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
Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CA...Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CAFs)are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development.In recent years,CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression.However,most studies on CAFs are limited to a few common cancers,and their association with OS remains elusive.This review describes the role and current knowledge of CAFs in OS,focusing on their potential cellular origin,classification,and diverse functionality.It was found that CAFs influenced OS tumor cell signaling,proliferation,invasion,metastasis,epithelial-mesenchymal transition,stemness maintenance,angiogenesis,and the ability to modify immune system components.Furthermore,findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation,targeting CAF-derived components,and depletion of CAFs by biomarkers.This review provides new insights and a theoretical basis for OS research.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.
基金supported by the National Natural Science Foundation of China(grant number 81773285)Beijing Chao-Yang Hospital Golden Seeds Foundation(grant number CYJZ202341).
文摘Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CAFs)are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development.In recent years,CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression.However,most studies on CAFs are limited to a few common cancers,and their association with OS remains elusive.This review describes the role and current knowledge of CAFs in OS,focusing on their potential cellular origin,classification,and diverse functionality.It was found that CAFs influenced OS tumor cell signaling,proliferation,invasion,metastasis,epithelial-mesenchymal transition,stemness maintenance,angiogenesis,and the ability to modify immune system components.Furthermore,findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation,targeting CAF-derived components,and depletion of CAFs by biomarkers.This review provides new insights and a theoretical basis for OS research.
