AIM: To explore the value of serum M2-pyruvate kinase (M2-PK) in colorectal cancer (CRC) mass screening. METHODS: We conducted a molecular epidemiology study in Hangzhou, China, from year 2006 to year 2008. Serum samp...AIM: To explore the value of serum M2-pyruvate kinase (M2-PK) in colorectal cancer (CRC) mass screening. METHODS: We conducted a molecular epidemiology study in Hangzhou, China, from year 2006 to year 2008. Serum samples were collected from 93 CRC, 41 advanced adenomas, 137 adenomas, 47 non-adenomatous polyps, and 158 normal participants in a community setting. Serum M2-PK and carcinoembryonic antigen (CEA) were measured using Enzyme-linked immunosorbent assay. SPSS 16.0 software was used to perform data analysis. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificities were estimated for serum M2-PK in diagnosis of colorectal lesions and compared with CEA. RESULTS: Average serum M2-PK value among 158 normal people was 2.96 U/mL and not affected by gender (P = 0.47) or age (P = 0.59). Average serum M2-PK (U/mL) was 14.75 among stage III and 13.10 among stage?I?and II CRC patients, about 4 times higher than that among normal people. Average serum M2-PK was 8.58, 6.70, 5.13 and 2.51 U/mL among advanced adenoma, adenomas, non-adenomatous polyps, and inflammatory bowel disease patients, respectively. AUC for serum M2-PK was greater than that for CEA among all colorectal lesions. AUC for serum M2-PK was 0.89 (0.84, 0.94) (95% confidence interval), higher than that for CEA [0.70 (0.62-0.79)] in CRC stage?I?and II, 0.89 (0.84-0.94) vs 0.73 (0.63-0.83) in CRC stage III, 0.81 (0.74-0.86) vs 0.63 (0.53 - 0.73) in advanced adenomas, 0.69 (0.64-0.76) vs 0.54 (0.47-0.60) in adenomas, and 0.69 (0.62-0.78) vs 0.58 (0.48-0.68) in non-adenomatous polyps. The diagnostic sensitivity for all colorectal lesions increased with decrease in the cut-off value of serum M2-PK. The diagnostic sensitivity (%) of serum M2-PK was 100.00 for CRC, 95.12 advanced adenoma, 82.48 adenoma, and 82.98 non-adenomatous polyp. There were no CRC cases missed and 40.51% of unnecessary colonoscopies were avoided when the cut-off value was 2.00 U/mL. CONCLUSION: Serum M2-PK can be used as a primary screening test in CRC mass screening. It may be a promising non-invasive biomarker for CRC early detection.展开更多
Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting t...Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.展开更多
基金Supported by The National 11th 5-Year Key Programs for Department of Science and Technology of China, No. 2006BAI02A08
文摘AIM: To explore the value of serum M2-pyruvate kinase (M2-PK) in colorectal cancer (CRC) mass screening. METHODS: We conducted a molecular epidemiology study in Hangzhou, China, from year 2006 to year 2008. Serum samples were collected from 93 CRC, 41 advanced adenomas, 137 adenomas, 47 non-adenomatous polyps, and 158 normal participants in a community setting. Serum M2-PK and carcinoembryonic antigen (CEA) were measured using Enzyme-linked immunosorbent assay. SPSS 16.0 software was used to perform data analysis. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificities were estimated for serum M2-PK in diagnosis of colorectal lesions and compared with CEA. RESULTS: Average serum M2-PK value among 158 normal people was 2.96 U/mL and not affected by gender (P = 0.47) or age (P = 0.59). Average serum M2-PK (U/mL) was 14.75 among stage III and 13.10 among stage?I?and II CRC patients, about 4 times higher than that among normal people. Average serum M2-PK was 8.58, 6.70, 5.13 and 2.51 U/mL among advanced adenoma, adenomas, non-adenomatous polyps, and inflammatory bowel disease patients, respectively. AUC for serum M2-PK was greater than that for CEA among all colorectal lesions. AUC for serum M2-PK was 0.89 (0.84, 0.94) (95% confidence interval), higher than that for CEA [0.70 (0.62-0.79)] in CRC stage?I?and II, 0.89 (0.84-0.94) vs 0.73 (0.63-0.83) in CRC stage III, 0.81 (0.74-0.86) vs 0.63 (0.53 - 0.73) in advanced adenomas, 0.69 (0.64-0.76) vs 0.54 (0.47-0.60) in adenomas, and 0.69 (0.62-0.78) vs 0.58 (0.48-0.68) in non-adenomatous polyps. The diagnostic sensitivity for all colorectal lesions increased with decrease in the cut-off value of serum M2-PK. The diagnostic sensitivity (%) of serum M2-PK was 100.00 for CRC, 95.12 advanced adenoma, 82.48 adenoma, and 82.98 non-adenomatous polyp. There were no CRC cases missed and 40.51% of unnecessary colonoscopies were avoided when the cut-off value was 2.00 U/mL. CONCLUSION: Serum M2-PK can be used as a primary screening test in CRC mass screening. It may be a promising non-invasive biomarker for CRC early detection.
文摘Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.
