metastasis causes severe complications,including death,in breast cancer patients.Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis.Tumor-derived factors play fundamental roles in this form of communication.To identify soluble factors released from cancer cells in bone metastasis,we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells.This subline(mtMDA)showed a markedly elevated ability to secrete S100A4 protein,which directly stimulated osteoclast formation via surface receptor RAGE.Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo.Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts.Furthermore,the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells.In addition,administration of an anti-S100A4 monoclonal antibody(mAb)that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice.Taken together,our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.展开更多
ABO blood group-incompatible(ABOi)transplantation has been developed to overcome the serious problem of donor organ shortage.However,antibody-mediated rejection(ABMR)remains as the main limitation to successful ABOi t...ABO blood group-incompatible(ABOi)transplantation has been developed to overcome the serious problem of donor organ shortage.However,antibody-mediated rejection(ABMR)remains as the main limitation to successful ABOi transplantation.Introduction of desensitization treatment improved the outcomes of ABOi transplantation by suppressing ABMR;however,this strong,nonspecific immunosuppression also increases infectious complications.Recently,chimeric antigen receptor regulatory T cells(CAR Tregs)were developed to improve the antigen specificity,viability,and suppressive activity of Tregs.C4d deposition is a marker of ABMR and is also found in most ABOi allograft tissues.Based on these findings,we developed anti-C4d CAR Tregs to suppress ABMR in ABOi allografts.展开更多
基金supported by grants from the National Research Foundation of Korea (NRF2017R1A2A1A17069648 and NRF-2018R1A5A2024418) to H.-H.K.the National Research Foundation of Korea (NRF-2017R1D1A1B03028003) to H.K.
文摘Bone destruction induced by breast cancer metastasis causes severe complications,including death,in breast cancer patients.Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis.Tumor-derived factors play fundamental roles in this form of communication.To identify soluble factors released from cancer cells in bone metastasis,we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells.This subline(mtMDA)showed a markedly elevated ability to secrete S100A4 protein,which directly stimulated osteoclast formation via surface receptor RAGE.Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo.Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts.Furthermore,the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells.In addition,administration of an anti-S100A4 monoclonal antibody(mAb)that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice.Taken together,our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.
基金This study was supported by a grant from the Ministry of Health and Welfare(No.HI18C0532),Republic of Korea
文摘ABO blood group-incompatible(ABOi)transplantation has been developed to overcome the serious problem of donor organ shortage.However,antibody-mediated rejection(ABMR)remains as the main limitation to successful ABOi transplantation.Introduction of desensitization treatment improved the outcomes of ABOi transplantation by suppressing ABMR;however,this strong,nonspecific immunosuppression also increases infectious complications.Recently,chimeric antigen receptor regulatory T cells(CAR Tregs)were developed to improve the antigen specificity,viability,and suppressive activity of Tregs.C4d deposition is a marker of ABMR and is also found in most ABOi allograft tissues.Based on these findings,we developed anti-C4d CAR Tregs to suppress ABMR in ABOi allografts.
