Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy ap...Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy approaches,these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells,the extracellular matrix,and blood vessels that form the tumor microenvironment(TME).The TME is known to be heterogeneous and dynamic,exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis.TME has been shown in several studies to promote malignancy,angiogenesis,and metastasis in tumors in general and melanoma in particular.Consequently,a significant number of studies in thefield of melanoma therapy have been redirected to investigate the effects of individual TME constituents,their prognostic significance for patients,and the potential of therapeutic intervention to improve overall patient survival.This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment:tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs).The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.展开更多
Tumor-associated lymphangiogenesis is thought to be an importantmetastaticstepin intrahepaticccholangiocarcinoma(ICC),while the origin of tumor-associated lymphatic vessels within tumors is little known.Cancerassociat...Tumor-associated lymphangiogenesis is thought to be an importantmetastaticstepin intrahepaticccholangiocarcinoma(ICC),while the origin of tumor-associated lymphatic vessels within tumors is little known.Cancerassociated fibroblasts(CAFs)enhance tumor progression through many aspects.2 CAFs have been discovered exhibiting cellular plasticity of phenotypic transition-such as epithelial-mesenchymal transition(EMT)which promotes increased migratory and invasive capabilities of cells.3However,mesenchymal-to-endothelial,(MEndT)transition is yet to be identified in tumor entities.展开更多
Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to...Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.展开更多
北京三里屯太古里路易威登之家是一处非凡建筑杰作,由著名建筑师青木淳设计,这栋建筑完美诠释了路易威登的精神内核:匠心与诗意。Le Café Louis Vuitton餐厅以沉浸式空间首次亮相北京。作为全新地标,这里不仅内设私人包厢,更有宽...北京三里屯太古里路易威登之家是一处非凡建筑杰作,由著名建筑师青木淳设计,这栋建筑完美诠释了路易威登的精神内核:匠心与诗意。Le Café Louis Vuitton餐厅以沉浸式空间首次亮相北京。作为全新地标,这里不仅内设私人包厢,更有宽敞露台以及用于举办活动的屋顶酒吧,向整座城市敞开怀抱。凭借青木淳建筑设计的独创性、艺术性与文化关联性,三里屯路易威登之家树立了创意与当代雅致的全新标杆。这里的每一处均诠释着路易威登精髓的“旅行艺术”。展开更多
Background:Lung cancer is a life-threatening disease that occurs worldwide,but is especially common in China.The crucial role of the tumour microenvironment(TME)in non-small cell lung cancer(NSCLC)has attracted recent...Background:Lung cancer is a life-threatening disease that occurs worldwide,but is especially common in China.The crucial role of the tumour microenvironment(TME)in non-small cell lung cancer(NSCLC)has attracted recent attention.Cancer-associated fibroblasts(CAFs)are the main factors that contribute to the TME function,and CAF exosomes are closely linked to NSCLC.Methods:The expression levels of miR-3124-5p and Toll-interacting protein(TOLLIP)were analysed by bioinformatics prediction combined with RT-qPCR/Western Blot detection.Fibroblasts were isolated and identified from clinical NSCLC tissues.Transmission electron microscopy and Western Blot were used to identify exosomes from these cells.Changes in proliferation(CCK-8 and clone formation),migration(wound healing),and invasion(transwell)of NSCLC cells were measured.The Luciferase reporter test was applied to clarify the binding of miR-3124-5p to TOLLIP.The TOLLIP/TLR4/MyD88/NF-κB pathway proteins were determined using Western blot analysis.Results:MiR-3124-5p is overexpressed in clinical tissues and cells of NSCLC.MiR-3124-5p was dramatically enriched in CAF-derived exosomes.Cellular experiments revealed that CAFs delivered miR-3124-5p into NSCLC cells via exosomes,stimulating cancer cell progression.MiR-3124-5p acted as a sponge to negatively regulate TOLLIP expression,which activated the TLR4/MyD88/NF-κB axis to promote the occurrence and development of NSCLC.Functional salvage tests were performed to determine whether CAF-exosome-derived miR-3124-5p plays a pro-cancer role in NSCLC by affecting the TOLLIP signalling pathway.Conclusions:These results provide an interesting direction for the diagnosis and therapy of NSCLC.展开更多
基金performed at the expense of the subsidy allocated to Kazan Federal University for the fulfillment of the stated task in the field of scientific activity,No.FZSM-2023-0011.
文摘Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy approaches,these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells,the extracellular matrix,and blood vessels that form the tumor microenvironment(TME).The TME is known to be heterogeneous and dynamic,exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis.TME has been shown in several studies to promote malignancy,angiogenesis,and metastasis in tumors in general and melanoma in particular.Consequently,a significant number of studies in thefield of melanoma therapy have been redirected to investigate the effects of individual TME constituents,their prognostic significance for patients,and the potential of therapeutic intervention to improve overall patient survival.This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment:tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs).The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.
基金supported by the National Natural Science Foundation of China(No.81902379)Cultivation Foundation of Renji Hospital,Shanghai,China(No.RJPY-LX-011)National Key Research on Precision Medicine of China(No.2018ZX10723204).
文摘Tumor-associated lymphangiogenesis is thought to be an importantmetastaticstepin intrahepaticccholangiocarcinoma(ICC),while the origin of tumor-associated lymphatic vessels within tumors is little known.Cancerassociated fibroblasts(CAFs)enhance tumor progression through many aspects.2 CAFs have been discovered exhibiting cellular plasticity of phenotypic transition-such as epithelial-mesenchymal transition(EMT)which promotes increased migratory and invasive capabilities of cells.3However,mesenchymal-to-endothelial,(MEndT)transition is yet to be identified in tumor entities.
基金supported by the National Natural Science Foundation of China(81988101,81830086,and 81972243)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081)+3 种基金Suzhou Top-Notch Talent Groups(ZXD2022003)Major Program of Shenzhen Bay Laboratory(S201101004)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088).
文摘Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.
文摘北京三里屯太古里路易威登之家是一处非凡建筑杰作,由著名建筑师青木淳设计,这栋建筑完美诠释了路易威登的精神内核:匠心与诗意。Le Café Louis Vuitton餐厅以沉浸式空间首次亮相北京。作为全新地标,这里不仅内设私人包厢,更有宽敞露台以及用于举办活动的屋顶酒吧,向整座城市敞开怀抱。凭借青木淳建筑设计的独创性、艺术性与文化关联性,三里屯路易威登之家树立了创意与当代雅致的全新标杆。这里的每一处均诠释着路易威登精髓的“旅行艺术”。
文摘Background:Lung cancer is a life-threatening disease that occurs worldwide,but is especially common in China.The crucial role of the tumour microenvironment(TME)in non-small cell lung cancer(NSCLC)has attracted recent attention.Cancer-associated fibroblasts(CAFs)are the main factors that contribute to the TME function,and CAF exosomes are closely linked to NSCLC.Methods:The expression levels of miR-3124-5p and Toll-interacting protein(TOLLIP)were analysed by bioinformatics prediction combined with RT-qPCR/Western Blot detection.Fibroblasts were isolated and identified from clinical NSCLC tissues.Transmission electron microscopy and Western Blot were used to identify exosomes from these cells.Changes in proliferation(CCK-8 and clone formation),migration(wound healing),and invasion(transwell)of NSCLC cells were measured.The Luciferase reporter test was applied to clarify the binding of miR-3124-5p to TOLLIP.The TOLLIP/TLR4/MyD88/NF-κB pathway proteins were determined using Western blot analysis.Results:MiR-3124-5p is overexpressed in clinical tissues and cells of NSCLC.MiR-3124-5p was dramatically enriched in CAF-derived exosomes.Cellular experiments revealed that CAFs delivered miR-3124-5p into NSCLC cells via exosomes,stimulating cancer cell progression.MiR-3124-5p acted as a sponge to negatively regulate TOLLIP expression,which activated the TLR4/MyD88/NF-κB axis to promote the occurrence and development of NSCLC.Functional salvage tests were performed to determine whether CAF-exosome-derived miR-3124-5p plays a pro-cancer role in NSCLC by affecting the TOLLIP signalling pathway.Conclusions:These results provide an interesting direction for the diagnosis and therapy of NSCLC.
