Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and ant...Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression.Herein,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.展开更多
Shenmai injection(SMI)is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer.Previously,we found that SMI synergistically enhanced the activity of chemotherapy on col...Shenmai injection(SMI)is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer.Previously,we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors.However,the underlying mechanisms and bioactive constituents remained unknown.In the present work,the regulatory effects of SMI on tumor vasculature were determined,and the potential anti-angiogenic components targeting tumor endothelial cells(TECs)were identified.Multidimensional pharmacokinetic profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.The results showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD-type ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In vivo bioactivity results showed that Rd suppressed neovascularization in tumors,normalized the structure of tumor vessels,and improved the anti-tumor effect of 5-fluorouracil(5 FU)in xenograft mice.Furthermore,Rd inhibited the migration and tube formation capacity of endothelial cells in vitro.In conclusion,Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.展开更多
Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion.Targeting the abnormal metabolism of tumor endothelial cells(TECs)may provide an opportunity to improve the outcome of immunothera...Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion.Targeting the abnormal metabolism of tumor endothelial cells(TECs)may provide an opportunity to improve the outcome of immunotherapy.Here,in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer(CRC),TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase(GAPDH)expression.Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs.Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor,which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH.Moreover,osimertinib and anti-PD-1 blockade synergistically retarded tumor growth.This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.展开更多
基金This work was financially supported by the projects of National Natural Science Foundation of China(82003991,82101844,and 82304953)Natural Science Foundation of Jiangsu Province(BK20230744,China)+1 种基金Jiangsu Specially Appointed Professorship Foundation(013038021001,China)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22-2045 and KYCX23-2038,China).
文摘Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression.Herein,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.
基金supported by the China National Nature Science Foundation(81573496,81773989,81530098 and 81573494)National Research Council of Science and Technology Major Project of China(2017ZX09201004-019 and 2019ZX09721001006-005)+6 种基金International Science and Technology Center Program of China(2017YFE0109600)Foundation for Innovative Research Groups of the National Natural Science Foundation of China(No.81421005)Jiangsu Province Nature Science Foundation(No.BK20160076,China)Jiangsu Province“333”project,ChinaSix talent peaks project in Jiangsu Province(YY-060),ChinaNational Basic Research Program of China(973 Program,No.2017YFA0205400)“Double First-Class”University project(CPU2018GF01,China)
文摘Shenmai injection(SMI)is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer.Previously,we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors.However,the underlying mechanisms and bioactive constituents remained unknown.In the present work,the regulatory effects of SMI on tumor vasculature were determined,and the potential anti-angiogenic components targeting tumor endothelial cells(TECs)were identified.Multidimensional pharmacokinetic profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.The results showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD-type ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In vivo bioactivity results showed that Rd suppressed neovascularization in tumors,normalized the structure of tumor vessels,and improved the anti-tumor effect of 5-fluorouracil(5 FU)in xenograft mice.Furthermore,Rd inhibited the migration and tube formation capacity of endothelial cells in vitro.In conclusion,Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.
基金This research was supported by National Natural Science Foundation of China(Nos.82073929,82104184,82103318,and 82173887)China Postdoctoral Science Foundation(No.2020M671662)+5 种基金the Jiangsu postdoctoral grant program(Nos.2020Z354 and 2020Z152,China)Leading Technology Foundation Research Project of Jiangsu Province(No.BK20192005,China)National Basic Research Program of China(973 Program,No.2017YFA0205400)the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZ202001,China)“Double First-Class”University project(No.CPU2018GF01,China)Jiangsu Province“333”project(China).
文摘Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion.Targeting the abnormal metabolism of tumor endothelial cells(TECs)may provide an opportunity to improve the outcome of immunotherapy.Here,in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer(CRC),TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase(GAPDH)expression.Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs.Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor,which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH.Moreover,osimertinib and anti-PD-1 blockade synergistically retarded tumor growth.This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.