BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis.Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer(CRC...BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis.Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer(CRC).AIM To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis.METHODS We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways.Patients were divided into two groups based on the methylation status of the six evaluated genes,namely,the<3 aberrancy group and≥3 aberrancy group.Various tumor stages were divided into two subgroups(local and advanced stages)on the basis of the pathological type of the following tissues:Tumor and adjacent normal tissues(matched normal).We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression(TTP)and overall survival.RESULTS We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue.The 5-year TTP survival curves showed a significant difference between the≥3 aberrancy group and the<3 aberrancy group.Compared with the<3 aberrancy group,a significantly shorter TTP was observed in the≥3 aberrancy group.We further analyzed the interaction between CRC prognosis and different cancer stages(local and advanced)according to the methylation status of the selected genes in both types of tissues.There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages.We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues.CONCLUSION Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC.We recommend using these novel markers to assist in clinical decision-making.展开更多
BACKGROUND Patients with colorectal cancer(CRC)undergo surgery,as well as perioperative chemoradiation or adjuvant chemotherapy primarily based on the tumor–node–metastasis(TNM)cancer staging system.However,treatmen...BACKGROUND Patients with colorectal cancer(CRC)undergo surgery,as well as perioperative chemoradiation or adjuvant chemotherapy primarily based on the tumor–node–metastasis(TNM)cancer staging system.However,treatment responses and prognostic outcomes of patients within the same stage vary markedly.The potential use of novel biomarkers can improve prognostication and shared decision making before implementation into certain therapies.AIM To investigate whether SUMF2,ADAMTS5,and PXDN methylation status could be associated with CRC prognosis.METHODS We conducted a Taiwan region cohort study involving 208 patients with CRC recruited from TriService General Hospital and applied the candidate gene approach to identify three genes involved in oncogenesis pathways.A methylation-specific polymerase chain reaction(MS-PCR)and Epi TYPER DNA methylation analysis were employed to detect methylation status and to quantify the methylation level of candidate genes in tumor tissue and adjacent normal tissue from participants.We evaluated SUMF2,ADAMTS5,and PXDN methylation as predictors of prognosis,including recurrence-free survival(RFS),progression-free survival(PFS),and overall survival(OS),using a Cox regression model and Kaplan–Meier analysis.RESULTS We revealed various outcomes related to methylation and prognosis.Significantly shorter PFS and OS were associated with the CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue compared with CpG_3+CpG_7 hypomethylation[hazard ratio(HR)=2.24,95%confidence interval(CI)=1.03-4.85 for PFS,HR=2.56 and 95%CI=1.08-6.04 for OS].By contrast,a significantly longer RFS was associated with CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue compared with CpG_2 and CpG_13 hypomethylation[HR(95%CI)=0.15(0.03-0.71)for CpG_2 and 0.20(0.04-0.97)for CpG_13].The relationship between the methylation status of PXDN and the prognosis of CRC did not reach statistical significance.CONCLUSION Our study found that CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue was associated with significantly shorter PFS and OS compared with CpG_3+CpG_7 hypomethylation.CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue was associated with a significantly longer RFS compared with CpG_2 and CpG_13 hypomethylation.These methylationrelated biomarkers which have implications for CRC prognosis prediction may aid physicians in clinical decision-making.展开更多
The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates u...The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.展开更多
The c-ras and its product P21 have been shown to play an important role in the initiation and development of some malignancies. The activation of c-ras may be associated with two mechanisms: (ⅰ) a point mutation of t...The c-ras and its product P21 have been shown to play an important role in the initiation and development of some malignancies. The activation of c-ras may be associated with two mechanisms: (ⅰ) a point mutation of the codon at position 12 or 61 of the genome leading to a single amino acid alteration in the corresponding product P21; (ⅱ) enhanced expression of ras family encode proteins with展开更多
基金Supported by the Ministry of Science and Technology,Taiwan,No.MOST 104-2314-B-016-010-MY2 and No.MOST 106-2320-B-016-018the Ministry of National Defense,Taiwan,No.MAB-107-075,No.MAB-108-057and No.MAB-109-061
文摘BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis.Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer(CRC).AIM To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis.METHODS We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways.Patients were divided into two groups based on the methylation status of the six evaluated genes,namely,the<3 aberrancy group and≥3 aberrancy group.Various tumor stages were divided into two subgroups(local and advanced stages)on the basis of the pathological type of the following tissues:Tumor and adjacent normal tissues(matched normal).We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression(TTP)and overall survival.RESULTS We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue.The 5-year TTP survival curves showed a significant difference between the≥3 aberrancy group and the<3 aberrancy group.Compared with the<3 aberrancy group,a significantly shorter TTP was observed in the≥3 aberrancy group.We further analyzed the interaction between CRC prognosis and different cancer stages(local and advanced)according to the methylation status of the selected genes in both types of tissues.There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages.We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues.CONCLUSION Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC.We recommend using these novel markers to assist in clinical decision-making.
基金Supported by Ministry of National Defense-Medical Affairs Bureau,Taiwan,No.MND-MAB-110-109,No.MND-MAB-D-111059Cheng-Hsin General Hospital,Taiwan,No.CHNDMC-111-4。
文摘BACKGROUND Patients with colorectal cancer(CRC)undergo surgery,as well as perioperative chemoradiation or adjuvant chemotherapy primarily based on the tumor–node–metastasis(TNM)cancer staging system.However,treatment responses and prognostic outcomes of patients within the same stage vary markedly.The potential use of novel biomarkers can improve prognostication and shared decision making before implementation into certain therapies.AIM To investigate whether SUMF2,ADAMTS5,and PXDN methylation status could be associated with CRC prognosis.METHODS We conducted a Taiwan region cohort study involving 208 patients with CRC recruited from TriService General Hospital and applied the candidate gene approach to identify three genes involved in oncogenesis pathways.A methylation-specific polymerase chain reaction(MS-PCR)and Epi TYPER DNA methylation analysis were employed to detect methylation status and to quantify the methylation level of candidate genes in tumor tissue and adjacent normal tissue from participants.We evaluated SUMF2,ADAMTS5,and PXDN methylation as predictors of prognosis,including recurrence-free survival(RFS),progression-free survival(PFS),and overall survival(OS),using a Cox regression model and Kaplan–Meier analysis.RESULTS We revealed various outcomes related to methylation and prognosis.Significantly shorter PFS and OS were associated with the CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue compared with CpG_3+CpG_7 hypomethylation[hazard ratio(HR)=2.24,95%confidence interval(CI)=1.03-4.85 for PFS,HR=2.56 and 95%CI=1.08-6.04 for OS].By contrast,a significantly longer RFS was associated with CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue compared with CpG_2 and CpG_13 hypomethylation[HR(95%CI)=0.15(0.03-0.71)for CpG_2 and 0.20(0.04-0.97)for CpG_13].The relationship between the methylation status of PXDN and the prognosis of CRC did not reach statistical significance.CONCLUSION Our study found that CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue was associated with significantly shorter PFS and OS compared with CpG_3+CpG_7 hypomethylation.CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue was associated with a significantly longer RFS compared with CpG_2 and CpG_13 hypomethylation.These methylationrelated biomarkers which have implications for CRC prognosis prediction may aid physicians in clinical decision-making.
基金UTRGV School of medicine start up,CPRIT TREC Award RP230419 and Integrated Cancer Research Core(ICRC)-RP210180Herb Kosten foundation for pancreatic cancer researchNational Institutes of Health grants R01CA206069,SC1GM139727,SC2GM139715,R01CA210192 and R01CA204552.
文摘The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.
文摘The c-ras and its product P21 have been shown to play an important role in the initiation and development of some malignancies. The activation of c-ras may be associated with two mechanisms: (ⅰ) a point mutation of the codon at position 12 or 61 of the genome leading to a single amino acid alteration in the corresponding product P21; (ⅱ) enhanced expression of ras family encode proteins with
