Osteocytes are the most abundant cells in bone,which is a frequent site of breast cancer metastasis.Here,we focused on Wnt signaling and evaluated tumor-osteocyte interactions.In animal experiments,mammary tumor cells...Osteocytes are the most abundant cells in bone,which is a frequent site of breast cancer metastasis.Here,we focused on Wnt signaling and evaluated tumor-osteocyte interactions.In animal experiments,mammary tumor cells were inoculated into the mammary fat pad and tibia.The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model.The results revealed that administration of osteocytes or their conditioned medium(CM)inhibited tumor progression and osteolysis.Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity,accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53.The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound.Notably,silencing Lrp5 in tumors inhibited tumor progression,while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression.Osteocytes exhibited elevated Lrp5 expression in response to tumor cells,implying that osteocytes protect bone through canonical Wnt signaling.Thus,our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes.We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.展开更多
基金This study was supported in part by funds from a breast cancer advocacy group,100 Voices of Hope(H.Y.)the Indiana University Precision Health Initiative(H.N.)NIH R01AR52144(H.Y.),R03CA238555(H.Y.),and R01AR053237(A.R.).
文摘Osteocytes are the most abundant cells in bone,which is a frequent site of breast cancer metastasis.Here,we focused on Wnt signaling and evaluated tumor-osteocyte interactions.In animal experiments,mammary tumor cells were inoculated into the mammary fat pad and tibia.The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model.The results revealed that administration of osteocytes or their conditioned medium(CM)inhibited tumor progression and osteolysis.Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity,accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53.The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound.Notably,silencing Lrp5 in tumors inhibited tumor progression,while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression.Osteocytes exhibited elevated Lrp5 expression in response to tumor cells,implying that osteocytes protect bone through canonical Wnt signaling.Thus,our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes.We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.
