目的探讨补体C5a/C5aR通路在结肠癌发病中对纤维介素蛋白-2凝血酶原酶(fibrinogen-like protein 2,FGL2)的调节机制,明确补体系统在结肠癌发病中的功能和作用。方法收集2013年12月至2015年7月第三军医大学西南医院普外科、新桥医院消化...目的探讨补体C5a/C5aR通路在结肠癌发病中对纤维介素蛋白-2凝血酶原酶(fibrinogen-like protein 2,FGL2)的调节机制,明确补体系统在结肠癌发病中的功能和作用。方法收集2013年12月至2015年7月第三军医大学西南医院普外科、新桥医院消化科15例经病理活检确诊的住院临床结肠癌患者癌及癌旁组织。采用免疫组织化学方法检测结肠癌患者癌及癌旁组织中补体活化片段C5b-9、活化C3及C5aR的表达,佐证补体系统在结肠癌中的活化状态;进一步通过体内外实验(Western blot)验证结肠癌患者癌及癌旁组织MAPK信号通路中P38的磷酸化水平及FGL2的沉积,明确结肠癌发病中补体C5a/C5aR通路与二者的调节关系。结果免疫组织化学及Western blot实验证实结肠癌患者癌组织C5b-9、活化C3及C5aR的表达明显高于癌旁组织,FGL2的沉积亦显著高于癌旁组织;体外结果提示C5a能促进巨噬细胞系Raw264.7MAPK通路中P38的磷酸化水平(P=0.0013)及FGL2的产生能力(P=0.0071),加入C5aR阻断剂之后,二者表达随之减弱。结论 C5a/C5aR通路能通过MAPK信号途径中的P38信号完成对FGL2的调节作用进而参与结肠癌的发病进程。展开更多
Photodynamic therapy(PDT)has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death(ICD)effects.However,the...Photodynamic therapy(PDT)has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death(ICD)effects.However,the strategy is limited in the innate hypoxic tumor microenvironment.There are two key elements for the realization of enhanced PDT:specific cellular uptake and release of the photosensitizer in the tumor,and a sufficient amount of oxygen to ensure photodynamic efficiency.Herein,self-oxygenated biomimetic nanoparticles(CS@M NPs)co-assembled by photosensitizer prodrug(Ce6-S-S-LA)and squalene(SQ)were engineered.In the treatment of triple negative breast cancer(TNBC),the oxygen carried by SQ can be converted to reactive oxygen species(ROS).Meanwhile,glutathione(GSH)consumption during transformation from Ce6-S-S-LA to chlorin e6(Ce6)avoided the depletion of ROS.The co-assembled(CS NPs)were encapsulated by homologous tumor cell membrane to improve the tumor targeting.The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin(CRT)and high mobility group protein B1(HMGB1),and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha(HIF-1α)-CD39-CD73-adenosine a2a receptor(A2AR)pathway,which not only promoted the maturation of dendritic cells(DC)and the presentation of tumor specific antigens,but also induced effective immune infiltration of tumors.Overall,the integrated nanoplatform implements the concept of multiple advantages of tumor targeting,reactive drug release,and synergistic photodynamic therapy-immunotherapy,which can achieve nearly 90%tumor suppression rate in orthotopic TNBC models.展开更多
基金supported by the Guangdong Nature Resource Center(No.(2020)037)Natural Science Foundation of Guangdong Province(Nos.22019A1515011498 and 2019A1515011619)+2 种基金Basic and Applied Basic Research Foundation of Guangdong Province(No.2020B1515120063)National Natural Science Foundation of China(No.81803877)supported by the China Postdoctoral Science Foundation(No.2022M721535)。
文摘Photodynamic therapy(PDT)has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death(ICD)effects.However,the strategy is limited in the innate hypoxic tumor microenvironment.There are two key elements for the realization of enhanced PDT:specific cellular uptake and release of the photosensitizer in the tumor,and a sufficient amount of oxygen to ensure photodynamic efficiency.Herein,self-oxygenated biomimetic nanoparticles(CS@M NPs)co-assembled by photosensitizer prodrug(Ce6-S-S-LA)and squalene(SQ)were engineered.In the treatment of triple negative breast cancer(TNBC),the oxygen carried by SQ can be converted to reactive oxygen species(ROS).Meanwhile,glutathione(GSH)consumption during transformation from Ce6-S-S-LA to chlorin e6(Ce6)avoided the depletion of ROS.The co-assembled(CS NPs)were encapsulated by homologous tumor cell membrane to improve the tumor targeting.The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin(CRT)and high mobility group protein B1(HMGB1),and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha(HIF-1α)-CD39-CD73-adenosine a2a receptor(A2AR)pathway,which not only promoted the maturation of dendritic cells(DC)and the presentation of tumor specific antigens,but also induced effective immune infiltration of tumors.Overall,the integrated nanoplatform implements the concept of multiple advantages of tumor targeting,reactive drug release,and synergistic photodynamic therapy-immunotherapy,which can achieve nearly 90%tumor suppression rate in orthotopic TNBC models.
