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
Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone.However,whether loading to a weight-bearing hind limb can inhibit distant t...Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone.However,whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown.We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells.The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase,a rate-limiting enzyme in dopamine synthesis,markedly reduced the progression of the brain tumors.The simultaneous application of fluphenazine(FP),an antipsychotic dopamine modulator,enhanced tumor suppression.Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2,respectively.Notably,dopamine downregulated Lrp5 via DRD1 in tumor cells.A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven,dopamine-mediated tumor suppression.The silencing of Lrp5 reduced CCN4,and the administration of CCN4 elevated oncogenic genes such as MMP9,Runx2,and Snail.In summary,this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1,indicating the possibility of developing an adjuvant bone-mediated loading therapy.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.
基金supported in part by funds from the NIH(R01 AR052144 and R03 CA238555 to H.Y.).
文摘Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone.However,whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown.We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells.The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase,a rate-limiting enzyme in dopamine synthesis,markedly reduced the progression of the brain tumors.The simultaneous application of fluphenazine(FP),an antipsychotic dopamine modulator,enhanced tumor suppression.Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2,respectively.Notably,dopamine downregulated Lrp5 via DRD1 in tumor cells.A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven,dopamine-mediated tumor suppression.The silencing of Lrp5 reduced CCN4,and the administration of CCN4 elevated oncogenic genes such as MMP9,Runx2,and Snail.In summary,this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1,indicating the possibility of developing an adjuvant bone-mediated loading therapy.
