Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis;a process known as tumor angiogenesis.Angiogenesis is largely involved in tumor survival,progression and spread,whic...Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis;a process known as tumor angiogenesis.Angiogenesis is largely involved in tumor survival,progression and spread,which are known to be significantly attributed to treatment failures.Over the past decades,efforts have been made to understand the difference between nor-mal and tumor vessels.It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes,which provides opportunities for developing novel anticancer strategies.Targeting tumor vasculature is not only a unique therapeutic interven-tion to starve neoplastic cells,but also enhances the efficacy of conventional cancer treatments.Vascular dis-rupting agents(VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors,cause catastrophic vascular shutdown within short time,and induce secondary tumor necrosis.VDAs are cytostatic;they can only inhibit tumor growth,but not eradicate the tumor.This novel drug mechanism has urged us to develop multiparametric imaging biomark-ers to monitor early hemodynamic alterations,cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected.In this article,we review the characteristics of tumor vessels,tubulin-destabilizing mechanisms of VDAs,and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials.We also compare the differ-ent tumor models adopted in the preclinical studies on VDAs.Multiparametric imaging biomarkers,mainly diffu-sion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging,are evalu-ated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.展开更多
Wedelolide is a coumarin-like active substance extracted from Ecliptae Herba.It not only has pharmacological effects of anti-pulmonary fibrosis,anti-arthritis,blood vessel protection and liver protection,but also effe...Wedelolide is a coumarin-like active substance extracted from Ecliptae Herba.It not only has pharmacological effects of anti-pulmonary fibrosis,anti-arthritis,blood vessel protection and liver protection,but also effectively inhibits the proliferation of cancer cells and induces apoptosis of cancer cells,thereby delaying the further development of malignant tumors.In this paper,the pharmacological effects and mechanisms of wedelactone were reviewed to lay a foundation for further study and clinical application of wedelactone.展开更多
BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether fr...BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma(HCC)is unknown,and the potential molecular mechanism(s)has not yet been determined.AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.METHODS In the present study,which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(http://tcmspw.com/tcmsp.php),Universal Protein database(http://www.uniprot.org),GeneCards:The Human Gene Database(http://www.genecards.org/)and Comparative Toxicogenomics Database(http://www.ctdbase.org/),the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted.The core prediction targets were screened by molecular docking.In vivo,SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model,and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d.The tumors were collected and evaluated:the tumor volume and growth rate were gauged to evaluate tumor growth;hematoxylineosin staining was performed to estimate histopathological changes;immunofluorescence(IF)was performed to detect the expression of CD31,α-SMA and collagen IV;transmission electron microscopy(TEM)was conducted to observe the morphological structure of vascular cells;enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of secreted HIF-1αand TNF-α;reverse transcription-polymerase chain reaction(RT-qPCR)was performed to measure the mRNA expression of HIF-1α,TNF-α,VEGF and MMP-9;and Western blot(WB)was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.RESULTS The result展开更多
OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianol...OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianolic acid B,exerted striking effects on modulating angiogenesis and vascular permeability,which suggests that they may be effective in treating vascular leak-driven diseases(e.g.tumor,cerebral cavernous malformation and diabetic retinopathy).However,the lack of reliable and advanced technologies and models sets up difficult hurdles for better understanding the role of TCM for promoting blood circulation and removing blood stasis.To this end,this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases.METHODS Two-photon laser scanning fluorescence microscopy was used to observe the interactions between neutrophils and blood vessels in a real-time manner.Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils.RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels.CCM2ECKO(deletion of CCM2 in endothelial cells)mice were employed to establish the cerebral cavernous malformation(CCM)animal model.Micro-computed tomography(micro-CT)was utilized to assess the CCM lesion.Müller cell-knockout mouse model was used to study the progression of diabetic retinopathy.Vascular permeability in this model was assessed by fluorescein angiography.RESULTS The interactions between neutrophils and endothelial cells involve a series of complicated processes,including rolling,adhesion,intraluminal crawling and transmigration,which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner.Dynamic flow system was capable of recapitulating the biological behaviors of neutrophils in vitro.Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 sp展开更多
Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival tim...Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival time of patients with advanced glioma is only 12 to 18 months due to the characteristics of high aggression,and the therapeutic effect was poor though surgery,chemotherapy,and targeted drug therapy being treated.Because of the presence of heterogeneity and the differentiation disorder,only a small number of glioma cells are the source of tumor growth and metastasis,which are highly resistant to traditional treatments.They are deemed as the“seed”tumor cells as they could get rid of the effect of the treatment and reconstruct the organization of tumor.They are also termed as brain tumor stem cell(BTSC)or glioma stem cells(GSCs)since neural stem cells share similar features with them.Recent data reveal that they are directly related with invasion,angiogenesis,tolerance,chemotherapy,recurrence of glioma.Based on the research result by the team,the paper elaborates the characteristics of GSCs and the relationship with the tumor angiogenesis.展开更多
背景与目的肿瘤微环境是肿瘤细胞赖以生存的复杂环境。其中肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)、肿瘤新生血管及程序性死亡受体1/程序性死亡受体-配体1(programmed cell death protein 1/programmed cell death ligan...背景与目的肿瘤微环境是肿瘤细胞赖以生存的复杂环境。其中肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)、肿瘤新生血管及程序性死亡受体1/程序性死亡受体-配体1(programmed cell death protein 1/programmed cell death ligand 1,PD-1/PD-L1)作为关键部分,在肿瘤发生、发展过程中起重要作用,影响患者预后。本研究旨在阐明TAMs、肿瘤新生血管和PD-L1的表达与非小细胞肺癌(non-small cell lung cancer,NSCLC)临床病理特征的相关性,并探讨它们对NSCLC预后的影响。方法收集92例NSCLC患者的临床病理资料及手术标本,采用免疫组化法检测癌组织和癌旁组织中TAMs、肿瘤新生血管和PD-L1的表达,采用配备有Olympus-DP72图像采集系统的OlympusBX51正置显微镜进行拍照并用Image-pro Plus 6.0软件进行半定量分析。结果癌组织与癌旁组织中TA Ms、肿瘤新生血管和PD-L1的表达差异无统计学意义(P>0.05)。根据肿瘤微环境中各组分的定量表达,可将其分为低、中、高表达组。癌组织中TAMs的低、中和高密度组的中位总生存(overall survival,OS)分别是36个月(95%CI:25.3-46.7)、26个月(95%CI:12.2-39.8)和16个月(95%CI:9.4-22.6),差异具有统计学意义(P=0.016);肿瘤新生血管的低、中和高密度组的中位OS分别为30个月(95%CI:22.5-37.5)、28个月(95%CI:18.1-37.9)和25个月(95%CI:14.6-35.4),差异无统计学意义(P=0.626);PD-L1的低、中和高表达组的中位OS分别为35个月(95%CI:29.4-40.6),28个月(95%CI:13.6-42.4)和17个月(95%CI:10.5-23.5),差异具有统计学意义(P=0.002)。联合低、中和高表达组的中位OS分别为36个月(95%CI:30.6-41.4)、26个月(95%CI:19.2-32.8)和9个月(95%CI:4.4-13.6),差异具有统计学意义(P=0.001)。Cox回归分析结果显示,病理分型、TAMs和PD-L1均为肺癌患者的独立预后因素。结论肿瘤微环境关键成分PD-L1及TAMs的表达与NSCLC患者的预后密切相关。展开更多
基金Supported by(partially) The grants awarded by Fonds voor Wetenschappelijk Onderzoek-Vlaanderen(FWO Vlaanderen) Impulsfinanciering project(ZWAP/05/018)Geconcerteerde Onderzoeksactie of the Flemish Government,OT project(OT/06/70)+1 种基金the K.U.Leuven Molecular Small Animal Imaging Center MoSAIC (KUL EF/05/08)the center of excellence In vivo Molecular Imaging Research of K.U.Leuven and a EU project Asia-Link CfP 2006-EuropeAid/123738/C/ACT/Multi-Proposal No.128-498/111
文摘Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis;a process known as tumor angiogenesis.Angiogenesis is largely involved in tumor survival,progression and spread,which are known to be significantly attributed to treatment failures.Over the past decades,efforts have been made to understand the difference between nor-mal and tumor vessels.It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes,which provides opportunities for developing novel anticancer strategies.Targeting tumor vasculature is not only a unique therapeutic interven-tion to starve neoplastic cells,but also enhances the efficacy of conventional cancer treatments.Vascular dis-rupting agents(VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors,cause catastrophic vascular shutdown within short time,and induce secondary tumor necrosis.VDAs are cytostatic;they can only inhibit tumor growth,but not eradicate the tumor.This novel drug mechanism has urged us to develop multiparametric imaging biomark-ers to monitor early hemodynamic alterations,cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected.In this article,we review the characteristics of tumor vessels,tubulin-destabilizing mechanisms of VDAs,and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials.We also compare the differ-ent tumor models adopted in the preclinical studies on VDAs.Multiparametric imaging biomarkers,mainly diffu-sion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging,are evalu-ated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.
基金Supported by the Talent Training Program for the Reform and Development of Local Colleges and Universities of the Central Government(2020GSP16)Innovation and Entrepreneurship Training Planning Project for University Students in Heilongjiang Province(202310223173).
文摘Wedelolide is a coumarin-like active substance extracted from Ecliptae Herba.It not only has pharmacological effects of anti-pulmonary fibrosis,anti-arthritis,blood vessel protection and liver protection,but also effectively inhibits the proliferation of cancer cells and induces apoptosis of cancer cells,thereby delaying the further development of malignant tumors.In this paper,the pharmacological effects and mechanisms of wedelactone were reviewed to lay a foundation for further study and clinical application of wedelactone.
基金the National Natural Science Foundation of China,No.U20A20408(Major Program)and No.82074450(General Program)Natural Science Foundation of Hunan Province,No.2020JJ4066+2 种基金Hunan Province Research and innovation projects for Postgraduates,No.CX20190541Hunan Province"domestic firstclass cultivation discipline"Integrated Traditional Chinese and Western medicine open fund project,No.2018ZXYJH03Hunan University Undergraduate Research Learning and Innovative Experiment Project,No.201609030114.
文摘BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma(HCC)is unknown,and the potential molecular mechanism(s)has not yet been determined.AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.METHODS In the present study,which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(http://tcmspw.com/tcmsp.php),Universal Protein database(http://www.uniprot.org),GeneCards:The Human Gene Database(http://www.genecards.org/)and Comparative Toxicogenomics Database(http://www.ctdbase.org/),the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted.The core prediction targets were screened by molecular docking.In vivo,SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model,and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d.The tumors were collected and evaluated:the tumor volume and growth rate were gauged to evaluate tumor growth;hematoxylineosin staining was performed to estimate histopathological changes;immunofluorescence(IF)was performed to detect the expression of CD31,α-SMA and collagen IV;transmission electron microscopy(TEM)was conducted to observe the morphological structure of vascular cells;enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of secreted HIF-1αand TNF-α;reverse transcription-polymerase chain reaction(RT-qPCR)was performed to measure the mRNA expression of HIF-1α,TNF-α,VEGF and MMP-9;and Western blot(WB)was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.RESULTS The result
文摘OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianolic acid B,exerted striking effects on modulating angiogenesis and vascular permeability,which suggests that they may be effective in treating vascular leak-driven diseases(e.g.tumor,cerebral cavernous malformation and diabetic retinopathy).However,the lack of reliable and advanced technologies and models sets up difficult hurdles for better understanding the role of TCM for promoting blood circulation and removing blood stasis.To this end,this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases.METHODS Two-photon laser scanning fluorescence microscopy was used to observe the interactions between neutrophils and blood vessels in a real-time manner.Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils.RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels.CCM2ECKO(deletion of CCM2 in endothelial cells)mice were employed to establish the cerebral cavernous malformation(CCM)animal model.Micro-computed tomography(micro-CT)was utilized to assess the CCM lesion.Müller cell-knockout mouse model was used to study the progression of diabetic retinopathy.Vascular permeability in this model was assessed by fluorescein angiography.RESULTS The interactions between neutrophils and endothelial cells involve a series of complicated processes,including rolling,adhesion,intraluminal crawling and transmigration,which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner.Dynamic flow system was capable of recapitulating the biological behaviors of neutrophils in vitro.Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 sp
文摘Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival time of patients with advanced glioma is only 12 to 18 months due to the characteristics of high aggression,and the therapeutic effect was poor though surgery,chemotherapy,and targeted drug therapy being treated.Because of the presence of heterogeneity and the differentiation disorder,only a small number of glioma cells are the source of tumor growth and metastasis,which are highly resistant to traditional treatments.They are deemed as the“seed”tumor cells as they could get rid of the effect of the treatment and reconstruct the organization of tumor.They are also termed as brain tumor stem cell(BTSC)or glioma stem cells(GSCs)since neural stem cells share similar features with them.Recent data reveal that they are directly related with invasion,angiogenesis,tolerance,chemotherapy,recurrence of glioma.Based on the research result by the team,the paper elaborates the characteristics of GSCs and the relationship with the tumor angiogenesis.
文摘背景与目的肿瘤微环境是肿瘤细胞赖以生存的复杂环境。其中肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)、肿瘤新生血管及程序性死亡受体1/程序性死亡受体-配体1(programmed cell death protein 1/programmed cell death ligand 1,PD-1/PD-L1)作为关键部分,在肿瘤发生、发展过程中起重要作用,影响患者预后。本研究旨在阐明TAMs、肿瘤新生血管和PD-L1的表达与非小细胞肺癌(non-small cell lung cancer,NSCLC)临床病理特征的相关性,并探讨它们对NSCLC预后的影响。方法收集92例NSCLC患者的临床病理资料及手术标本,采用免疫组化法检测癌组织和癌旁组织中TAMs、肿瘤新生血管和PD-L1的表达,采用配备有Olympus-DP72图像采集系统的OlympusBX51正置显微镜进行拍照并用Image-pro Plus 6.0软件进行半定量分析。结果癌组织与癌旁组织中TA Ms、肿瘤新生血管和PD-L1的表达差异无统计学意义(P>0.05)。根据肿瘤微环境中各组分的定量表达,可将其分为低、中、高表达组。癌组织中TAMs的低、中和高密度组的中位总生存(overall survival,OS)分别是36个月(95%CI:25.3-46.7)、26个月(95%CI:12.2-39.8)和16个月(95%CI:9.4-22.6),差异具有统计学意义(P=0.016);肿瘤新生血管的低、中和高密度组的中位OS分别为30个月(95%CI:22.5-37.5)、28个月(95%CI:18.1-37.9)和25个月(95%CI:14.6-35.4),差异无统计学意义(P=0.626);PD-L1的低、中和高表达组的中位OS分别为35个月(95%CI:29.4-40.6),28个月(95%CI:13.6-42.4)和17个月(95%CI:10.5-23.5),差异具有统计学意义(P=0.002)。联合低、中和高表达组的中位OS分别为36个月(95%CI:30.6-41.4)、26个月(95%CI:19.2-32.8)和9个月(95%CI:4.4-13.6),差异具有统计学意义(P=0.001)。Cox回归分析结果显示,病理分型、TAMs和PD-L1均为肺癌患者的独立预后因素。结论肿瘤微环境关键成分PD-L1及TAMs的表达与NSCLC患者的预后密切相关。
