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Volume 21,Issue 1,2014 Table of Contents
1 Importance of monitoring therapeutic cancer vaccine-mediated immune responses in clinical settings
2014, 21(1):1-6.
DOI: 10.3872/j.issn.1007-385X.2014.1.001
Abstract:
Activation of immune cells is the first biological event after administration of a therapeutic cancer vaccine, thus serving as an indicator of success in the induction of immune response. Therefore, monitoring the activation status of immune cells is of pivotal importance in the clinical application of therapeutic cancer vaccines. Currently, a “gold standard” for monitoring cancer vaccine-mediated immune cell activation is lacking. Although several methods have been developed to measure the clinical immune response, how to improve the reproducibility and comparability of these methods remains a significant challenge and the usefulness of these methods has yet to be further evaluated in clinical studies with a large sample size. Moreover, the complexity of the immune response including inconvenient immune response, immune-related adverse effect and antigen cascade, hampers meaningful comparisons among studies. In recent years, several international working groups have established immune response monitoring standards including the minimal information about T cell assays (MIATA) proposed by an international team of academic researchers and industry experts, and the clinical considerations for therapeutic cancer vaccines developed by FDA. At present in China, inadequate attention has been paid to the clinical immune response monitoring, and the monitoring methods have not been standardized. This review aims: 1) to analyze the problems and challenges that the cancer immunotherapy monitoring in China faces; and 2) to propose how to enforce and improve the monitoring of immune responses in cancer patients after treatment with cancer vaccines through basic research and clinical trials in China.
Activation of immune cells is the first biological event after administration of a therapeutic cancer vaccine, thus serving as an indicator of success in the induction of immune response. Therefore, monitoring the activation status of immune cells is of pivotal importance in the clinical application of therapeutic cancer vaccines. Currently, a “gold standard” for monitoring cancer vaccine-mediated immune cell activation is lacking. Although several methods have been developed to measure the clinical immune response, how to improve the reproducibility and comparability of these methods remains a significant challenge and the usefulness of these methods has yet to be further evaluated in clinical studies with a large sample size. Moreover, the complexity of the immune response including inconvenient immune response, immune-related adverse effect and antigen cascade, hampers meaningful comparisons among studies. In recent years, several international working groups have established immune response monitoring standards including the minimal information about T cell assays (MIATA) proposed by an international team of academic researchers and industry experts, and the clinical considerations for therapeutic cancer vaccines developed by FDA. At present in China, inadequate attention has been paid to the clinical immune response monitoring, and the monitoring methods have not been standardized. This review aims: 1) to analyze the problems and challenges that the cancer immunotherapy monitoring in China faces; and 2) to propose how to enforce and improve the monitoring of immune responses in cancer patients after treatment with cancer vaccines through basic research and clinical trials in China.
2014, 21(1):7-13.
DOI: 10.3872/j.issn.1007-385X.2014.01.002
Abstract:
Objective:To study the inhibitory effect of the anti-CD133 single chain variable fragment (ScFv) labeled with 131I on CD133＋cancer stem cells (CSCs) sorted form human hepatocellular liver carcinoma HepG2 cells in vitro. Methods: CD133+ and CD133- CSCs were isolated from HepG2 cells through magnetic-activated cell sorting (MACS). CD133 expression in both sorted and unsorted cells was analyzed by flow cytometry (FCM). The property of CD133＋ CSCs was validated by sphere-forming assay and colony formation assay in vitro and tumor formation assay in nude BALB/c mice in vivo. The monoclonal antibody CD133 was labeled with 131I using the chloramines T method and the labeling rate, specific activity and radioactivity were evaluated. CD133+ CSCs were treated with 131I, CD133 ScFv, 131I-CD133 ScFv, and 131I＋CD133 ScFv. At 12, 24 and 48 hours after treatment, cell proliferation and cell cycle progression were assessed by MTT assay and FCM respectively. Results: CD133 was detected in (97.71±1.13)% of the sorted CD133＋ HepG2 cells but in only (1.52±0.78)% of unsorted HepG2 cells (P＝0.0001). As compared with CD133- HepG2 cells, CD133＋ HepG2 cells showed a higher tumor sphere formation ability (\[45.03±1.35\]% vs \[7.4±054\]%, P<0.001). The 131I labeling rate of CD133 ScFv was 88.92%, and the radiochemical-purity was 98.63%. A maximal CD133+ cell growth inhibition of (89.58±0.74)% was observed (P<0.05) when 131I was used at 3.7 MBq/100 μl and CD133 ScFv was used at 1 μg/100 μl, significantly higher than other doses (P<0.05). The proportion of G0/G1 phase arrest in cells treated with 131I-CD133 ScFv was significantly reduced as compared with treatments (P<005). Conclusion: Radioisotope 131I labeled CD133 ScFv may effectively inhibit growth of CD133-positive human hepatocellular carcinoma cells in vitro.
Objective:To study the inhibitory effect of the anti-CD133 single chain variable fragment (ScFv) labeled with 131I on CD133＋cancer stem cells (CSCs) sorted form human hepatocellular liver carcinoma HepG2 cells in vitro. Methods: CD133+ and CD133- CSCs were isolated from HepG2 cells through magnetic-activated cell sorting (MACS). CD133 expression in both sorted and unsorted cells was analyzed by flow cytometry (FCM). The property of CD133＋ CSCs was validated by sphere-forming assay and colony formation assay in vitro and tumor formation assay in nude BALB/c mice in vivo. The monoclonal antibody CD133 was labeled with 131I using the chloramines T method and the labeling rate, specific activity and radioactivity were evaluated. CD133+ CSCs were treated with 131I, CD133 ScFv, 131I-CD133 ScFv, and 131I＋CD133 ScFv. At 12, 24 and 48 hours after treatment, cell proliferation and cell cycle progression were assessed by MTT assay and FCM respectively. Results: CD133 was detected in (97.71±1.13)% of the sorted CD133＋ HepG2 cells but in only (1.52±0.78)% of unsorted HepG2 cells (P＝0.0001). As compared with CD133- HepG2 cells, CD133＋ HepG2 cells showed a higher tumor sphere formation ability (\[45.03±1.35\]% vs \[7.4±054\]%, P<0.001). The 131I labeling rate of CD133 ScFv was 88.92%, and the radiochemical-purity was 98.63%. A maximal CD133+ cell growth inhibition of (89.58±0.74)% was observed (P<0.05) when 131I was used at 3.7 MBq/100 μl and CD133 ScFv was used at 1 μg/100 μl, significantly higher than other doses (P<0.05). The proportion of G0/G1 phase arrest in cells treated with 131I-CD133 ScFv was significantly reduced as compared with treatments (P<005). Conclusion: Radioisotope 131I labeled CD133 ScFv may effectively inhibit growth of CD133-positive human hepatocellular carcinoma cells in vitro.
2014, 21(1):14-19.
DOI: 10.3872/j.issn.1007-385X.2014.1.003
Abstract:
Objective:To investigate the effect of TLR4 signaling on breast cancer cell proliferation/apoptosis and the underlying mechanism in vitro.Methods: Breast carcinoma 4TI cells were stimulated with 100 ng/ml lipopolysaccharide (LPS) after a preincubation with DMSO or NF-κB inhibitor PDTC for 30 min. At 6, 12, 18 and 24 h after LPS stimulation, levels of miR-21 were measured by qRT-PCR, phospho-NF-κBp65 was determined by Western blotting analysis. Apoptosis and cell viability in 4T1 cells transfected with mock (control) or an miR-21/inhibitor were assessed by Annexin-V/PI staining and MTT assay,respectively. Results: LPS induced significant increasement of miR-21 level and NF-κB activation in 4T1 cells in a time-dependent manner (18 h: 207±0.33 vs 1; t=5.61, P=0.03), which were significantly attenuated by NF-κB inhibitor PDTC. Transfection of 4T1 cells with miR21 inhibitor resulted in a significant increase in apoptosis (0.70±0.10 vs 2.14±0.32; t=-7.357,P=0.002) and a significant decrease in cell growth (042±0.02 vs 0.55±0.01；t=-8.528, P=0.001), as compared with transfection with mock. Conclusion: Activation of TLR4 signaling pathways may up-regulate miR-21 through NF-κB activation in breast carcinoma 4T1 cells. Targeted inhibition of miR-21with a sequence-specific inhibitor can effectively induce apoptosis and suppress 4T1 cell growth, thus having a great potential in the treatment of breast carcinoma.
Objective:To investigate the effect of TLR4 signaling on breast cancer cell proliferation/apoptosis and the underlying mechanism in vitro.Methods: Breast carcinoma 4TI cells were stimulated with 100 ng/ml lipopolysaccharide (LPS) after a preincubation with DMSO or NF-κB inhibitor PDTC for 30 min. At 6, 12, 18 and 24 h after LPS stimulation, levels of miR-21 were measured by qRT-PCR, phospho-NF-κBp65 was determined by Western blotting analysis. Apoptosis and cell viability in 4T1 cells transfected with mock (control) or an miR-21/inhibitor were assessed by Annexin-V/PI staining and MTT assay,respectively. Results: LPS induced significant increasement of miR-21 level and NF-κB activation in 4T1 cells in a time-dependent manner (18 h: 207±0.33 vs 1; t=5.61, P=0.03), which were significantly attenuated by NF-κB inhibitor PDTC. Transfection of 4T1 cells with miR21 inhibitor resulted in a significant increase in apoptosis (0.70±0.10 vs 2.14±0.32; t=-7.357,P=0.002) and a significant decrease in cell growth (042±0.02 vs 0.55±0.01；t=-8.528, P=0.001), as compared with transfection with mock. Conclusion: Activation of TLR4 signaling pathways may up-regulate miR-21 through NF-κB activation in breast carcinoma 4T1 cells. Targeted inhibition of miR-21with a sequence-specific inhibitor can effectively induce apoptosis and suppress 4T1 cell growth, thus having a great potential in the treatment of breast carcinoma.
2014, 21(1):20-24.
DOI: 10.3872/j.issn.1007-385X.2014.01.004
Abstract:
Objective : To determine the effect of the FLT3-specific inhibitor sorafenib in combination with arsenic trioxide on the proliferation, cell cycle and apoptosis of leukemia MV-4-11 cells，a biphenotypic B myelomonocytic leukemia cell line with FLT3-ITD mutations, as a model in vitro. Methods: Logarithmic phase MV-4-11 cells were cultured in the absence (control) or presence of sorafenib (1, 10, 100, 1 000, 5 000, 10 000 nmol/L), arsenic trioxide (0.125,0.25,0.5,1.0,2.0 μmol/L), and sorafenib (10 μmol/L) and arsenic trioxide (1.0 μmol/L) in combination, respectively, for 48 h cell proliferation was assessed by CCK-8 assay, apoptosis and cell cycle progression by flow cytometry. Results: Sorafenib and arsenic trioxide, each alone, inhibited MV-4-11 cell proliferation in a concentration dependent manner. However, the inhibitory effect was more significant (P<0.01) when 10 nmol/L sorafenib and 1.0 μmol/L arsenic trioxide were used in combination (\[70.72±1.03\]%) than each alone (\[47.24±1.27\]% and \[20.28±0.70\]%); the interaction coefficient for these two drugs was 0.696. Sorafenib alone resulted in cell cycle arrest in G0/G1 phase and sorafenib in combination with arsenic trioxide increased cell cycle arrest. Similarly, both sorafenib and arsenic trioxide induced MV-4-11 cell apoptosis, but they were more effective in combination than each in itself (89.06% vs 6827%, 7871%; P<0.05). Conclusion: Sorafenib and arsenic trioxide, each in itself, are capable of inhibiting proliferation, blocking cycle progression, and induing apoptosis in FLT3-mutated myeloid leukemia cells.
Objective : To determine the effect of the FLT3-specific inhibitor sorafenib in combination with arsenic trioxide on the proliferation, cell cycle and apoptosis of leukemia MV-4-11 cells，a biphenotypic B myelomonocytic leukemia cell line with FLT3-ITD mutations, as a model in vitro. Methods: Logarithmic phase MV-4-11 cells were cultured in the absence (control) or presence of sorafenib (1, 10, 100, 1 000, 5 000, 10 000 nmol/L), arsenic trioxide (0.125,0.25,0.5,1.0,2.0 μmol/L), and sorafenib (10 μmol/L) and arsenic trioxide (1.0 μmol/L) in combination, respectively, for 48 h cell proliferation was assessed by CCK-8 assay, apoptosis and cell cycle progression by flow cytometry. Results: Sorafenib and arsenic trioxide, each alone, inhibited MV-4-11 cell proliferation in a concentration dependent manner. However, the inhibitory effect was more significant (P<0.01) when 10 nmol/L sorafenib and 1.0 μmol/L arsenic trioxide were used in combination (\[70.72±1.03\]%) than each alone (\[47.24±1.27\]% and \[20.28±0.70\]%); the interaction coefficient for these two drugs was 0.696. Sorafenib alone resulted in cell cycle arrest in G0/G1 phase and sorafenib in combination with arsenic trioxide increased cell cycle arrest. Similarly, both sorafenib and arsenic trioxide induced MV-4-11 cell apoptosis, but they were more effective in combination than each in itself (89.06% vs 6827%, 7871%; P<0.05). Conclusion: Sorafenib and arsenic trioxide, each in itself, are capable of inhibiting proliferation, blocking cycle progression, and induing apoptosis in FLT3-mutated myeloid leukemia cells.
2014, 21(1):25-30.
DOI: 10.3872/j.issn.1007-385X.2014.01.005
Abstract:
Objective:To investigate the influence of curcumin (Cur) on the extrinsic apoptosis pathway of human multiple myeloma cell line ARH-77. Methods: ARH-77 cells were treated with Cur at 6.25, 12.5, 25, 50, 100 and 200 μmol/L. At 12, 24 and 48 h after treatment, cell viability was analyzed by MTT assay and growth inhibition was accordingly calculated. At 24 h after treatment, changes in the cell morphology were assessed by Hoechst 33258 staining, cell cycle progression and levels of Fas/Fasl and TRAIL/TRAIL-R were analyzed by flow cytometry, and the activity of caspase 8 was determined by colorimetry. Results: Cur significantly inhibited the growth of ARH-77 cells in a time- and dose-dependent manner. At 24 h after treatment, Cur induced apoptosis in ARH-77 cells in a dose-dependent manner; the percentage of apoptotic cells was (10.35±0.35)% at 6.25 μmol/L, (1435±1.34)% at 12.5 μmol/L and (36.65±106)% at 25 μmol/L, significantly higher than that in untreated control cells (\[3.83±0.32\]%, P<0.01). Apoptotic bodies and cell cycle arrest at the G0/G1 phase were seen in ARH-77cells treated with 25 μmol/L Cur. Caspase 8 activity was significantly higher in ARH-77 cells treated with Cur at 6.26 μmol/L(0.223±0.018), 12.5 μmol/L (0.263±0.019), or 25.0 μmol/L (0.240±0.035) than in untreated control cells (0.154±0.007) (P<0.05). Compared with the non-treatment control, 24 h Cur treatment at 6.25 μmol/L significantly increased the protein levels of Fas (\[99.05±0.49\]% vs \[92.10±0.7\]%, P＝0.000), FasL (\[9.05±0.78\]% vs \[1.73±1.19\]%, P＝0008), TRAIL (\[1.35±0.07\]% vs \[0.55±0.07\]%, P＝0.008), DR4, DcR1 and DcR2 but significantly decreased DR5 (\[0.95±0.07\]% vs \[7.70±0.29]%, P＝0.001). The effect of Cur on DcR1 (\[4.35±1.20\]% vs \[14.25±0.21\]%, P＝0.008) and DcR2 (\[0.75±0.21\]% vs \[1.65±0.71\]%, P＝0.03) were more pronounced at 25.0 μmol/L than at 12.5 μmol/L. Conclusion: Cur is able to inhibit the growth of ARH-77 cells through activating the extrinsic apoptosis pathway and thereby may offer a potential therapeutic agent for multiple myeloma.
Objective:To investigate the influence of curcumin (Cur) on the extrinsic apoptosis pathway of human multiple myeloma cell line ARH-77. Methods: ARH-77 cells were treated with Cur at 6.25, 12.5, 25, 50, 100 and 200 μmol/L. At 12, 24 and 48 h after treatment, cell viability was analyzed by MTT assay and growth inhibition was accordingly calculated. At 24 h after treatment, changes in the cell morphology were assessed by Hoechst 33258 staining, cell cycle progression and levels of Fas/Fasl and TRAIL/TRAIL-R were analyzed by flow cytometry, and the activity of caspase 8 was determined by colorimetry. Results: Cur significantly inhibited the growth of ARH-77 cells in a time- and dose-dependent manner. At 24 h after treatment, Cur induced apoptosis in ARH-77 cells in a dose-dependent manner; the percentage of apoptotic cells was (10.35±0.35)% at 6.25 μmol/L, (1435±1.34)% at 12.5 μmol/L and (36.65±106)% at 25 μmol/L, significantly higher than that in untreated control cells (\[3.83±0.32\]%, P<0.01). Apoptotic bodies and cell cycle arrest at the G0/G1 phase were seen in ARH-77cells treated with 25 μmol/L Cur. Caspase 8 activity was significantly higher in ARH-77 cells treated with Cur at 6.26 μmol/L(0.223±0.018), 12.5 μmol/L (0.263±0.019), or 25.0 μmol/L (0.240±0.035) than in untreated control cells (0.154±0.007) (P<0.05). Compared with the non-treatment control, 24 h Cur treatment at 6.25 μmol/L significantly increased the protein levels of Fas (\[99.05±0.49\]% vs \[92.10±0.7\]%, P＝0.000), FasL (\[9.05±0.78\]% vs \[1.73±1.19\]%, P＝0008), TRAIL (\[1.35±0.07\]% vs \[0.55±0.07\]%, P＝0.008), DR4, DcR1 and DcR2 but significantly decreased DR5 (\[0.95±0.07\]% vs \[7.70±0.29]%, P＝0.001). The effect of Cur on DcR1 (\[4.35±1.20\]% vs \[14.25±0.21\]%, P＝0.008) and DcR2 (\[0.75±0.21\]% vs \[1.65±0.71\]%, P＝0.03) were more pronounced at 25.0 μmol/L than at 12.5 μmol/L. Conclusion: Cur is able to inhibit the growth of ARH-77 cells through activating the extrinsic apoptosis pathway and thereby may offer a potential therapeutic agent for multiple myeloma.
6 Effect of c-FLIP-L on the sensitivity of breast cancer MDA-MB-231 cells to TRAIL-induced apoptosis
2014, 21(1):31-37.
DOI: 10.3872/j.issn.1007-385X.2014.01.006
Abstract:
Objective : To study the effect of c-FLIP-L on TRAIL-induced breast cancer apoptosis. Methods: c-FLIP-L was silenced in breast cancer MDA-MB-231 cells by siRNA. After c-FLIP-L silencing, cell proliferation was assessed by MTT assay, cell apoptosis by Annexin-V FITC/PI double staining flow cytometry, invasive potential by matrigel invasion assay, and protein and mRNA levels of c-FLIP-L, caspase-3, caspase-8, MMP-2, MMP-9 in transfected cells by Western blotting and RT-PCR respectively. Results: The sequence-specific siRNA significantly decreased c-FLIP-L mRNA (3712±3.02 vs 183.21±8.31, 174.65±10.06; P<0.05) and protein levels as compared with the control. At 72 h after treatment, c-FLIP-L siRNA and TRAIL, either in combination or each alone, significantly inhibited proliferation (\[75.51±2.01\]% vs \[33.75±1.60\]%, \[34.31±2.01\]%; P<0.01), induced apoptosis (\[76.30±4.11\]% vs \[38.95±2.14\]%, \[29.28±1.66\]%; P<0.05), decreased the invasive capacity. Enhanced casepase-3 and casepase-8 expression,and inhibited MMP-2 and MMP-9 expression in MDA-MB-231 cells. Conclusion: Inhibition of c-FLIP-L expression may increase the sensitivity of breast cancer cells to TRAIL-induced apoptosis, possibly through enhancing the expression of caspase-3, caspase-8 and inhibiting the expression of MMP-2 and MMP-9.
Objective : To study the effect of c-FLIP-L on TRAIL-induced breast cancer apoptosis. Methods: c-FLIP-L was silenced in breast cancer MDA-MB-231 cells by siRNA. After c-FLIP-L silencing, cell proliferation was assessed by MTT assay, cell apoptosis by Annexin-V FITC/PI double staining flow cytometry, invasive potential by matrigel invasion assay, and protein and mRNA levels of c-FLIP-L, caspase-3, caspase-8, MMP-2, MMP-9 in transfected cells by Western blotting and RT-PCR respectively. Results: The sequence-specific siRNA significantly decreased c-FLIP-L mRNA (3712±3.02 vs 183.21±8.31, 174.65±10.06; P<0.05) and protein levels as compared with the control. At 72 h after treatment, c-FLIP-L siRNA and TRAIL, either in combination or each alone, significantly inhibited proliferation (\[75.51±2.01\]% vs \[33.75±1.60\]%, \[34.31±2.01\]%; P<0.01), induced apoptosis (\[76.30±4.11\]% vs \[38.95±2.14\]%, \[29.28±1.66\]%; P<0.05), decreased the invasive capacity. Enhanced casepase-3 and casepase-8 expression,and inhibited MMP-2 and MMP-9 expression in MDA-MB-231 cells. Conclusion: Inhibition of c-FLIP-L expression may increase the sensitivity of breast cancer cells to TRAIL-induced apoptosis, possibly through enhancing the expression of caspase-3, caspase-8 and inhibiting the expression of MMP-2 and MMP-9.
2014, 21(1):38-43.
DOI: 10.3872/j.issn.1007-385X.2014.01.007
Abstract:
Objective :To investigate the effect of Epigallocatechin-3-gallate (EGCG) on hepatocellular carcinoma cell growth and the molecular mechanisms underlying the effect in vitro. Methods: Three human hepatocellular carcinoma cell lines (i.e., HepG2, Sk-hep1 and SMMC7721) were used in this study. Cells were cultured in the presence of 0, 40, 80 or 120 μg/ml EGCG. At 24, 48 and 72 h after EGCG treatment, cell viability was assessed by MTT assay, apoptosis by AO/EB staining, cell cycle progression by flow cytometer, and mRNA and protein levels of HO11, IL-10 and TNF-α by Realtime PCR and Western blotting respectively. Results: EGCG treatment significantly induced cell attachment (P<005), increased the proportion of apoptotic cells (P<0.01), and induced G2/M arrest (P<0.01) in all three cell lines tested as compared with the control. HO-1, IL-10 and TNF-α mRNA levels were 0.58±0.15, 5.91±1.11 and 529±1.14 in EGCG-treated Sk-hep1 cells, significantly different from the levels in the control cells (P＝0.008, P＝0002, P＝0.003). EGCG resulted in a significant decrease in HO-1 protein content as compared with the control (0.16±0.04 vs 0.33±0.08, P<0.05). In contrast, EGCG significantly increased levels of IL-10 protein (0.42± 006 vs 0.24±0.08, P<0.05) and TNF-α protein (0.95±0.17 vs 0.58±0.08, P<0.05). Conclusions: EGCG may inhibit proliferation and block cell cycle progression and induce apoptosis in hepatocellular carcinoma cells. The mechanism(s) underlying these effects of EGCG may involve modulation of HO-1, IL-10 and TNF-α expression.
Objective :To investigate the effect of Epigallocatechin-3-gallate (EGCG) on hepatocellular carcinoma cell growth and the molecular mechanisms underlying the effect in vitro. Methods: Three human hepatocellular carcinoma cell lines (i.e., HepG2, Sk-hep1 and SMMC7721) were used in this study. Cells were cultured in the presence of 0, 40, 80 or 120 μg/ml EGCG. At 24, 48 and 72 h after EGCG treatment, cell viability was assessed by MTT assay, apoptosis by AO/EB staining, cell cycle progression by flow cytometer, and mRNA and protein levels of HO11, IL-10 and TNF-α by Realtime PCR and Western blotting respectively. Results: EGCG treatment significantly induced cell attachment (P<005), increased the proportion of apoptotic cells (P<0.01), and induced G2/M arrest (P<0.01) in all three cell lines tested as compared with the control. HO-1, IL-10 and TNF-α mRNA levels were 0.58±0.15, 5.91±1.11 and 529±1.14 in EGCG-treated Sk-hep1 cells, significantly different from the levels in the control cells (P＝0.008, P＝0002, P＝0.003). EGCG resulted in a significant decrease in HO-1 protein content as compared with the control (0.16±0.04 vs 0.33±0.08, P<0.05). In contrast, EGCG significantly increased levels of IL-10 protein (0.42± 006 vs 0.24±0.08, P<0.05) and TNF-α protein (0.95±0.17 vs 0.58±0.08, P<0.05). Conclusions: EGCG may inhibit proliferation and block cell cycle progression and induce apoptosis in hepatocellular carcinoma cells. The mechanism(s) underlying these effects of EGCG may involve modulation of HO-1, IL-10 and TNF-α expression.
2014, 21(1):44-48.
DOI: 10.3872/j.issn.1007-385X.2014.01.008
Abstract:
Objective:To determine the effect of siRNA silencing of signal transducer and activators of transcription 3 ( STAT3) gene on proliferation/apoptosis, invasion, colony formation, and Mcl-1 and caspase3 expression of colorectal cancer SW480 cells in vitro. Methods: SW480 cells were infected by a GFP-STAT3-siRNA-carrying lentivirus vector or a GFP-carrying control vector. At 72 h after infection, mRNA and protein levels of STAT3, Mcl-1, and caspase3 were analyzed by Real-time PCR and Western blotting respectively, apoptosis by flow cytometry, the invasive activity by transwell assays in the infected SW480 cells. Results: The colony forming ability of SW480 cells was significantly suppressed after infection with the lentiviral vector carrying GFP-STAT3-siRNA as compared to the GFP-carrying control vector (P<005). Infection with the lentirival vector carrying GFP-STAT3-siRNA significantly decreased mRNA and protein levels of STAT3 and Mc1-1 (P<0.05), significantly increased mRNA and protein levels of caspase3 (P<0.05), significantly increased the percentage of apoptotic cells (11.9% vs 4.92%, P<0.05), and significantly reduced the invasive activity (178.49±15.42 vs 320.61±13.30, P<0.05) in SW480 cells as compared with the control vector infection. Conclusion: Silencing of the STAT3 gene in colorectal cancer cells promotes apoptosis and inhibits invasion and colony formation, possibly through modulating the expression of Mc1-1 and caspase3.
Objective:To determine the effect of siRNA silencing of signal transducer and activators of transcription 3 ( STAT3) gene on proliferation/apoptosis, invasion, colony formation, and Mcl-1 and caspase3 expression of colorectal cancer SW480 cells in vitro. Methods: SW480 cells were infected by a GFP-STAT3-siRNA-carrying lentivirus vector or a GFP-carrying control vector. At 72 h after infection, mRNA and protein levels of STAT3, Mcl-1, and caspase3 were analyzed by Real-time PCR and Western blotting respectively, apoptosis by flow cytometry, the invasive activity by transwell assays in the infected SW480 cells. Results: The colony forming ability of SW480 cells was significantly suppressed after infection with the lentiviral vector carrying GFP-STAT3-siRNA as compared to the GFP-carrying control vector (P<005). Infection with the lentirival vector carrying GFP-STAT3-siRNA significantly decreased mRNA and protein levels of STAT3 and Mc1-1 (P<0.05), significantly increased mRNA and protein levels of caspase3 (P<0.05), significantly increased the percentage of apoptotic cells (11.9% vs 4.92%, P<0.05), and significantly reduced the invasive activity (178.49±15.42 vs 320.61±13.30, P<0.05) in SW480 cells as compared with the control vector infection. Conclusion: Silencing of the STAT3 gene in colorectal cancer cells promotes apoptosis and inhibits invasion and colony formation, possibly through modulating the expression of Mc1-1 and caspase3.
2014, 21(1):49-54.
DOI: 10.3872/j.issn.1007-385X.2014.01.009
Abstract:
Objective : To determine the effects of microRNA-21 (miR-21) inhibition on the various functional aspects (e.g., proliferation, apoptosis, cell cycle and invasion and migration) of colon cancer HCT116 cells in vitro. Methods: HCT116 cells were transfected with an miR-21 inhibitor, a non-sequence specific inhibitor as a negative control and the transfection reagent as a mock control, respectively. The level of miR-21 in transfected HCT116 was determined by Real-time PCR. The Proliferation, apoptosis, cell cycle progression, invasion and migration of the transfectants were evaluated by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry (FCM), transwell invasion and migration assays, respectively. Protein level of phosphatase and tensin homolog (PTEN) and PTEN promoter activity in HCT116 cells after transfection were evaluated by Western blotting analysis and the luciferase reporter assay, respectively. Results: The level of miR-21 was significantly lower in HCT116 cells transfected with the miR-21 inhibitor than in cells transfected with non-specific inhibitor or mock. At 72 hours after transfection, the miR-21 inhibitor significantly suppressed HCT116 cell proliferation (1.05±0.45 vs 1.43±0.02 and 1.45±0.01, P<0.001), significantly increased HCT116 cell apoptosis (\[16.30±1.00\]% vs \[1.87±0.53\]% and \[1.86±0.12\]%, P<0.0001) and HCT cell cycle arrest in G0/G1 phase, and significantly decreased the invasion (50±2.0 vs 115±3.0 and 111±3.0, P<0.0001) and migration abilities (22±20 vs 52.3±2.5 and 53.0±1.0, P<0.0001), as compared with the two controls. Moreover, miR-21 inhibition resulted in remarkable increases in protein levels and activity of PTEN in HCT116 cells. Conclusion: MicroRNA21 may regulate proliferation/apoptosis, invasion and migration of colorectal cancer cells, possibly through modulating the expression and activity of PTEN.
Objective : To determine the effects of microRNA-21 (miR-21) inhibition on the various functional aspects (e.g., proliferation, apoptosis, cell cycle and invasion and migration) of colon cancer HCT116 cells in vitro. Methods: HCT116 cells were transfected with an miR-21 inhibitor, a non-sequence specific inhibitor as a negative control and the transfection reagent as a mock control, respectively. The level of miR-21 in transfected HCT116 was determined by Real-time PCR. The Proliferation, apoptosis, cell cycle progression, invasion and migration of the transfectants were evaluated by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry (FCM), transwell invasion and migration assays, respectively. Protein level of phosphatase and tensin homolog (PTEN) and PTEN promoter activity in HCT116 cells after transfection were evaluated by Western blotting analysis and the luciferase reporter assay, respectively. Results: The level of miR-21 was significantly lower in HCT116 cells transfected with the miR-21 inhibitor than in cells transfected with non-specific inhibitor or mock. At 72 hours after transfection, the miR-21 inhibitor significantly suppressed HCT116 cell proliferation (1.05±0.45 vs 1.43±0.02 and 1.45±0.01, P<0.001), significantly increased HCT116 cell apoptosis (\[16.30±1.00\]% vs \[1.87±0.53\]% and \[1.86±0.12\]%, P<0.0001) and HCT cell cycle arrest in G0/G1 phase, and significantly decreased the invasion (50±2.0 vs 115±3.0 and 111±3.0, P<0.0001) and migration abilities (22±20 vs 52.3±2.5 and 53.0±1.0, P<0.0001), as compared with the two controls. Moreover, miR-21 inhibition resulted in remarkable increases in protein levels and activity of PTEN in HCT116 cells. Conclusion: MicroRNA21 may regulate proliferation/apoptosis, invasion and migration of colorectal cancer cells, possibly through modulating the expression and activity of PTEN.
2014, 21(1):55-61.
DOI: 10.3872/j.issn.1007-385X.2014.01.010
Abstract:
Objective : To study the inhibiting effect of a vaccine against epidermal growth factor receptor substrate 8 (EPS8) on the growth of breast cancer cells and the possible underlying mechanisms. Methods: Recombinant mouse EPS8 protein was prepared through gene recombination, expression and purification. A vaccine was generated using this recombinant EPS8 protein and BALB/c mice were immunized with this vaccine (n=8) or an adjuvant (n=8). The titer of anti-EPS8 antibody before and at different time points after immunization was assessed by indirect ELISA. Proportion of T lymphocyte subsets in the spleen of immunized mice was determined through flow cytometry before and after immunization. Seven days after the third immunization with ESP8 vaccine or the adjuvant, mice were injected with 4T1 breast cancer cells. In the two groups of animals, survival time, tumor volume, and tumor weight were assessed and the rate of tumor growth inhibition was accordingly calculated. In tumor-bearing animals, T lymphocyte subsets in the spleen were analyzed by flow cytometry, and CTL killing rate was measured by LDH assay. Results: High levels of Eps8 protein were detected in 4T1 cells. Anti-EPS8 antibody was produced inmice immunized with the EPS8 vaccine; its titer was increasing with the frequency of immunization. Survival time was significantly higher mice (P<0.05), tumor weight was significantly lower (\[2.21±0.35\] g vs \[3.31±0.88\] g, P＜0.05), the proportion of CD4＋T cells and ratio of CD4＋/CD8＋in the spleen were significantly higher (P<0.001), those control animals and the CD4＋CD25＋Treg/CD4＋T cell ratio in the spleen was significantly lower (P<0.001) in mice immunized against ESP8 than in control animals. There was no difference in the percentage of CD8＋ T cells in the spleen between two groups (P>0.05). EPS8 vaccination resulted a significant increase in the killing activity of CTLs as compared with the control (\[19.05±4.41\]% vs \[13.36±310\]%, P<0.05). Conclusion: EPS8 vaccination may induce the mice functional humoral immune response, reduce the proportion of Treg cells, and enhance the cytotoxicity of T cells in mice with breast cancer, thereby suppressing tumor growth and prolong survival.
Objective : To study the inhibiting effect of a vaccine against epidermal growth factor receptor substrate 8 (EPS8) on the growth of breast cancer cells and the possible underlying mechanisms. Methods: Recombinant mouse EPS8 protein was prepared through gene recombination, expression and purification. A vaccine was generated using this recombinant EPS8 protein and BALB/c mice were immunized with this vaccine (n=8) or an adjuvant (n=8). The titer of anti-EPS8 antibody before and at different time points after immunization was assessed by indirect ELISA. Proportion of T lymphocyte subsets in the spleen of immunized mice was determined through flow cytometry before and after immunization. Seven days after the third immunization with ESP8 vaccine or the adjuvant, mice were injected with 4T1 breast cancer cells. In the two groups of animals, survival time, tumor volume, and tumor weight were assessed and the rate of tumor growth inhibition was accordingly calculated. In tumor-bearing animals, T lymphocyte subsets in the spleen were analyzed by flow cytometry, and CTL killing rate was measured by LDH assay. Results: High levels of Eps8 protein were detected in 4T1 cells. Anti-EPS8 antibody was produced inmice immunized with the EPS8 vaccine; its titer was increasing with the frequency of immunization. Survival time was significantly higher mice (P<0.05), tumor weight was significantly lower (\[2.21±0.35\] g vs \[3.31±0.88\] g, P＜0.05), the proportion of CD4＋T cells and ratio of CD4＋/CD8＋in the spleen were significantly higher (P<0.001), those control animals and the CD4＋CD25＋Treg/CD4＋T cell ratio in the spleen was significantly lower (P<0.001) in mice immunized against ESP8 than in control animals. There was no difference in the percentage of CD8＋ T cells in the spleen between two groups (P>0.05). EPS8 vaccination resulted a significant increase in the killing activity of CTLs as compared with the control (\[19.05±4.41\]% vs \[13.36±310\]%, P<0.05). Conclusion: EPS8 vaccination may induce the mice functional humoral immune response, reduce the proportion of Treg cells, and enhance the cytotoxicity of T cells in mice with breast cancer, thereby suppressing tumor growth and prolong survival.
2014, 21(1):62-66.
DOI: 10.3872/j.issn.1007-385X.2014.01.011
Abstract:
Objective : To investigate the inhibitory effect of albendazole on colon carcinoma cell invasion and migration as well as the mechanisms underlying the effect. Methods: Colon carcinoma SW480 cells were treated with albendazole at 0 mg/ml, 1.0 mg/ml and 2.0 mg/ml. Cell proliferation was assessed by a cell proliferation assay using a cell counting Kit-8 (CCK-8), cell migration and invasion by wound-healing assays and transwell chamber assays, respectively, and protein levels of E-cadherin, MMP-2 and MMP-9 by immunocytochemistry and Western blotting. Results: Compared with the control (0 mg/ml), 1.0 mg/ml and 2.0 mg/ml albendazole significantly inhibited SW480 cell proliferation (P<005), and significantly decreased the invasion and migration in SW480 cells at both concentrations tested (P<0.05). Albendazole treatments significantly reduced the protein level of MMP-2 and MMP-9 but increased the protein level of E-cadherin. Conclusion: Albendazole can inhibit the invasion and migration of SW480 cells, at least partially through up-regulating the expression of E-cadherin and down-regulating the expression of MMP-2 and MMP-9.
Objective : To investigate the inhibitory effect of albendazole on colon carcinoma cell invasion and migration as well as the mechanisms underlying the effect. Methods: Colon carcinoma SW480 cells were treated with albendazole at 0 mg/ml, 1.0 mg/ml and 2.0 mg/ml. Cell proliferation was assessed by a cell proliferation assay using a cell counting Kit-8 (CCK-8), cell migration and invasion by wound-healing assays and transwell chamber assays, respectively, and protein levels of E-cadherin, MMP-2 and MMP-9 by immunocytochemistry and Western blotting. Results: Compared with the control (0 mg/ml), 1.0 mg/ml and 2.0 mg/ml albendazole significantly inhibited SW480 cell proliferation (P<005), and significantly decreased the invasion and migration in SW480 cells at both concentrations tested (P<0.05). Albendazole treatments significantly reduced the protein level of MMP-2 and MMP-9 but increased the protein level of E-cadherin. Conclusion: Albendazole can inhibit the invasion and migration of SW480 cells, at least partially through up-regulating the expression of E-cadherin and down-regulating the expression of MMP-2 and MMP-9.
2014, 21(1):67-72.
DOI: 10.3872/j.issn.1007-385X.2014.01.012
Abstract:
Objective : To investigate the expression and aberrant methylation of the atrogin-1 gene in gastric cardia adenocarcinoma (GCA). Methods: Tumor and normal tissue samples were collected from GCA patients (n=139) undergoing surgical treatment in the Fourth Hospital of Hebei Medical University between 2004 and 2008. DNA methylation in the atrogin-1 promoter was analyzed by bisulfite conversion-methylation specific polymerase chain reaction (BS-MSP), atrogin-1 mRNA abundance by RT-PCR, and density of immunoreactive signals for atrogin-1 and Smad4 by immunohistochemical staining. Results: The frequency of aberrant DNA methylation in the promoter region of atrogin-1 was significantly higher inGCA than in normal tissues (44.6% vs 3.6%, P<0.05). The methylation status of atrogin-1 in tumor tissues was associated with TNM stage and the degree of histological differentiation of the tumor (P<0.05). The mRNA and protein levels of atrogin-1 were significantly decreased in tumor tissues as compared with normal tissues (0.482 5±0.175 4 vs 0.896 9±0.290 1 and 34.5% vs 82.0%, respectively, P<0.01). there was a negative correlation between atrogin-1 methylation and atrogin-1 mRNA and protein levels (r=-0.256，P<0.01). Smad4 protein was detected in 46.0% of tumor tissues but in 95.7% of non-tumor tissue (P<0.01) and the protein level of smad4 was positively associated with that of atrogin-1 (r＝0604，P<0.01). Conclusion: Hypermethylation in the promoter region of the atrogin-1 gene and the resultant decrease in atrogin-1 protein synthesis may play an important role in the pathogenesis of gastric cardia adenocarcinoma.
Objective : To investigate the expression and aberrant methylation of the atrogin-1 gene in gastric cardia adenocarcinoma (GCA). Methods: Tumor and normal tissue samples were collected from GCA patients (n=139) undergoing surgical treatment in the Fourth Hospital of Hebei Medical University between 2004 and 2008. DNA methylation in the atrogin-1 promoter was analyzed by bisulfite conversion-methylation specific polymerase chain reaction (BS-MSP), atrogin-1 mRNA abundance by RT-PCR, and density of immunoreactive signals for atrogin-1 and Smad4 by immunohistochemical staining. Results: The frequency of aberrant DNA methylation in the promoter region of atrogin-1 was significantly higher inGCA than in normal tissues (44.6% vs 3.6%, P<0.05). The methylation status of atrogin-1 in tumor tissues was associated with TNM stage and the degree of histological differentiation of the tumor (P<0.05). The mRNA and protein levels of atrogin-1 were significantly decreased in tumor tissues as compared with normal tissues (0.482 5±0.175 4 vs 0.896 9±0.290 1 and 34.5% vs 82.0%, respectively, P<0.01). there was a negative correlation between atrogin-1 methylation and atrogin-1 mRNA and protein levels (r=-0.256，P<0.01). Smad4 protein was detected in 46.0% of tumor tissues but in 95.7% of non-tumor tissue (P<0.01) and the protein level of smad4 was positively associated with that of atrogin-1 (r＝0604，P<0.01). Conclusion: Hypermethylation in the promoter region of the atrogin-1 gene and the resultant decrease in atrogin-1 protein synthesis may play an important role in the pathogenesis of gastric cardia adenocarcinoma.
Ma Yue
,
Shen Xianji
,
Han Chuanjun
,
Lü Huixin
,
Yang Yang
,
Han Longzhe
,
Lin Zhenhua
,
Gao Meihua
2014, 21(1):73-78.
DOI: 10.3872/j.issn.1007-385X.2014.01.013
Abstract:
Objective : To investigate the clinical significance of S-phase kinase-associated protein 2 (Skp2) measurement in the diagnosis and prognosis of cervical squamous cell carcinoma (SCC). Methods: Paraffin-embedded blocks of cervical tissue specimens collected from 25 healthy women, 84 women with cervical intraepithelial neoplasia (CIN) and 163 women with SCC who were cared in the Second People’s Hospital Affiliated to Shanghai Jiaotong University and Yanbian Women’s and Children’s Hospital between 2004 and 2008 were obtained. Protein content of Skp2 and the presence of human papillomavirus (HPV) in these specimens were analyzed by immunohistochemical staining and PCR, respectively. The correlation between Skp2 content and prognostic scores was also analyzed. Results: While Skp2 protein was undetectable in the 25 healthy control subjects, it was detected in 84.0% (137/163) of SCC patients, 37.9% (10/29) of CIN-1 patients, 81.6% (31/38) of CIN-2 patients and 82.4% (14/17) of CIN-3 patients (P<0.01). Skp2 protein content was closely related with HPV infection and the International Federation of Gynecology and Obstetrics (FIGO) clinical stage. The lesion-free survival and overall survival rates were 55.5% and 59.1%, respectively, in Skp2-positive patients and were 96.2% and 88.5% (Log-rank 11.530 and 10.154, P＝001), respectively, in Skp2-negative patients. Skp2 content in the cervical epithelium was not correlated with patient age, Ki-67 expression and pathological grade of cervical cancer. Conclusion: Skp2 may be a biomarker of cervical squamous cell carcinoma cell proliferation and therefore Skp2 protein content measurement may have a clinical significance in the diagnosis and prognosis of cervical cancer.
Objective : To investigate the clinical significance of S-phase kinase-associated protein 2 (Skp2) measurement in the diagnosis and prognosis of cervical squamous cell carcinoma (SCC). Methods: Paraffin-embedded blocks of cervical tissue specimens collected from 25 healthy women, 84 women with cervical intraepithelial neoplasia (CIN) and 163 women with SCC who were cared in the Second People’s Hospital Affiliated to Shanghai Jiaotong University and Yanbian Women’s and Children’s Hospital between 2004 and 2008 were obtained. Protein content of Skp2 and the presence of human papillomavirus (HPV) in these specimens were analyzed by immunohistochemical staining and PCR, respectively. The correlation between Skp2 content and prognostic scores was also analyzed. Results: While Skp2 protein was undetectable in the 25 healthy control subjects, it was detected in 84.0% (137/163) of SCC patients, 37.9% (10/29) of CIN-1 patients, 81.6% (31/38) of CIN-2 patients and 82.4% (14/17) of CIN-3 patients (P<0.01). Skp2 protein content was closely related with HPV infection and the International Federation of Gynecology and Obstetrics (FIGO) clinical stage. The lesion-free survival and overall survival rates were 55.5% and 59.1%, respectively, in Skp2-positive patients and were 96.2% and 88.5% (Log-rank 11.530 and 10.154, P＝001), respectively, in Skp2-negative patients. Skp2 content in the cervical epithelium was not correlated with patient age, Ki-67 expression and pathological grade of cervical cancer. Conclusion: Skp2 may be a biomarker of cervical squamous cell carcinoma cell proliferation and therefore Skp2 protein content measurement may have a clinical significance in the diagnosis and prognosis of cervical cancer.
2014, 21(1):79-85.
DOI: 10.3872/j.issn.1007-385X.2014.01.014
Abstract:
Objective : To systematically evaluate the efficacy and safety of the concurrent use of anti-VEGF and anti-EGFR antibodies in patients with metastatic colorectal cancer. Methods: PubMed/MEDLINE，Ovid/EMBASE, Cochrane and some other databases together with related meeting abstracts were searched for randomized controlled trials on this topic by two independent researchers. Data were extracted from the included studies and analyzed using Review Manager 5.0.23. Results: A total of 2059 patients in five studies were included in this Meta-analysis. Compared with the control treatment involving an anti-VEGF or anti-EGFR antibody alone, the concurrent use of anti-VEGF and anti-EGFR antibodies decreased the progression-free survival (RR＝1.12, 95% CI: 1.05-1.19) as. Patients in the two treatment groups did not differ significantly in either overall survival (RR＝1.17, 95% CI: 098-1.40) or overall response rate (RR＝097, 95% CI: 0.89-1.07). There were significant differences between the two groups in grade 3/4 adverse cutaneous events (RR＝12.62, 95% CI: 1.90-83.84), grade 3/4 infection (RR＝153, 95% CI: 1.13-2.08), grade 3/4 hypertension (RR＝0.61, 95% CI: 0.42-0.87), and grade 3/4 adverse events of nervous system (RR＝0.54, 95% CI: 037-0.80) but not in grade 3/4 adverse gastrointestinal events (RR＝1.48, 95% CI: 0.79-2.77) and grade 3/4 venous thrombosis (RR＝1.18, 95% CI: 0.84-1.65). Conclusion: The concurrent use of anti-VEGF and anti-EGFR antibodies offer no additional benefits for patients with metastatic colorectal cancer as compared with the use of theses antibodies each alone and therefore should not be recommended in clinics.
Objective : To systematically evaluate the efficacy and safety of the concurrent use of anti-VEGF and anti-EGFR antibodies in patients with metastatic colorectal cancer. Methods: PubMed/MEDLINE，Ovid/EMBASE, Cochrane and some other databases together with related meeting abstracts were searched for randomized controlled trials on this topic by two independent researchers. Data were extracted from the included studies and analyzed using Review Manager 5.0.23. Results: A total of 2059 patients in five studies were included in this Meta-analysis. Compared with the control treatment involving an anti-VEGF or anti-EGFR antibody alone, the concurrent use of anti-VEGF and anti-EGFR antibodies decreased the progression-free survival (RR＝1.12, 95% CI: 1.05-1.19) as. Patients in the two treatment groups did not differ significantly in either overall survival (RR＝1.17, 95% CI: 098-1.40) or overall response rate (RR＝097, 95% CI: 0.89-1.07). There were significant differences between the two groups in grade 3/4 adverse cutaneous events (RR＝12.62, 95% CI: 1.90-83.84), grade 3/4 infection (RR＝153, 95% CI: 1.13-2.08), grade 3/4 hypertension (RR＝0.61, 95% CI: 0.42-0.87), and grade 3/4 adverse events of nervous system (RR＝0.54, 95% CI: 037-0.80) but not in grade 3/4 adverse gastrointestinal events (RR＝1.48, 95% CI: 0.79-2.77) and grade 3/4 venous thrombosis (RR＝1.18, 95% CI: 0.84-1.65). Conclusion: The concurrent use of anti-VEGF and anti-EGFR antibodies offer no additional benefits for patients with metastatic colorectal cancer as compared with the use of theses antibodies each alone and therefore should not be recommended in clinics.
15 Research progress of clincal translation on signal pathway and relevant drugs in tumor angiogenesis
2014, 21(1):86-94.
DOI: 10.3872/j.issn.1007-385X.2014.01.015
Abstract:
Angiogenesis plays an important role in almost all aspects of tumor biology, including the occurrence, proliferation, progression and metastasis. Accordingly, inhibition of tumor angiogenesis through targeting key molecules in the signal pathways involved in angiogenesis has become a subject of extensive and intensive research in the field of anti-tumor drug development. Amongst these molecules are VEGF/VEGFR, Angiopoietin(Ang)/Tie, platelet derived growth factor, fibroblast growth factor, Delta-like Ligand (DLL4)/Notch, transforming growth factor β, hepatocyte growth factor, and endothelin. A few drugs, such as bevacizumab, sorafinib and sunitinib, targeting angiogenic molecules have been approved by FDA and their clinical use has generated satisfactory results in treating colorectal cancer, renal cell carcinoma, non small cell lung cancer, hepatocellular carcinoma and gastrointestinal stroma tumor; dozens of unapproved drugs in this class are under evaluation in clinical trials. This article aims to review recent advances in both bench-top and translational research on essential signal pathways involved in tumor angiogenesis.
Angiogenesis plays an important role in almost all aspects of tumor biology, including the occurrence, proliferation, progression and metastasis. Accordingly, inhibition of tumor angiogenesis through targeting key molecules in the signal pathways involved in angiogenesis has become a subject of extensive and intensive research in the field of anti-tumor drug development. Amongst these molecules are VEGF/VEGFR, Angiopoietin(Ang)/Tie, platelet derived growth factor, fibroblast growth factor, Delta-like Ligand (DLL4)/Notch, transforming growth factor β, hepatocyte growth factor, and endothelin. A few drugs, such as bevacizumab, sorafinib and sunitinib, targeting angiogenic molecules have been approved by FDA and their clinical use has generated satisfactory results in treating colorectal cancer, renal cell carcinoma, non small cell lung cancer, hepatocellular carcinoma and gastrointestinal stroma tumor; dozens of unapproved drugs in this class are under evaluation in clinical trials. This article aims to review recent advances in both bench-top and translational research on essential signal pathways involved in tumor angiogenesis.
2014, 21(1):95-97.
DOI: 10.3872/j.issn.1007-385X.2014.01.016
Abstract:
目的： 研究细胞因子诱导的体外细胞经过链式激活后获得的链式CIK细胞对白血病K562细胞的杀伤效应。 方法: 采用血细胞单采机从外周血分离单个核细胞（peripheral blood mononuclear cell, PBMC），经过细胞因子诱导、扩增、培养得到链式CIK细胞，以CIK细胞作对照，检测链式CIK细胞的增殖能力， LDH释放法测定其对K562细胞的杀伤活性。 结果: 链式CIK细胞组在培养第5、第14天的细胞数低于CIK细胞组（P<0.01）；链式CIK细胞对K562细胞的杀伤活性在效靶比40 ∶1和20 ∶1时分别为（56.1±2.24）%、（34.4±3.56）%，均低于CIK细胞（均P<0.01）。 结论: 链式CIK细胞是一种培养周期短、对白血病K562杀伤活性较弱的免疫细胞。
目的： 研究细胞因子诱导的体外细胞经过链式激活后获得的链式CIK细胞对白血病K562细胞的杀伤效应。 方法: 采用血细胞单采机从外周血分离单个核细胞（peripheral blood mononuclear cell, PBMC），经过细胞因子诱导、扩增、培养得到链式CIK细胞，以CIK细胞作对照，检测链式CIK细胞的增殖能力， LDH释放法测定其对K562细胞的杀伤活性。 结果: 链式CIK细胞组在培养第5、第14天的细胞数低于CIK细胞组（P<0.01）；链式CIK细胞对K562细胞的杀伤活性在效靶比40 ∶1和20 ∶1时分别为（56.1±2.24）%、（34.4±3.56）%，均低于CIK细胞（均P<0.01）。 结论: 链式CIK细胞是一种培养周期短、对白血病K562杀伤活性较弱的免疫细胞。
2014, 21(1):98-103.
DOI: 10.3872/j.issn.1007-385X.2014.1.017
Abstract:
近年来肿瘤治疗领域受到关注的热点之一是免疫治疗与化疗的联合应用，大量基础与临床的研究结果表明，恰当的免疫化疗（chemoimmunotherapy） 能够取得较单一疗法更优的抗肿瘤效果，超越了以往认为化疗对免疫系统具有抑制作用、免疫治疗与化疗难以一起应用的传统观念。免疫化疗具有协同抗肿瘤效果的机制是多方面的，化疗可通过增强肿瘤细胞免疫原性、去除免疫抑制以及调节免疫应答反应等方式增强免疫治疗效果；另外，免疫治疗能够逆转肿瘤细胞的化疗耐药性，从而提高肿瘤细胞对化疗药物的敏感性并降低化疗的毒性作用等。目前，肿瘤免疫治疗与化疗协同作用的机制尚未完全清楚，相信通过其相关机制的不断阐明，将进一步提高免疫化疗的抗肿瘤效果并推动其临床应用。
近年来肿瘤治疗领域受到关注的热点之一是免疫治疗与化疗的联合应用，大量基础与临床的研究结果表明，恰当的免疫化疗（chemoimmunotherapy） 能够取得较单一疗法更优的抗肿瘤效果，超越了以往认为化疗对免疫系统具有抑制作用、免疫治疗与化疗难以一起应用的传统观念。免疫化疗具有协同抗肿瘤效果的机制是多方面的，化疗可通过增强肿瘤细胞免疫原性、去除免疫抑制以及调节免疫应答反应等方式增强免疫治疗效果；另外，免疫治疗能够逆转肿瘤细胞的化疗耐药性，从而提高肿瘤细胞对化疗药物的敏感性并降低化疗的毒性作用等。目前，肿瘤免疫治疗与化疗协同作用的机制尚未完全清楚，相信通过其相关机制的不断阐明，将进一步提高免疫化疗的抗肿瘤效果并推动其临床应用。
2014, 21(1):104-108.
DOI: 10.3872/j.issn.1007-385X.2014.1.018
Abstract:
抗原特异性T细胞是肿瘤过继免疫治疗的核心，靶向性强、杀伤活性高、毒性作用小、疗效卓越的临床级细胞的制备是提高治疗效果的关键。近年来，全封闭自动化T细胞分离系统提高了安全性，新型人工抗原提呈方法和γc家族细胞因子增加了T细胞扩增效率，低分化表型T细胞的选择提高了有效性，而T细胞受体和嵌合抗原受体基因修饰赋予T细胞抗原特异性杀伤性能，病毒基因转导和理化基因转染T细胞方法的不断改进为基因修饰重定向T细胞的抗原特异性提供了保障。越来越多的临床试验展示了令人鼓舞的治疗效果，为肿瘤过继免疫治疗注入了新的生命力。
抗原特异性T细胞是肿瘤过继免疫治疗的核心，靶向性强、杀伤活性高、毒性作用小、疗效卓越的临床级细胞的制备是提高治疗效果的关键。近年来，全封闭自动化T细胞分离系统提高了安全性，新型人工抗原提呈方法和γc家族细胞因子增加了T细胞扩增效率，低分化表型T细胞的选择提高了有效性，而T细胞受体和嵌合抗原受体基因修饰赋予T细胞抗原特异性杀伤性能，病毒基因转导和理化基因转染T细胞方法的不断改进为基因修饰重定向T细胞的抗原特异性提供了保障。越来越多的临床试验展示了令人鼓舞的治疗效果，为肿瘤过继免疫治疗注入了新的生命力。
2014, 21(1):109-113.
DOI: 10.3872/j.issn.1007-385X.2014.01.019
Abstract:
人组织激肽释放酶10（Kallikrein10，KLK10），是Kallikrein家族(KLK 1-15)的成员之一。KLK10编码激肽释放酶10（hK10），hK10是一种分泌型丝氨酸蛋白酶，生理功能不明。KLK10与多种恶性肿瘤的发生、发展密切相关，KLK10异常表达受甲基化、激素受体等多种因素的调节，miRNA对KLK10的调控也成为新的热点。KLK10与KLK家族其他成员在部分肿瘤中平行表达，KLK10与其他KLKs可能存在共同的激素和miRNA调节通路。KLK10作为一种新的肿瘤生物学标志物，在卵巢癌、乳腺癌和胃结直肠癌等恶性肿瘤的早期诊断和预后评估及靶向治疗中的意义也日益显现。
人组织激肽释放酶10（Kallikrein10，KLK10），是Kallikrein家族(KLK 1-15)的成员之一。KLK10编码激肽释放酶10（hK10），hK10是一种分泌型丝氨酸蛋白酶，生理功能不明。KLK10与多种恶性肿瘤的发生、发展密切相关，KLK10异常表达受甲基化、激素受体等多种因素的调节，miRNA对KLK10的调控也成为新的热点。KLK10与KLK家族其他成员在部分肿瘤中平行表达，KLK10与其他KLKs可能存在共同的激素和miRNA调节通路。KLK10作为一种新的肿瘤生物学标志物，在卵巢癌、乳腺癌和胃结直肠癌等恶性肿瘤的早期诊断和预后评估及靶向治疗中的意义也日益显现。
2014, 21(1):114-118.
DOI: 10.3872/j.issn.1007-385X.2014.01.020
Abstract:
近年来，纳米材料凭借其独特的光、声、电、磁、热和力学特性在生物医学领域中得到广泛应用，也为卵巢癌的早期诊断、精确分期和肿瘤病灶的定位带来福音。在卵巢癌细胞分离中，修饰靶向分子后的磁性纳米材料能特异性地捕获卵巢癌细胞，并在外加磁场作用下将其分离，为卵巢癌患者体内扩散的癌细胞的检测和清除提供了技术手段；在卵巢癌检测技术中，纳米材料制成的生物传感器能够有效提高卵巢癌患者样本分析的效率、选择性及特异性；纳米材料制成的造影剂不仅能同时适用于多种成像技术，还可以提高其对卵巢癌组织的成像灵敏度与分辨率，实现卵巢癌的分子成像；纳米材料与质谱分析结合后，可有效提高其检测的灵敏度，在卵巢癌的蛋白组学分析中发挥更好的作用。
近年来，纳米材料凭借其独特的光、声、电、磁、热和力学特性在生物医学领域中得到广泛应用，也为卵巢癌的早期诊断、精确分期和肿瘤病灶的定位带来福音。在卵巢癌细胞分离中，修饰靶向分子后的磁性纳米材料能特异性地捕获卵巢癌细胞，并在外加磁场作用下将其分离，为卵巢癌患者体内扩散的癌细胞的检测和清除提供了技术手段；在卵巢癌检测技术中，纳米材料制成的生物传感器能够有效提高卵巢癌患者样本分析的效率、选择性及特异性；纳米材料制成的造影剂不仅能同时适用于多种成像技术，还可以提高其对卵巢癌组织的成像灵敏度与分辨率，实现卵巢癌的分子成像；纳米材料与质谱分析结合后，可有效提高其检测的灵敏度，在卵巢癌的蛋白组学分析中发挥更好的作用。
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- 《中国肿瘤生物治疗杂志》
- 1994年创刊
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- 刊号：ISSN 1007-385X
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Supported by:Beijing E-Tiller Technology Development Co., Ltd.