Objective:There is currently no consensus on whether extra-gastrointestinal stromal tumors(EGISTs)and gastrointestinal stromal tumors(GISTs)are the same type of tumor,and whether the diagnosis and treatment of EGISTs ...Objective:There is currently no consensus on whether extra-gastrointestinal stromal tumors(EGISTs)and gastrointestinal stromal tumors(GISTs)are the same type of tumor,and whether the diagnosis and treatment of EGISTs can directly replicate the current diagnostic and treatment standards for GISTs.This study aims to further elucidate the clinical and pathological characteristics,diagnosis,treatment,and prognosis of EGISTs by analyzing the research results of domestic scholars in the field of EGISTs in the past decade.Methods:A review was conducted on original Chinese and English research articles published from 2013 to 2022 focusing on EGISTs.A descriptive approach was used to extract key information from the literature,including patient demographics,tumor location,tumor diameter,mitotic figures,risk stratification,immunohistochemical markers,cell type,and prognostic factors.The data were subjected to statistical analysis.Results:A total of 12 articles containing 780 EGIST patients were included.The male-to female incidence of EGISTs was 0.92꞉1.The most common sites of EGISTs were mesentery(30.96%),peritoneum or retroperitoneum(28.53%),omentum(20.32%),and pelvic cavity(12.52%).52.77%of EGISTs had tumor diameters greater than 10 cm,and the proportions of EGISTs with nuclear fission patterns greater than 5/50 high power field(HPF)and greater than 10/50 HPF were 51.24%and 26.11%,respectively.The proportion of high-risk EGISTs was 79.05%.The positive rates of immune markers CD117,CD34,and DOG-1 in EGISTs were 82.3%,69.0%,and 79.5%,respectively.The proportion of Ki-67>5%was 49.2%,and the proportion of Ki-67>10%was 24.8%.The proportions of EGISTs in spindle cells,epithelial cells,and mixed cells were 74.4%,14.8%,and 13.1%,respectively.The diameter of the tumor,resection method,risk level,Ki-67 index,mitotic counts,presence of rupture/bleeding/necrosis/peripheral tissue invasion/recurrence and metastasis,as well as the use of imatinib treatment after surgery were important factors affecting the prognosis of EGISTs.Conclusion:Current medical research is relatively well cognizant of GISTs with primary sites in the gastrointestinal tract.Compared with GISTs,EGISTs have large tumor diameters,high mitotic counts,a high percentage of high-risk grades,relatively unique molecular expression,and high aggressiveness.EGISTs differ from GISTs in clinicopathological characteristics.Whether EGISTs and GISTs share a common origin remains unclear.If they are distinct tumor entities,separate diagnostic and treatment guidelines for EGISTs should be established.If EGISTs are ultimately confirmed to be a special subtype of GISTs,then directly applying existing GIST-based standards to EGISTs may be inappropriate.A more scientific approach would involve subclassifying EGISTs based on anatomical location and then tailoring treatment strategies accordingly with reference to GIST guidelines.展开更多
In this work,iron-doped carbon dots(Fe-CDs)with strong peroxidase-mimicking activity were synthesized for tumor-specific therapy.Their intrinsic red fluorescence enabled high-contrast cellular imaging,revealing prefer...In this work,iron-doped carbon dots(Fe-CDs)with strong peroxidase-mimicking activity were synthesized for tumor-specific therapy.Their intrinsic red fluorescence enabled high-contrast cellular imaging,revealing preferen⁃tial mitochondrial accumulation.In the acidic and hydrogen peroxide(H_(2)O_(2))-rich tumor microenvironment,Fe-CDs catalyzed hydroxyl radical(·OH)generation,inducing oxidative stress and lipid peroxidation,ultimately triggering ferroptosis.In vitro and in vivo studies demonstrated potent tumor inhibition.Furthermore,Fe-CDs exhibited excel⁃lent biocompatibility with no significant systemic toxicity.By integrating fluorescence imaging and catalytic therapy,this study presents a promising nanoplatform for tumor treatment and ferroptosis research.展开更多
Potassium-calcium activates channel subfamily N member 3(KCNN3/SK3/KCa2.3)is involved in regulating cellular calcium signaling,muscle contraction and neurotransmitter release.Dysregulation of the KCNN3 channel is asso...Potassium-calcium activates channel subfamily N member 3(KCNN3/SK3/KCa2.3)is involved in regulating cellular calcium signaling,muscle contraction and neurotransmitter release.Dysregulation of the KCNN3 channel is associated with the development of various tumors.We use bioinformatics analysis to identify whether KCNN3 regulates the occurrence and development of stomach adenocarcinoma(STAD)as a prognostic target.By analyzing the Human Protein Atlas(HPA)database and The Cancer Genome Atlas(TCGA)database,we found that the protein and mRNA levels of KCNN3 were dramatically reduced in STAD,and TCGA database showed that KCNN3 significantly correlated with the prognosis and clinical features of STAD.In addition,we found that high expression of KCNN3 in STAD reduced the IC 50 of several drugs in STAD cells,suggesting that high expression of KCNN3 correlated with the drug sensitivity of STAD.To investigate the underlying biological mechanism,we identified a potential KCNN3 interaction factor,tumor necrosis factor receptor superfamily member 7(CD27/TNFRSF7),which is expressed at low levels in STAD.RT-qPCR and Western blotting confirmed that KCNN3 and CD27 positively correlated with each other at protein and mRNA levels,and co-immunoprecipitation and immunofluorescence experiments confirmed that the two proteins interact and colocalize in the cytoplasm.Moreover,we confirmed the inhibitory effect of KCNN3 on the proliferation,migration and invasion of human STAD cells in vitro and in vivo through subcutaneous tumorigenesis and cellular experiments.Furthermore,GO/KEGG enrichment analysis showed that KCNN3 was enriched in signaling pathways regulating the immune response and calcium or metal ion transport.Lastly,we verified through cell co-culture,RT-qPCR and CCK8 assays that high expression of KCNN3 can promote the increase of T cell activating factor and the killing effect of T cells on STAD cells.Therefore,our results suggest that KCNN3 is a potential inhibitory factor affecting the occurrence and progression of STAD.展开更多
OBJECTIVE Previous work has shown that gap junction intercel ular communication(GJIC)enhances cisplatin(Pt)toxicity in testicular tumor cells but decreases it in non-tumor testicular cells.In this study,these differen...OBJECTIVE Previous work has shown that gap junction intercel ular communication(GJIC)enhances cisplatin(Pt)toxicity in testicular tumor cells but decreases it in non-tumor testicular cells.In this study,these different GJIC-propagated effects were demonstrated in tumor versus non-tumor cells from other organ tissues(liver and lung).METHODS We use several different mani pulations(no cell contact,pharmacological inhibition,and si RNA suppression)to down-regulate GJIC function.The in vivo results using xenograft tumor models were consistent with those from the above-mentioned cells.To better understand the mechanism(s)involved,we studied the effects of GJIC on Pt accumulation in tumor and non-tumor cells from the liver and lung.RESULTS The intracel ular Pt and DNA-Pt adduct contents clearly increased in non-tumor cells but decreasedin tumor cells when GJIC was downregulated.Further analysis indicated that the opposite effectsof GJIC on Pt accumulation in normal versus tumor cells from the liver were due to its different effects on copper transporter1 and multidrug resistance-associated protein2,membrane transporters attributed to intracellular Pt transfer.CONCLUSION GJIC protects normal organs from cisplatin toxicity while enhancing it in tumor cells via its different effects on intracellular Pt transfer.展开更多
Bone tumour is one of most common primary cancer which exhibits cancerous osteoblastic differentiation and malignant osteoid in patients.At present,chemotherapy(pre-and post-operative)is used as a standard treatment p...Bone tumour is one of most common primary cancer which exhibits cancerous osteoblastic differentiation and malignant osteoid in patients.At present,chemotherapy(pre-and post-operative)is used as a standard treatment protocol for bone tumour.However,drugs used in the treatment of bone tumour induce high toxicity to normal tissues including anaemia,neutropenia,thrombocytopenia,and heart damage which further reduce the survival rate of patients.Therefore,there is an urgent need to develop a new therapeutic approach for the treatment such that it induce maximum cell killing effect in tumor cells while sparing the healthy bone cells.In this article,some new perspectives were provided on the development of bone-targeted nano-drug carriers for bone cancer treatment.We hope such discussions wouldencourage more detailed and careful studies to support product development of bone-targeted drug carriers for bone cancer treatment.展开更多
Folic acid conjugated chitosan was prepared by cross-linking reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDC), and then used as a template to prepare folic acid-chitosan(FA-CS) conjugate...Folic acid conjugated chitosan was prepared by cross-linking reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDC), and then used as a template to prepare folic acid-chitosan(FA-CS) conjugated nanoparticles and load mitoxantrone nanoparticles(FA-CSNP/MTX). Drug dissolution testing, CCK-8 method, and confocal microscopy were used to detect their controlled-release capability in different situations and the specific uptake by HONE1 cells. The experimental results show that the nanoparticles have uniform size distribution of 48-58 nm. The highest encapsulation rate of the particles on mitoxantrone hydrochloride(MTX) is(77.5±1.9)%, and the drug loading efficiency is(18.4±0.4)%. The sustained release effect, cell growth inhibition activity and targeting effect of the FA-CS/MTX nanoparticles are good in artificial gastric fluid and intestinal fluid. It is demonstrated that the FA-CSNP system is a potentially useful system for the targeted delivery of anticancer drug MTX.展开更多
OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(Lo...OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(LoVo)xenografts were treated with SMI 10 mL·kg^-1 daily for 1 or 8 d.Multidimensional PK profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.For PD studies,the tumor-bearing mice Intravital multi-photon imaging and CD31 immunofluorescence staining were used to evaluate the number of microves⁃sels and braches.Double staining of CD31 and α-SMA was performed to evaluate pericytes coverage ratios around vessels.ELISA was performed to determine the concentrations of VEGF and FGF in tumor tissues.For synergistic anti-tumor study,the tumor-bearing mice were treated with SMI 10 mL·kg^-1 daily,Rd 5 mg·kg^-1 daily with or without 5-FU 15 mg·kg^-1 every 3 d for 20 d.HPLC-MS/MS was used to determine the concentrations of 5-FU in plasma and tumor tissues.RESULTS SMI decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and improved vascular pericytes coverage(P<0.05).PK studies 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 ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In fact,the proportion of Rd in the detectable components of SMI gradually increased in the following order:SMI formula(2.8%),plasma(16.0%),tumor tissues(34.3%),and TECs(40.3%).In vivo bioactivity results showed that Rd 5 mg·kg^-1 daily significantly decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and increased pericytes coverage(P<0.05)while Rd 0.5 mg·kg^-1 daily,Rb1 and Rg1 had no significant effect on them.Rd 5 mg·kg^-1 suppressed the expression of VEGF and FGF simultaneously.Rd 5 mg·kg^-1 enhanced the antitumor effect of 5-FU via increasing the distribution of 5-FU in tumor tissues(P<0.05)in xenograft mice.CONCLUSION Ginsenoside Rd may be the major bioactive anti-angiogenic constituent targeting TECs after SMI treatment.展开更多
Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in ...Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.展开更多
OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the benefi...OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the beneficial effects of GYⅡon murine breast cancer models.METHODS Inhibition of tumor growth and metastasis was evaluated by assessment of tumor weight and analysis of bioluminescent signal after a homograft inoculation.Viability of cultured breast cancer cells was determined using MTT assay andreal-time cell analysis(RTCA).Cell migratory ability was evaluated by Transwell?assay and wound healing assay.Subsequently,the potential anti-tumor and anti-metastatic mechanism was investigated by Western blotting and Immunohistochemistry.RESULTS GYⅡshowed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model.And GYⅡsuppressed theproliferation of 4T1 and MCF-7 cells in a dose-dependent manner.A better inhibitory effect on 4T1 cells proliferation and migration was found in sub-fractions(SF)of GYⅡ.Moreover,heparanase expression and degree of angiogenesis were reduced in tumor tissues.Western blotting analysis showed decreased expression of heparanase and growth factors in the cells treated with GYⅡand its sub-fractions(SF2 and SF3),there by a reduction in phosphorylation of ERK and AKT.CONCLUSION GYⅡexerts anti-tumor growth and anti-metastatic effects on murine breast cancer model.Sub-fractions 2 and 3 exhibits higher potency of the anti-tumor activity that is,at least partly,associated with decreased heparanase and growth factor sexpression,which subsequently sup-pressed activation of ERK and AKT pathways.展开更多
Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We de...Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We demon- strated that CA1P also showed an outstanding anti-cancer effect on hepatocellular carcinoma （HCC） in vivo and in vitro. As determined by DCFH-DA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the down-regulation of Mcl-1. Additonal western blot and immunofluorescence assays further indi- cated that CA1P inhibited Wnt/β-catenin pathway through GSK-3β activition with an increasing of Mcl phosphoryl- ation and subsequent degradation mediated by tubulin-dynactin p l50-AKT signaling pathway axis. Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK-3β inhibitor （ CHIR-99021 ）. Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage （TAM） apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGF-β were also altered. Adoptive transfer of macrophages reinstated tumor growth treated by CA1P. These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel anti-HCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment. The findings would be beneficial for exploring new application of anti-microtubu- lar drugs on oncotherapy.展开更多
OBJECTIVE To investigate the effect of microR NA-10a on the development of granulosa cells tumor(GCT).METHODS FISH was used to detect the miR-10a expression in tissues from GCT patients.Several functional assays were ...OBJECTIVE To investigate the effect of microR NA-10a on the development of granulosa cells tumor(GCT).METHODS FISH was used to detect the miR-10a expression in tissues from GCT patients.Several functional assays were performed to investigate the effect of miR-10a on proliferation,migration,invasion,spheroid formation and repressed anticancer drug-induced apoptosis of GCT in vitro.CRISPR-Cas9 system mediated miR-10a knockout in cancer GC and two mice GCT models were constructed to show the knockdown effect of miR-10a on cancer GC both in vitro and in vivo.RNA-seq,Western blot,luciferase reporter assay and FISH were used to identify potential direct functional targets and related pathways of miR-10a in cancer GC.RESULTS Strong miR-10a signal was detected in tissues from malignant GCT patients.And amplification of miR-10a negatively correlated with overall survival rate of ovarian cancer patients.In addition,ectopic expression of miR-10a significantly promoted cell proliferation,migration,invasion,spheroid formation and repressed anticancer drug-induced apoptosis in vitro.CRISPR-Cas9 system mediated miR-10a knockout in cancer GC showed opposite phenotype compared to miR-10a overexpressed cancer GC.By using xenograft and orthotropic models,the oncogenic role of miR-10a was further confirmed in vivo.RNA-seq,Western blot,luciferase reporter assay and FISH were used to identified PTEN/TET2 as direct functional targets of miR-10a in cancer GC;Akt and Wnt were found as two associated signaling pathways of miR-10a in cancer GC.CONCLUSION Taken together,our results demonstrate that the miR-10a is positively involved indevelopment of GCT.展开更多
In recent years,studies have shown that there is a correlation between sleep disorders and cancer,but at the present stage,the research on sleep disorders and tumor related animal models is relatively insufficient.Our...In recent years,studies have shown that there is a correlation between sleep disorders and cancer,but at the present stage,the research on sleep disorders and tumor related animal models is relatively insufficient.Our research will focus on mice bearing B16F10-luc-G5 melanoma tumor with sleep fragmentation,detecting promoting effect of sleep fragmentation(SF)on the metastasis of melanoma.At the same time,we used Ganoderma lucidum poly⁃saccharides peptide(GL-pp,80 mg·kg-1),a component of traditional Chinese medicine Ganoderma lucidum,which has long enjoyed a good reputation at home and abroad,to observe its anti-tumor metastasis effects on B16F10-luc-G5 mice with SF.Then we used whole proteomics to analyze the difference proteins expressed in lung tissue and compared between groups,includes mice bearing B16F10-luc-G5,mice bearing B16F10-luc-G5 with SF and GL-pp administered mice bearing B16F10-luc-G5 with SF.With the analysis using bioinformatics,we found several key proteins,their genes name are Adcy9,ptk2,Yap1 and Lpin2,Per1 and Tim.And several important clusters,they are,immune system,platelet aggres⁃sion,energy metabolism,cell cytoskeleton,cell adhesion and circadian rhythms.Moreover,we detected the TLR4 signal pathway and macrophage differentiation to reconfirm the results of proteomics and trying to elucidate the mechanism of SF on tumor growth and metastasis and the effects of GL-pp.展开更多
Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogene...Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogeneous with diverse subpopulations of distinct genotypes and phenotypes and the frequency of CTCs is correlated with poor prognosis and overall survival in cancer patients.Less than 0.01%of them may eventually generate metastatic tumors in secondary sites,indicating the inefficiency of metastasis.Nevertheless,metastasis accounts for over 90%of cancer-related deaths,suggesting that a subpopulation of CTCs are able to survive the metastatic process and form metastases.To target metastasis,it is thus essential to understand the roles of various factors during dissemination in the survival and functions of CTCs.However,the effects of hemodynamic shear stress on biophysical properties and functions of CTCs in suspension are not fully understood.This study was to investigate the effect of hemodynamic shear stress on the survival and anti-chemotherapy ability of suspended circulating tumor cells during metastasis,and the effect of actomyosin activity on this regulation.In this study,we developed a circulatory system to generate physiologic levels of hemodynamic shear stress,which mimicked certain important aspects of the CTC microenvironment in blood circulation.The survival of tumor cells in suspension,as a model for real CTCs,under different shear stress and circulation duration was examined.We found that the majority of breast tumor cells s in suspension can be eliminated by hemodynamic shear stress.The surviving cells exhibit unique biophysical properties,including significantly retarded cell adhesion,mesenchymal-like cell morphology,and reduced F-actin expression and cellular stiffness.Cancer stem cells which has been reported in other papers have lower stiffness compared with conventional tumor cells showed significantly higher survival in blood flow.Importantly,low actomyosin activity promotes the survival of CTCs in blood shear flow while high actomyosin activity inhibits tumor cells surviving shear stress treatment.These findings might be explained by the up-and down-regulation of the anti-apoptosis genes.Soft surviving tumor cells held survival advantages in shear flow and higher resistance to chemotherapy.Metastasis is closely linked with chemoresistance.However,the underlying mechanisms have not been fully understood,in particular,the roles of hemodynamic shear stress and actomyosin-dependent cell mechanics in drug resistance of CTCs remain unclear.Inhibiting actomyosin activity in suspended tumor cells enhanced chemoresistance,while activating actomyosin suppressed this ability.These findings might be associated with the corresponding changes in multidrug resistance related genes.Our study unveils the regulatory roles of actomyosin in the survival and drug resistance of circulating tumor cells in hemodynamic shear flow,which imply the importance of fluid shear stress and actomyosin activity in tumor metastasis.Our findings reveal a new mechanism by which circulating tumor cells are able to survive hemodynamic shear stress and chemotherapy and may offer a new potential strategy to target circulating tumor cells in shear flow and combat chemoresistance through actomyosin.展开更多
Background Signal transducer and activator of transcription 3 （STAT3） is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 promi-...Background Signal transducer and activator of transcription 3 （STAT3） is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 promi- ses to be an attractive strategy for treatment of advanced metastatic tumors. Although many STAT3 inhibitors targe- ting the SH2 domain have been reported, few have moved into clinical trials. Targeting the DNA-binding domain （DBD） of STAT3, however, has been avoided due to its ＇ undruggable＇ nature and potentially limited selectivity. Aim This study aims at developing effective and specific inhibitors targeting DNA binding domain of STAT3. Methods： This study reported an improved in-silico approach targeting the DBD of STAT3 that resulted in a small- molecule STAT3 inhibitor （inS3-54） and describe an extensive structure and activity-guided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound （inS3-54A18） with increased specificity and pharmacological properties. Results： InS3-54A18 not only binds directly to the DBD and inhibits the DNA-binding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin-6-stimulated expression of STAT3 downstream target genes. InS3-54A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals. Conclusion： InS3-54A18 may serve as a potential candidate for further development as anticancer therapeutics tar-geting the DBD of human STAT3 and DBD of transcription factors may not be ＇ undruggable＇ as previously thought.展开更多
Aim Hypoxia-inducible factor 1 （HIF-1） , a heterodimeric transcription factor that mediates the adap- tation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a poten...Aim Hypoxia-inducible factor 1 （HIF-1） , a heterodimeric transcription factor that mediates the adap- tation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Kamebakaurin is a diterpenoid compound isolated from Isodonexcia （Maxin.） Hara, which has been used for anti-inflammatory activities. But its antitumor activity has not been reported. Kamebakaurin showed the potent inhibitory activity against HIF-1 activation by COC12 induced hypoxia in various human cancer cell lines. This compound significantly decreased the hypoxia-induced accumulation of HIF-lot protein, whereas it did not af- fect the expressions of topoisomerase-I （Topo-I）. Further analysis revealed that kamebakaurin inhibited HIF-lα protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-lα protein. Fur- thermore, kamebakaurin prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor （VEGF） and erythropoietin （EPO）. However, kamebakaurin caused cell growth inhibition via cell cycle ar- rest at G1 in tumor cells. In vivo studies, we further confirmed the inhibitory effect of kamebakaurin on the expres- sion of HIF-lα proteins, leading to a decrease growth of HCT116 cells in a xenograft tumor model. These resultsshow that kamebakaurin is an effective inhibitor of HIF-1 and provide new perspectives into its anticancer activity.展开更多
The p53 and CD44 expression of 10 cases in canine breast tumor were examined utilizing immunohistochemical assay with rabbit anti-mouse polyclonal antibodies against p53 or CD44, respectively. The p53 expression was s...The p53 and CD44 expression of 10 cases in canine breast tumor were examined utilizing immunohistochemical assay with rabbit anti-mouse polyclonal antibodies against p53 or CD44, respectively. The p53 expression was significantly higher in malignant than in benign breast tumor. The expression of CD44 was not significantly different in malignant breast cancer and benign breast tumor. This suggests that p53 can be used as an indicator for animal prognosis.展开更多
To investigate tumor angiogenesis under the influence of Endostatin,mathematical modeling and numerical simulation of tumor angiogenesis are performed,with the mechanical environment in matrix,the inhibiting effects o...To investigate tumor angiogenesis under the influence of Endostatin,mathematical modeling and numerical simulation of tumor angiogenesis are performed,with the mechanical environment in matrix,the inhibiting effects of Angiostatin and Endostatin into consideration.The展开更多
Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cel...Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cells,(2) delivery of specific enzymes展开更多
基金supported by the National Natural Science Foundation(81960508)。
文摘Objective:There is currently no consensus on whether extra-gastrointestinal stromal tumors(EGISTs)and gastrointestinal stromal tumors(GISTs)are the same type of tumor,and whether the diagnosis and treatment of EGISTs can directly replicate the current diagnostic and treatment standards for GISTs.This study aims to further elucidate the clinical and pathological characteristics,diagnosis,treatment,and prognosis of EGISTs by analyzing the research results of domestic scholars in the field of EGISTs in the past decade.Methods:A review was conducted on original Chinese and English research articles published from 2013 to 2022 focusing on EGISTs.A descriptive approach was used to extract key information from the literature,including patient demographics,tumor location,tumor diameter,mitotic figures,risk stratification,immunohistochemical markers,cell type,and prognostic factors.The data were subjected to statistical analysis.Results:A total of 12 articles containing 780 EGIST patients were included.The male-to female incidence of EGISTs was 0.92꞉1.The most common sites of EGISTs were mesentery(30.96%),peritoneum or retroperitoneum(28.53%),omentum(20.32%),and pelvic cavity(12.52%).52.77%of EGISTs had tumor diameters greater than 10 cm,and the proportions of EGISTs with nuclear fission patterns greater than 5/50 high power field(HPF)and greater than 10/50 HPF were 51.24%and 26.11%,respectively.The proportion of high-risk EGISTs was 79.05%.The positive rates of immune markers CD117,CD34,and DOG-1 in EGISTs were 82.3%,69.0%,and 79.5%,respectively.The proportion of Ki-67>5%was 49.2%,and the proportion of Ki-67>10%was 24.8%.The proportions of EGISTs in spindle cells,epithelial cells,and mixed cells were 74.4%,14.8%,and 13.1%,respectively.The diameter of the tumor,resection method,risk level,Ki-67 index,mitotic counts,presence of rupture/bleeding/necrosis/peripheral tissue invasion/recurrence and metastasis,as well as the use of imatinib treatment after surgery were important factors affecting the prognosis of EGISTs.Conclusion:Current medical research is relatively well cognizant of GISTs with primary sites in the gastrointestinal tract.Compared with GISTs,EGISTs have large tumor diameters,high mitotic counts,a high percentage of high-risk grades,relatively unique molecular expression,and high aggressiveness.EGISTs differ from GISTs in clinicopathological characteristics.Whether EGISTs and GISTs share a common origin remains unclear.If they are distinct tumor entities,separate diagnostic and treatment guidelines for EGISTs should be established.If EGISTs are ultimately confirmed to be a special subtype of GISTs,then directly applying existing GIST-based standards to EGISTs may be inappropriate.A more scientific approach would involve subclassifying EGISTs based on anatomical location and then tailoring treatment strategies accordingly with reference to GIST guidelines.
文摘In this work,iron-doped carbon dots(Fe-CDs)with strong peroxidase-mimicking activity were synthesized for tumor-specific therapy.Their intrinsic red fluorescence enabled high-contrast cellular imaging,revealing preferen⁃tial mitochondrial accumulation.In the acidic and hydrogen peroxide(H_(2)O_(2))-rich tumor microenvironment,Fe-CDs catalyzed hydroxyl radical(·OH)generation,inducing oxidative stress and lipid peroxidation,ultimately triggering ferroptosis.In vitro and in vivo studies demonstrated potent tumor inhibition.Furthermore,Fe-CDs exhibited excel⁃lent biocompatibility with no significant systemic toxicity.By integrating fluorescence imaging and catalytic therapy,this study presents a promising nanoplatform for tumor treatment and ferroptosis research.
文摘Potassium-calcium activates channel subfamily N member 3(KCNN3/SK3/KCa2.3)is involved in regulating cellular calcium signaling,muscle contraction and neurotransmitter release.Dysregulation of the KCNN3 channel is associated with the development of various tumors.We use bioinformatics analysis to identify whether KCNN3 regulates the occurrence and development of stomach adenocarcinoma(STAD)as a prognostic target.By analyzing the Human Protein Atlas(HPA)database and The Cancer Genome Atlas(TCGA)database,we found that the protein and mRNA levels of KCNN3 were dramatically reduced in STAD,and TCGA database showed that KCNN3 significantly correlated with the prognosis and clinical features of STAD.In addition,we found that high expression of KCNN3 in STAD reduced the IC 50 of several drugs in STAD cells,suggesting that high expression of KCNN3 correlated with the drug sensitivity of STAD.To investigate the underlying biological mechanism,we identified a potential KCNN3 interaction factor,tumor necrosis factor receptor superfamily member 7(CD27/TNFRSF7),which is expressed at low levels in STAD.RT-qPCR and Western blotting confirmed that KCNN3 and CD27 positively correlated with each other at protein and mRNA levels,and co-immunoprecipitation and immunofluorescence experiments confirmed that the two proteins interact and colocalize in the cytoplasm.Moreover,we confirmed the inhibitory effect of KCNN3 on the proliferation,migration and invasion of human STAD cells in vitro and in vivo through subcutaneous tumorigenesis and cellular experiments.Furthermore,GO/KEGG enrichment analysis showed that KCNN3 was enriched in signaling pathways regulating the immune response and calcium or metal ion transport.Lastly,we verified through cell co-culture,RT-qPCR and CCK8 assays that high expression of KCNN3 can promote the increase of T cell activating factor and the killing effect of T cells on STAD cells.Therefore,our results suggest that KCNN3 is a potential inhibitory factor affecting the occurrence and progression of STAD.
基金The project supported by National Natural Science Foundation of China(81373439,81473234 and U1303221)
文摘OBJECTIVE Previous work has shown that gap junction intercel ular communication(GJIC)enhances cisplatin(Pt)toxicity in testicular tumor cells but decreases it in non-tumor testicular cells.In this study,these different GJIC-propagated effects were demonstrated in tumor versus non-tumor cells from other organ tissues(liver and lung).METHODS We use several different mani pulations(no cell contact,pharmacological inhibition,and si RNA suppression)to down-regulate GJIC function.The in vivo results using xenograft tumor models were consistent with those from the above-mentioned cells.To better understand the mechanism(s)involved,we studied the effects of GJIC on Pt accumulation in tumor and non-tumor cells from the liver and lung.RESULTS The intracel ular Pt and DNA-Pt adduct contents clearly increased in non-tumor cells but decreasedin tumor cells when GJIC was downregulated.Further analysis indicated that the opposite effectsof GJIC on Pt accumulation in normal versus tumor cells from the liver were due to its different effects on copper transporter1 and multidrug resistance-associated protein2,membrane transporters attributed to intracellular Pt transfer.CONCLUSION GJIC protects normal organs from cisplatin toxicity while enhancing it in tumor cells via its different effects on intracellular Pt transfer.
基金The project supported by National Natural Science Foundation of China(81300964)the China Postdoctoral Science Foundation(2013M531611,2014T70648)
文摘Bone tumour is one of most common primary cancer which exhibits cancerous osteoblastic differentiation and malignant osteoid in patients.At present,chemotherapy(pre-and post-operative)is used as a standard treatment protocol for bone tumour.However,drugs used in the treatment of bone tumour induce high toxicity to normal tissues including anaemia,neutropenia,thrombocytopenia,and heart damage which further reduce the survival rate of patients.Therefore,there is an urgent need to develop a new therapeutic approach for the treatment such that it induce maximum cell killing effect in tumor cells while sparing the healthy bone cells.In this article,some new perspectives were provided on the development of bone-targeted nano-drug carriers for bone cancer treatment.We hope such discussions wouldencourage more detailed and careful studies to support product development of bone-targeted drug carriers for bone cancer treatment.
基金Projects(31201074,81371013) supported by the National Natural Science Foundation of ChinaProject(2011105102016) supported by the Key Program of Medical Health of Dongguan City,Guangdong Province,ChinaProject(2011108102026) supported by Dongguan Universities Program,China
文摘Folic acid conjugated chitosan was prepared by cross-linking reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDC), and then used as a template to prepare folic acid-chitosan(FA-CS) conjugated nanoparticles and load mitoxantrone nanoparticles(FA-CSNP/MTX). Drug dissolution testing, CCK-8 method, and confocal microscopy were used to detect their controlled-release capability in different situations and the specific uptake by HONE1 cells. The experimental results show that the nanoparticles have uniform size distribution of 48-58 nm. The highest encapsulation rate of the particles on mitoxantrone hydrochloride(MTX) is(77.5±1.9)%, and the drug loading efficiency is(18.4±0.4)%. The sustained release effect, cell growth inhibition activity and targeting effect of the FA-CS/MTX nanoparticles are good in artificial gastric fluid and intestinal fluid. It is demonstrated that the FA-CSNP system is a potentially useful system for the targeted delivery of anticancer drug MTX.
基金National Nature Science Foundation of China(81773989and 81530098)
文摘OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(LoVo)xenografts were treated with SMI 10 mL·kg^-1 daily for 1 or 8 d.Multidimensional PK profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.For PD studies,the tumor-bearing mice Intravital multi-photon imaging and CD31 immunofluorescence staining were used to evaluate the number of microves⁃sels and braches.Double staining of CD31 and α-SMA was performed to evaluate pericytes coverage ratios around vessels.ELISA was performed to determine the concentrations of VEGF and FGF in tumor tissues.For synergistic anti-tumor study,the tumor-bearing mice were treated with SMI 10 mL·kg^-1 daily,Rd 5 mg·kg^-1 daily with or without 5-FU 15 mg·kg^-1 every 3 d for 20 d.HPLC-MS/MS was used to determine the concentrations of 5-FU in plasma and tumor tissues.RESULTS SMI decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and improved vascular pericytes coverage(P<0.05).PK studies 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 ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In fact,the proportion of Rd in the detectable components of SMI gradually increased in the following order:SMI formula(2.8%),plasma(16.0%),tumor tissues(34.3%),and TECs(40.3%).In vivo bioactivity results showed that Rd 5 mg·kg^-1 daily significantly decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and increased pericytes coverage(P<0.05)while Rd 0.5 mg·kg^-1 daily,Rb1 and Rg1 had no significant effect on them.Rd 5 mg·kg^-1 suppressed the expression of VEGF and FGF simultaneously.Rd 5 mg·kg^-1 enhanced the antitumor effect of 5-FU via increasing the distribution of 5-FU in tumor tissues(P<0.05)in xenograft mice.CONCLUSION Ginsenoside Rd may be the major bioactive anti-angiogenic constituent targeting TECs after SMI treatment.
基金This work was supported by the National Natural Science Foundation(82172594 and 82373046)the Hunan Graduate Research Innovation Project(CX20230318),China.
文摘Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.
基金The project supported by National Natural Science Foundation of China(81202840,81373815)Specialized Research Fund for the Doctoral Program of Higher Education of China(20131107110014)+1 种基金Beijing Natural Science Foundation(7162084)Swedish Cancer Foundation(150815)
文摘OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the beneficial effects of GYⅡon murine breast cancer models.METHODS Inhibition of tumor growth and metastasis was evaluated by assessment of tumor weight and analysis of bioluminescent signal after a homograft inoculation.Viability of cultured breast cancer cells was determined using MTT assay andreal-time cell analysis(RTCA).Cell migratory ability was evaluated by Transwell?assay and wound healing assay.Subsequently,the potential anti-tumor and anti-metastatic mechanism was investigated by Western blotting and Immunohistochemistry.RESULTS GYⅡshowed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model.And GYⅡsuppressed theproliferation of 4T1 and MCF-7 cells in a dose-dependent manner.A better inhibitory effect on 4T1 cells proliferation and migration was found in sub-fractions(SF)of GYⅡ.Moreover,heparanase expression and degree of angiogenesis were reduced in tumor tissues.Western blotting analysis showed decreased expression of heparanase and growth factors in the cells treated with GYⅡand its sub-fractions(SF2 and SF3),there by a reduction in phosphorylation of ERK and AKT.CONCLUSION GYⅡexerts anti-tumor growth and anti-metastatic effects on murine breast cancer model.Sub-fractions 2 and 3 exhibits higher potency of the anti-tumor activity that is,at least partly,associated with decreased heparanase and growth factor sexpression,which subsequently sup-pressed activation of ERK and AKT pathways.
文摘Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We demon- strated that CA1P also showed an outstanding anti-cancer effect on hepatocellular carcinoma （HCC） in vivo and in vitro. As determined by DCFH-DA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the down-regulation of Mcl-1. Additonal western blot and immunofluorescence assays further indi- cated that CA1P inhibited Wnt/β-catenin pathway through GSK-3β activition with an increasing of Mcl phosphoryl- ation and subsequent degradation mediated by tubulin-dynactin p l50-AKT signaling pathway axis. Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK-3β inhibitor （ CHIR-99021 ）. Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage （TAM） apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGF-β were also altered. Adoptive transfer of macrophages reinstated tumor growth treated by CA1P. These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel anti-HCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment. The findings would be beneficial for exploring new application of anti-microtubu- lar drugs on oncotherapy.
基金supported by Natural Science Foundation of Anhui Province for Young Scholars(1708085QH200)
文摘OBJECTIVE To investigate the effect of microR NA-10a on the development of granulosa cells tumor(GCT).METHODS FISH was used to detect the miR-10a expression in tissues from GCT patients.Several functional assays were performed to investigate the effect of miR-10a on proliferation,migration,invasion,spheroid formation and repressed anticancer drug-induced apoptosis of GCT in vitro.CRISPR-Cas9 system mediated miR-10a knockout in cancer GC and two mice GCT models were constructed to show the knockdown effect of miR-10a on cancer GC both in vitro and in vivo.RNA-seq,Western blot,luciferase reporter assay and FISH were used to identify potential direct functional targets and related pathways of miR-10a in cancer GC.RESULTS Strong miR-10a signal was detected in tissues from malignant GCT patients.And amplification of miR-10a negatively correlated with overall survival rate of ovarian cancer patients.In addition,ectopic expression of miR-10a significantly promoted cell proliferation,migration,invasion,spheroid formation and repressed anticancer drug-induced apoptosis in vitro.CRISPR-Cas9 system mediated miR-10a knockout in cancer GC showed opposite phenotype compared to miR-10a overexpressed cancer GC.By using xenograft and orthotropic models,the oncogenic role of miR-10a was further confirmed in vivo.RNA-seq,Western blot,luciferase reporter assay and FISH were used to identified PTEN/TET2 as direct functional targets of miR-10a in cancer GC;Akt and Wnt were found as two associated signaling pathways of miR-10a in cancer GC.CONCLUSION Taken together,our results demonstrate that the miR-10a is positively involved indevelopment of GCT.
文摘In recent years,studies have shown that there is a correlation between sleep disorders and cancer,but at the present stage,the research on sleep disorders and tumor related animal models is relatively insufficient.Our research will focus on mice bearing B16F10-luc-G5 melanoma tumor with sleep fragmentation,detecting promoting effect of sleep fragmentation(SF)on the metastasis of melanoma.At the same time,we used Ganoderma lucidum poly⁃saccharides peptide(GL-pp,80 mg·kg-1),a component of traditional Chinese medicine Ganoderma lucidum,which has long enjoyed a good reputation at home and abroad,to observe its anti-tumor metastasis effects on B16F10-luc-G5 mice with SF.Then we used whole proteomics to analyze the difference proteins expressed in lung tissue and compared between groups,includes mice bearing B16F10-luc-G5,mice bearing B16F10-luc-G5 with SF and GL-pp administered mice bearing B16F10-luc-G5 with SF.With the analysis using bioinformatics,we found several key proteins,their genes name are Adcy9,ptk2,Yap1 and Lpin2,Per1 and Tim.And several important clusters,they are,immune system,platelet aggres⁃sion,energy metabolism,cell cytoskeleton,cell adhesion and circadian rhythms.Moreover,we detected the TLR4 signal pathway and macrophage differentiation to reconfirm the results of proteomics and trying to elucidate the mechanism of SF on tumor growth and metastasis and the effects of GL-pp.
基金the support from National Natural Science Foundation of China ( 11672255)Shenzhen Science and Technology Innovation Commission ( JCYJ20170303160515987, JCYJ20170413154735522 )+1 种基金Early Career Scheme from Research Grants Council of the Hong Kong Special Administrative Region,China ( PolyU 252094 /17E)the internal grant from the Hong Kong Polytechnic University ( 1-ZE4Q,1-ZVJ8)
文摘Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogeneous with diverse subpopulations of distinct genotypes and phenotypes and the frequency of CTCs is correlated with poor prognosis and overall survival in cancer patients.Less than 0.01%of them may eventually generate metastatic tumors in secondary sites,indicating the inefficiency of metastasis.Nevertheless,metastasis accounts for over 90%of cancer-related deaths,suggesting that a subpopulation of CTCs are able to survive the metastatic process and form metastases.To target metastasis,it is thus essential to understand the roles of various factors during dissemination in the survival and functions of CTCs.However,the effects of hemodynamic shear stress on biophysical properties and functions of CTCs in suspension are not fully understood.This study was to investigate the effect of hemodynamic shear stress on the survival and anti-chemotherapy ability of suspended circulating tumor cells during metastasis,and the effect of actomyosin activity on this regulation.In this study,we developed a circulatory system to generate physiologic levels of hemodynamic shear stress,which mimicked certain important aspects of the CTC microenvironment in blood circulation.The survival of tumor cells in suspension,as a model for real CTCs,under different shear stress and circulation duration was examined.We found that the majority of breast tumor cells s in suspension can be eliminated by hemodynamic shear stress.The surviving cells exhibit unique biophysical properties,including significantly retarded cell adhesion,mesenchymal-like cell morphology,and reduced F-actin expression and cellular stiffness.Cancer stem cells which has been reported in other papers have lower stiffness compared with conventional tumor cells showed significantly higher survival in blood flow.Importantly,low actomyosin activity promotes the survival of CTCs in blood shear flow while high actomyosin activity inhibits tumor cells surviving shear stress treatment.These findings might be explained by the up-and down-regulation of the anti-apoptosis genes.Soft surviving tumor cells held survival advantages in shear flow and higher resistance to chemotherapy.Metastasis is closely linked with chemoresistance.However,the underlying mechanisms have not been fully understood,in particular,the roles of hemodynamic shear stress and actomyosin-dependent cell mechanics in drug resistance of CTCs remain unclear.Inhibiting actomyosin activity in suspended tumor cells enhanced chemoresistance,while activating actomyosin suppressed this ability.These findings might be associated with the corresponding changes in multidrug resistance related genes.Our study unveils the regulatory roles of actomyosin in the survival and drug resistance of circulating tumor cells in hemodynamic shear flow,which imply the importance of fluid shear stress and actomyosin activity in tumor metastasis.Our findings reveal a new mechanism by which circulating tumor cells are able to survive hemodynamic shear stress and chemotherapy and may offer a new potential strategy to target circulating tumor cells in shear flow and combat chemoresistance through actomyosin.
文摘Background Signal transducer and activator of transcription 3 （STAT3） is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 promi- ses to be an attractive strategy for treatment of advanced metastatic tumors. Although many STAT3 inhibitors targe- ting the SH2 domain have been reported, few have moved into clinical trials. Targeting the DNA-binding domain （DBD） of STAT3, however, has been avoided due to its ＇ undruggable＇ nature and potentially limited selectivity. Aim This study aims at developing effective and specific inhibitors targeting DNA binding domain of STAT3. Methods： This study reported an improved in-silico approach targeting the DBD of STAT3 that resulted in a small- molecule STAT3 inhibitor （inS3-54） and describe an extensive structure and activity-guided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound （inS3-54A18） with increased specificity and pharmacological properties. Results： InS3-54A18 not only binds directly to the DBD and inhibits the DNA-binding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin-6-stimulated expression of STAT3 downstream target genes. InS3-54A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals. Conclusion： InS3-54A18 may serve as a potential candidate for further development as anticancer therapeutics tar-geting the DBD of human STAT3 and DBD of transcription factors may not be ＇ undruggable＇ as previously thought.
文摘Aim Hypoxia-inducible factor 1 （HIF-1） , a heterodimeric transcription factor that mediates the adap- tation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Kamebakaurin is a diterpenoid compound isolated from Isodonexcia （Maxin.） Hara, which has been used for anti-inflammatory activities. But its antitumor activity has not been reported. Kamebakaurin showed the potent inhibitory activity against HIF-1 activation by COC12 induced hypoxia in various human cancer cell lines. This compound significantly decreased the hypoxia-induced accumulation of HIF-lot protein, whereas it did not af- fect the expressions of topoisomerase-I （Topo-I）. Further analysis revealed that kamebakaurin inhibited HIF-lα protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-lα protein. Fur- thermore, kamebakaurin prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor （VEGF） and erythropoietin （EPO）. However, kamebakaurin caused cell growth inhibition via cell cycle ar- rest at G1 in tumor cells. In vivo studies, we further confirmed the inhibitory effect of kamebakaurin on the expres- sion of HIF-lα proteins, leading to a decrease growth of HCT116 cells in a xenograft tumor model. These resultsshow that kamebakaurin is an effective inhibitor of HIF-1 and provide new perspectives into its anticancer activity.
基金Natural Science Foundation of Heilongjiang Province (C2004-32)
文摘The p53 and CD44 expression of 10 cases in canine breast tumor were examined utilizing immunohistochemical assay with rabbit anti-mouse polyclonal antibodies against p53 or CD44, respectively. The p53 expression was significantly higher in malignant than in benign breast tumor. The expression of CD44 was not significantly different in malignant breast cancer and benign breast tumor. This suggests that p53 can be used as an indicator for animal prognosis.
基金supported by the National Natural Science Foundation of China,No.10372026,10772751Shanghai Leading Academic Discipline Project B112
文摘To investigate tumor angiogenesis under the influence of Endostatin,mathematical modeling and numerical simulation of tumor angiogenesis are performed,with the mechanical environment in matrix,the inhibiting effects of Angiostatin and Endostatin into consideration.The
基金supported by a predoctoral fellowship from the National Institutes of Health and a research grant from the National Science Foundation
文摘Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cells,(2) delivery of specific enzymes
基金This work was supported in part by the-National Natural Science Foundation of China （61403342, 61273286, U1509207, 61325019, 113 02195）, and Hubei Key Laboratory of Intelligent Vision Based Monitoring for Hydroelectric Engineering （2014KLA09）.
