Recently we have synthesized a novel small retinoid molecule WYC-209 that can effectively inhibit proliferation of malignant murine melanoma tumor-repopulating cells(TRCs).The molecule can induce 100%TRCs apoptosis at...Recently we have synthesized a novel small retinoid molecule WYC-209 that can effectively inhibit proliferation of malignant murine melanoma tumor-repopulating cells(TRCs).The molecule can induce 100%TRCs apoptosis at 10μM concentration.However,how WYC-209 induces TRCs apoptosis is still elusive.Here we demonstrate that WYC-209 at>6μM concentration started to induce TRCs apoptosis primarily via the caspase 3 pathway by releasing cytochrome c from mitochondria.Interestingly,we found that at concentrations<6μM WYC-209 induced TRCs to elevate dormancy marker COUP TF1 but induced no changes in apoptosis marker P53.Furthermore,proliferation markers Ki67 and PCNA decreased with the increase of WYC-209 concentrations,suggesting that low concentrations of WYC-209 inhibit TRCs growth by inducing cell dormancy instead of causing apoptosis.In addition,TRC traction forces were almost abolished when WYC-209 concentration was at 5μM,preceding the initiation of apoptosis.Our findings demonstrate that inhibition of TRCs by anti-cancer molecule WYC-209 is concentration-dependent and WYC-209 inhibits cellular force generation of the tumor-repopulating cells before inducing apoptosis.展开更多
Despite their mutual antagonism,inflammation and immunosuppression coexist in tumor microenvironments due to tumor and immune cell interactions,but the underlying mechanism remains unclear.Previously,we showed that tu...Despite their mutual antagonism,inflammation and immunosuppression coexist in tumor microenvironments due to tumor and immune cell interactions,but the underlying mechanism remains unclear.Previously,we showed that tumor cell-derived microparticles induce an M2 phenotype characterized by immunosuppression in tumor-infiltrating macrophages.Here,we further showed that lung cancer microparticles(L-MPs)induce macrophages to release a key proinflammatory cytokine,IL-1β,thus promoting lung cancer development.The underlying mechanism involves the activation of TLR3 and the NLRP3 inflammasome by L-MPs.More importantly,tyrosine kinase inhibitor treatment-induced L-MPs also induce human macrophages to release IL-1β,leading to a tumor-promoting effect in a humanized mouse model.These findings demonstrated that in addition to their antiinflammatory effect,L-MPs induce a proinflammatory phenotype in tumor-infiltrating macrophages,promoting the development of inflammatory and immunosuppressive tumor microenvironments.展开更多
基金supported by funds from Huazhong University of Science and Technology
文摘Recently we have synthesized a novel small retinoid molecule WYC-209 that can effectively inhibit proliferation of malignant murine melanoma tumor-repopulating cells(TRCs).The molecule can induce 100%TRCs apoptosis at 10μM concentration.However,how WYC-209 induces TRCs apoptosis is still elusive.Here we demonstrate that WYC-209 at>6μM concentration started to induce TRCs apoptosis primarily via the caspase 3 pathway by releasing cytochrome c from mitochondria.Interestingly,we found that at concentrations<6μM WYC-209 induced TRCs to elevate dormancy marker COUP TF1 but induced no changes in apoptosis marker P53.Furthermore,proliferation markers Ki67 and PCNA decreased with the increase of WYC-209 concentrations,suggesting that low concentrations of WYC-209 inhibit TRCs growth by inducing cell dormancy instead of causing apoptosis.In addition,TRC traction forces were almost abolished when WYC-209 concentration was at 5μM,preceding the initiation of apoptosis.Our findings demonstrate that inhibition of TRCs by anti-cancer molecule WYC-209 is concentration-dependent and WYC-209 inhibits cellular force generation of the tumor-repopulating cells before inducing apoptosis.
基金supported by the National Natural Science Foundation of China(81788101,81601366,and 81661128007)the CAMS Initiative for Innovative Medicine(2016-I2M-1-007).
文摘Despite their mutual antagonism,inflammation and immunosuppression coexist in tumor microenvironments due to tumor and immune cell interactions,but the underlying mechanism remains unclear.Previously,we showed that tumor cell-derived microparticles induce an M2 phenotype characterized by immunosuppression in tumor-infiltrating macrophages.Here,we further showed that lung cancer microparticles(L-MPs)induce macrophages to release a key proinflammatory cytokine,IL-1β,thus promoting lung cancer development.The underlying mechanism involves the activation of TLR3 and the NLRP3 inflammasome by L-MPs.More importantly,tyrosine kinase inhibitor treatment-induced L-MPs also induce human macrophages to release IL-1β,leading to a tumor-promoting effect in a humanized mouse model.These findings demonstrated that in addition to their antiinflammatory effect,L-MPs induce a proinflammatory phenotype in tumor-infiltrating macrophages,promoting the development of inflammatory and immunosuppressive tumor microenvironments.
