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Volume 19,Issue 6,2012 Table of Contents
2012, 19(6):569-576.
DOI: 10.3872/j.issn.1007-385X.2012.6.001
Abstract:
Extensive investigations of oncolytic adenoviruse (OA) from the laboratory to the clinic have been made in the past decades. There are a few strategies for improving the potential targeted therapy of OA in cancer, including transcriptional targeting by mutating functional genes (such as E1A or E1B ) of Ad genome which is involved in the control of cell cycle checkpoints in cells and/or utilizing tumor-specific promoter control of E1A expression, transductional targeting by changing tropism of OA with different types or incorporated by RGD motif into tumor cells, and cell carriers for delivery of OA to the distant tumor sites. Enhanced anti-tumor immune response, apoptosis or suicide of tumor cells elicited by OA, as vector, enabling express immunoregulatory or therapeutic genes contribute to generate synergetic antitumor effects with OA. Clinical trials of OA for various solid tumors have been carried out, in which the application for patients is safe, presenting well tolerated, mild to moderate adverse events, though few objective tumor responses to patients have been observed. Combination of OA with other therapies, such as chemotherapy or radiotherapy can improve clinical efficacy. Future directions of OA development should be focus on strengthening the research on OA-associated immunological mechanisms, breaking through some technical bottlenecks hampering deep studies of OA, optimizing cell carries for targeting of OA to distant tumor sites, and looking for more potential targets such cancer stem cells. In addition, enlarging the range of clinical OA trials and reinforcing the investigations to combine OA with other therapeutic approaches, particularly with immunotherapy, are needed.
Extensive investigations of oncolytic adenoviruse (OA) from the laboratory to the clinic have been made in the past decades. There are a few strategies for improving the potential targeted therapy of OA in cancer, including transcriptional targeting by mutating functional genes (such as E1A or E1B ) of Ad genome which is involved in the control of cell cycle checkpoints in cells and/or utilizing tumor-specific promoter control of E1A expression, transductional targeting by changing tropism of OA with different types or incorporated by RGD motif into tumor cells, and cell carriers for delivery of OA to the distant tumor sites. Enhanced anti-tumor immune response, apoptosis or suicide of tumor cells elicited by OA, as vector, enabling express immunoregulatory or therapeutic genes contribute to generate synergetic antitumor effects with OA. Clinical trials of OA for various solid tumors have been carried out, in which the application for patients is safe, presenting well tolerated, mild to moderate adverse events, though few objective tumor responses to patients have been observed. Combination of OA with other therapies, such as chemotherapy or radiotherapy can improve clinical efficacy. Future directions of OA development should be focus on strengthening the research on OA-associated immunological mechanisms, breaking through some technical bottlenecks hampering deep studies of OA, optimizing cell carries for targeting of OA to distant tumor sites, and looking for more potential targets such cancer stem cells. In addition, enlarging the range of clinical OA trials and reinforcing the investigations to combine OA with other therapeutic approaches, particularly with immunotherapy, are needed.
2012, 19(6):577-581.
DOI: 10.3872/j.issn.1007-385X.2012.6.002
Abstract:
Objective:To evaluate the efficacy of cytokine-induced killer cells (CIKs) in the treatment of melanoma．Methods: Thirty-eight post-operated melanoma patients in Tumor Hospital Affiliated to Tianjin Medical University from January 2005 to December 2010 receiving CIK treatment were obtained (CIK group) as a treatment group, and 114 melanoma patients without treatment were obtained as a control group. Pairing considerations included clinical stage, gender, age, ulceration, lactate dehydrogenase （LDH） activity, pathological type, and the Karnofsky performance status scale (KPS). The follow-up period was from March 2005 to March 2012. The endpoint of clinical efficacy was overall survival (OS)．Results: The 1-, 3-, 5-year OS rates in the CIK and control groups were 86.8% vs 74.6% (P=0.097), 76.3% vs 46.5% (P=0.001) and 71.1% vs 43.9% (P=0.004), respectively. The median OS in the CIK group was significantly longer than that in the control group (the OS in CIK group did not reach median OS, and was 20.1 months in the control group, P=0.004). The frequency of CIK immunotherapy may be related to the OS of melanoma patients (P=0051). It seemed a trend to prolong the OS of patients with melanoma when CIK treatment >8 times. Univariate and multivariate analysis showed that the pathological type and LDH activity were independent factors for the clinical efficacy of CIK in treatment of patients with melanoma. Conclusion: CIK immunotherapy can prolong OS in melanoma patients, and increasing CIK frequency may enhance the clinical efficacy.
Objective:To evaluate the efficacy of cytokine-induced killer cells (CIKs) in the treatment of melanoma．Methods: Thirty-eight post-operated melanoma patients in Tumor Hospital Affiliated to Tianjin Medical University from January 2005 to December 2010 receiving CIK treatment were obtained (CIK group) as a treatment group, and 114 melanoma patients without treatment were obtained as a control group. Pairing considerations included clinical stage, gender, age, ulceration, lactate dehydrogenase （LDH） activity, pathological type, and the Karnofsky performance status scale (KPS). The follow-up period was from March 2005 to March 2012. The endpoint of clinical efficacy was overall survival (OS)．Results: The 1-, 3-, 5-year OS rates in the CIK and control groups were 86.8% vs 74.6% (P=0.097), 76.3% vs 46.5% (P=0.001) and 71.1% vs 43.9% (P=0.004), respectively. The median OS in the CIK group was significantly longer than that in the control group (the OS in CIK group did not reach median OS, and was 20.1 months in the control group, P=0.004). The frequency of CIK immunotherapy may be related to the OS of melanoma patients (P=0051). It seemed a trend to prolong the OS of patients with melanoma when CIK treatment >8 times. Univariate and multivariate analysis showed that the pathological type and LDH activity were independent factors for the clinical efficacy of CIK in treatment of patients with melanoma. Conclusion: CIK immunotherapy can prolong OS in melanoma patients, and increasing CIK frequency may enhance the clinical efficacy.
2012, 19(6):582-587.
DOI: 10.3872/j.issn.1007-385X.2012.6.003
Abstract:
Objective:To explore the effect of miRNA-200c on chemosensitivity of drug-resistant human gastric cancer SGC7901/DDP cells to cisplatin (DDP) and its mechanism. Methods: The expressions of E-cadherin, PTEN, p-Akt and total Akt proteins in SGC7901/DDP cells and its parental SGC7901 cells were detected by Western blotting. miRNA-200c precursor (Pre-200c) was transiently transfected into SGC7901/DDP cells to increase the expression of miRNA-200c. The drug sensitivity of cells to cisplatin and the expression level of p-Akt were detected by MTT assay and Western blotting, respectively. Finally, SGC7901/DDP cells were treated with LY94002 to inactivate the phosphorylation of Akt, and the sensitivity of SGC7901/DDP cells to DDP was detected. Results: Compared with SGC7901 cells, the expression of p-Akt protein in SGC7901/DDP cells was significantly increased (\[1.02±0.09\] vs \[0.17±0.02\], P<0.05), while the expressions of E-cadherin and PTEN protein were significantly decreased (\[0.10±0.03\] vs \[0.47±0.06\]; \[0.18±006\] vs \[0.87±0.06\] respectively, P<0.05). The IC50 of cisplatin in the Pre-200c tansfected group was significantly lower than that in the negative control group (\[7.52±0.19\] mg/L vs \[12.18±0.29\] mg/L, P<0.05). Furthermore, the expression of p-Akt protein in the Pre-200c transfected group was significantly lower than that in the control group (\[0.22±0.04\] vs \[0.69±0.09\], P<0.05); the level of p-Akt protein was significantly inhibited (\[0.18±0.06\] vs \[0.66±0.10\], P<0.05) in SGC7901/DDP cells treated with LY94002. Moreover, the IC50 of DDP in the LY94002 treated group was significantly lower than that in the control group (\[6.80±0.28\] mg/L vs \[11.94±1.73\] mg/L, P<0.05). Conclusion: Drug resistance phenotype of SGC7901/DDP cells may be associated with the loss of E-cadherin and PTEN proteins and abnormally activation of Akt signaling pathway, and the chemotherapeutic sensitization of miRNA-200c may be through the inactivation of Akt signal pathway.
Objective:To explore the effect of miRNA-200c on chemosensitivity of drug-resistant human gastric cancer SGC7901/DDP cells to cisplatin (DDP) and its mechanism. Methods: The expressions of E-cadherin, PTEN, p-Akt and total Akt proteins in SGC7901/DDP cells and its parental SGC7901 cells were detected by Western blotting. miRNA-200c precursor (Pre-200c) was transiently transfected into SGC7901/DDP cells to increase the expression of miRNA-200c. The drug sensitivity of cells to cisplatin and the expression level of p-Akt were detected by MTT assay and Western blotting, respectively. Finally, SGC7901/DDP cells were treated with LY94002 to inactivate the phosphorylation of Akt, and the sensitivity of SGC7901/DDP cells to DDP was detected. Results: Compared with SGC7901 cells, the expression of p-Akt protein in SGC7901/DDP cells was significantly increased (\[1.02±0.09\] vs \[0.17±0.02\], P<0.05), while the expressions of E-cadherin and PTEN protein were significantly decreased (\[0.10±0.03\] vs \[0.47±0.06\]; \[0.18±006\] vs \[0.87±0.06\] respectively, P<0.05). The IC50 of cisplatin in the Pre-200c tansfected group was significantly lower than that in the negative control group (\[7.52±0.19\] mg/L vs \[12.18±0.29\] mg/L, P<0.05). Furthermore, the expression of p-Akt protein in the Pre-200c transfected group was significantly lower than that in the control group (\[0.22±0.04\] vs \[0.69±0.09\], P<0.05); the level of p-Akt protein was significantly inhibited (\[0.18±0.06\] vs \[0.66±0.10\], P<0.05) in SGC7901/DDP cells treated with LY94002. Moreover, the IC50 of DDP in the LY94002 treated group was significantly lower than that in the control group (\[6.80±0.28\] mg/L vs \[11.94±1.73\] mg/L, P<0.05). Conclusion: Drug resistance phenotype of SGC7901/DDP cells may be associated with the loss of E-cadherin and PTEN proteins and abnormally activation of Akt signaling pathway, and the chemotherapeutic sensitization of miRNA-200c may be through the inactivation of Akt signal pathway.
2012, 19(6):588-593.
DOI: 10.3872/j.issn.1007-385X.2012.6.004
Abstract:
Objective:To investigate the structure characteristics and roles of vasculogenic mimicry in the xenografts of human osteosarcoma cells in nude mice. Methods: The models of xenografts of MG-63 human osteosarcoma cells in nude mice and xenografts of UMR106 osteosarcoma cells in nude rats were constructed. The construction features of vasculogenic mimicry and their relationship with tumor microvascular in transplanted osteosarcoma were observed by CD34 and CD147 immunofluorescence staining and GFP staining. Results:CD147 was positive for MG-63-cell-transplanted osteosarcoma tissues and CD34 wsa positive for vascular endothelial cells. The construction of vasculogenic mimicry was observed in the central area of transplanted osteosarcoma, which was constituted mainly by osteosarcoma cells and had the function of the blood vessel. The construction of tumor microvascular was observed in the surrounding area of transplanted osteosarcoma, which was constituted mainly by vascular endothelial cells and connected to vasculogenic mimicry by certain pipeline sample structure. Conclusion:Vasculogenic mimicry in osteosarcoma tissues functions as the blood vessels and can be connected to tumor microvascular so that they can induce tumor microvascular infiltrating into internal tumors.
Objective:To investigate the structure characteristics and roles of vasculogenic mimicry in the xenografts of human osteosarcoma cells in nude mice. Methods: The models of xenografts of MG-63 human osteosarcoma cells in nude mice and xenografts of UMR106 osteosarcoma cells in nude rats were constructed. The construction features of vasculogenic mimicry and their relationship with tumor microvascular in transplanted osteosarcoma were observed by CD34 and CD147 immunofluorescence staining and GFP staining. Results:CD147 was positive for MG-63-cell-transplanted osteosarcoma tissues and CD34 wsa positive for vascular endothelial cells. The construction of vasculogenic mimicry was observed in the central area of transplanted osteosarcoma, which was constituted mainly by osteosarcoma cells and had the function of the blood vessel. The construction of tumor microvascular was observed in the surrounding area of transplanted osteosarcoma, which was constituted mainly by vascular endothelial cells and connected to vasculogenic mimicry by certain pipeline sample structure. Conclusion:Vasculogenic mimicry in osteosarcoma tissues functions as the blood vessels and can be connected to tumor microvascular so that they can induce tumor microvascular infiltrating into internal tumors.
2012, 19(6):594-598.
DOI: 10.3872/j.issn.1007-385X.2012.6.005
Abstract:
Objective:To explore an in vitro expansion method of NK cells by CD137 monoclonal antibody combination with IL-15, and to study the cytotoxicity of expanded NK cells against lung cancer cells. Methods:CD3-CD56+NK cells were isolated from peripheral blood mononuclear cells (PBMCs) using negative MACS, and divided into five groups: a control group, IL-2, IL-2+ CD137mAb，IL-2+IL-15, and IL-2+IL-15+ CD137mAb groups. The expansion, phenotype and cytotoxicity of lung cancer A549 cells and IFN-γ secretion of NK cells were evaluated by MTT, FACS, LDH, and ELISA, respectively. Results: The purity of NK cells increased to (93.28+3.21)% after MACS sorting. In group IL-2+IL-15+CD137mAb, the NK cells were expanded obviously higher than were those in IL-2+CD137mAb，IL-2+IL-15，IL-2 and control groups（86.20±5.00 vs 60.01±5.00, 49.06±4.39, 17.04±1.49, 3.95+0.23, P<0.01). The cytotoxicity of expanded NK cells in group IL-2+IL-15+CD137mAb was significantly higher than that in the other groups (\[93.14±327\]% vs \[83.15±403\]%, \[7125±3.24\]%, \[62.27±3.01\]%, \[49.38±2.35\]%, P<0.01). In group IL-2+IL-15+CD137mAb, the IFN-γ level in cell supernatant was significantly higher than that in IL-2+CD137mAb, IL-2+IL-15, IL-2 and control groups (\[296.25±9.79\] vs \[260.47±11.55\], \[201.13±6.36\], \[138.36±6.09\], \[38.42±3.56\] pg/ml; P<0.01).Conclusion: CD137 monoclonal antibody combination with IL-15 can efficiently expand NK cells with an effective cytotoxicity on lung cancer A549 cells.
Objective:To explore an in vitro expansion method of NK cells by CD137 monoclonal antibody combination with IL-15, and to study the cytotoxicity of expanded NK cells against lung cancer cells. Methods:CD3-CD56+NK cells were isolated from peripheral blood mononuclear cells (PBMCs) using negative MACS, and divided into five groups: a control group, IL-2, IL-2+ CD137mAb，IL-2+IL-15, and IL-2+IL-15+ CD137mAb groups. The expansion, phenotype and cytotoxicity of lung cancer A549 cells and IFN-γ secretion of NK cells were evaluated by MTT, FACS, LDH, and ELISA, respectively. Results: The purity of NK cells increased to (93.28+3.21)% after MACS sorting. In group IL-2+IL-15+CD137mAb, the NK cells were expanded obviously higher than were those in IL-2+CD137mAb，IL-2+IL-15，IL-2 and control groups（86.20±5.00 vs 60.01±5.00, 49.06±4.39, 17.04±1.49, 3.95+0.23, P<0.01). The cytotoxicity of expanded NK cells in group IL-2+IL-15+CD137mAb was significantly higher than that in the other groups (\[93.14±327\]% vs \[83.15±403\]%, \[7125±3.24\]%, \[62.27±3.01\]%, \[49.38±2.35\]%, P<0.01). In group IL-2+IL-15+CD137mAb, the IFN-γ level in cell supernatant was significantly higher than that in IL-2+CD137mAb, IL-2+IL-15, IL-2 and control groups (\[296.25±9.79\] vs \[260.47±11.55\], \[201.13±6.36\], \[138.36±6.09\], \[38.42±3.56\] pg/ml; P<0.01).Conclusion: CD137 monoclonal antibody combination with IL-15 can efficiently expand NK cells with an effective cytotoxicity on lung cancer A549 cells.
2012, 19(6):599-603.
DOI: 10.3872/j.issn.1007-385X.2012.6.006
Abstract:
Objective:To investigate the expression levl of microRNA-34a (miR-34a) in human glioma tissues, and further explore the role of miR-34a on proliferation and apoptosis of glioma SHG-44 cells. Methods: Twenty glioma samples were collected from the Department of Neurosurgery, Affiliated Hospital of Qingdao Medical College (January 2007 to December 2010). The normal brain tissues were obtained from 5 patients with severe traumatic brain injury who required post-trauma surgery. The expression level of MiR-34a in glioma tissues was detected by real-time PCR. After transfection of miR-34a mimics into SHG-44 cells, the proliferation, cell cycle and apoptosis were measured by MTT and flow cytometry, respectively. Results: The expression level of miR-34a was lower in the glioma tissues compared with the normal brain tissues, and miR-34a expression level was lower in the glima tissues of phase Ⅲ/Ⅳ than in phase Ⅰ/Ⅱ. The cell proliferation inhibitory rate increased signficantly in the miR-34a transfected group compared to the blank group (\[37.24±572\] % vs \[4.19±063\]%, P<0.01), the ratio of cells arrest at G1 phase was significantly higher in the miR-34a mimics transfected group compared to the blank group (\[61.78±2.01\]% vs \[50.91±1.19\]%, P<0.05), and the cell apoptosis in the miR-34a transfected group was significantly increased compared to the blank group (\[15.28±365\]% vs \[2.07±0.84\]%, P<001). Conclusion: MiR-34a was lowly expressed in human glioma tissues. MiR-34a can inhibit SHG-44 cell proliferation, thus inducing SHG-44 cell cycle arrest and promoting SHG-44 cell apoptosis.
Objective:To investigate the expression levl of microRNA-34a (miR-34a) in human glioma tissues, and further explore the role of miR-34a on proliferation and apoptosis of glioma SHG-44 cells. Methods: Twenty glioma samples were collected from the Department of Neurosurgery, Affiliated Hospital of Qingdao Medical College (January 2007 to December 2010). The normal brain tissues were obtained from 5 patients with severe traumatic brain injury who required post-trauma surgery. The expression level of MiR-34a in glioma tissues was detected by real-time PCR. After transfection of miR-34a mimics into SHG-44 cells, the proliferation, cell cycle and apoptosis were measured by MTT and flow cytometry, respectively. Results: The expression level of miR-34a was lower in the glioma tissues compared with the normal brain tissues, and miR-34a expression level was lower in the glima tissues of phase Ⅲ/Ⅳ than in phase Ⅰ/Ⅱ. The cell proliferation inhibitory rate increased signficantly in the miR-34a transfected group compared to the blank group (\[37.24±572\] % vs \[4.19±063\]%, P<0.01), the ratio of cells arrest at G1 phase was significantly higher in the miR-34a mimics transfected group compared to the blank group (\[61.78±2.01\]% vs \[50.91±1.19\]%, P<0.05), and the cell apoptosis in the miR-34a transfected group was significantly increased compared to the blank group (\[15.28±365\]% vs \[2.07±0.84\]%, P<001). Conclusion: MiR-34a was lowly expressed in human glioma tissues. MiR-34a can inhibit SHG-44 cell proliferation, thus inducing SHG-44 cell cycle arrest and promoting SHG-44 cell apoptosis.
2012, 19(6):604-608.
DOI: 10.3872/j.issn.1007-385X.2012.6.007
Abstract:
Objective:To study the inhibitory effect of umbilical cord blood mesenchymal stem cells (UCBMSCs) infected with reconstructed lentivirus-TNF-α on growth of gastric cancer transplantation tumors, based on UCBMSC as a TNF-α carrier. Methods: The human gastric cancer SGC-7901 cells were injected into nude mice subcutaneously groin. The model of transplanted SGC-7901 cells in nude mice was set up. The reconstructed lentivirus (Lv-TNF-α) and empty lentivirus (Lv-EGFP) were added to UCBMSC, and UCBMSC-TNF-α cells and control UCBMSC-EGFP cells were obtained. Tumor-bearing nude mice were separated into three groups randomly: a UCBMSC-TNF-α group, an UCBMSC-EGFP group and a NaCl group. The nude mice in these three groups were injected around the tumor with UCBMSC-TNF-α cells, UCBMSC-EGFP cells or NaCl. The transplanted gastric cancer volume and weight was observed; the expressions of TNF-α mRNA and protein in the three groups were determined by RT-PCR and ELISA; and the necrosis areas in the tumors were observed by H-E staining. Results: The transplantation tumor model was established in the nude mice successfully. The transplanted tumor average volume in the three groups were (0.51±0.27), (0.64±0.36) and (1.21±0.80) cm3, and the transplanted tumor average volume in the UCBMSC-TNF-α group was minimum (F=3.88，P<005); The expressions of TNF-α mRNA in the three groups were (1.92±0.12), (1.21±0.26) and (0.81±0.22), and the expression of TNF-α mRNA in the UCBMSC-TNF-α group was maximum (F=54.82, P<0.01); The expressions of TNF-α protein in the three groups were (148.29±3.76), (78.22±6.24) and (42.80±3.02) pg/ml, and the expression of TNF-α protein in the UCBMSC-TNF-α group was maximum (F=694.54, P<0.01); H-E stained biopsy revealed that the largest tumor necrosis was in the UCBMSC-TNF-α treatment group. Conclusion: Transgenic UCBMSCs can paracrine TNF-α, which has an inhibitory effect on gastric cancer.
Objective:To study the inhibitory effect of umbilical cord blood mesenchymal stem cells (UCBMSCs) infected with reconstructed lentivirus-TNF-α on growth of gastric cancer transplantation tumors, based on UCBMSC as a TNF-α carrier. Methods: The human gastric cancer SGC-7901 cells were injected into nude mice subcutaneously groin. The model of transplanted SGC-7901 cells in nude mice was set up. The reconstructed lentivirus (Lv-TNF-α) and empty lentivirus (Lv-EGFP) were added to UCBMSC, and UCBMSC-TNF-α cells and control UCBMSC-EGFP cells were obtained. Tumor-bearing nude mice were separated into three groups randomly: a UCBMSC-TNF-α group, an UCBMSC-EGFP group and a NaCl group. The nude mice in these three groups were injected around the tumor with UCBMSC-TNF-α cells, UCBMSC-EGFP cells or NaCl. The transplanted gastric cancer volume and weight was observed; the expressions of TNF-α mRNA and protein in the three groups were determined by RT-PCR and ELISA; and the necrosis areas in the tumors were observed by H-E staining. Results: The transplantation tumor model was established in the nude mice successfully. The transplanted tumor average volume in the three groups were (0.51±0.27), (0.64±0.36) and (1.21±0.80) cm3, and the transplanted tumor average volume in the UCBMSC-TNF-α group was minimum (F=3.88，P<005); The expressions of TNF-α mRNA in the three groups were (1.92±0.12), (1.21±0.26) and (0.81±0.22), and the expression of TNF-α mRNA in the UCBMSC-TNF-α group was maximum (F=54.82, P<0.01); The expressions of TNF-α protein in the three groups were (148.29±3.76), (78.22±6.24) and (42.80±3.02) pg/ml, and the expression of TNF-α protein in the UCBMSC-TNF-α group was maximum (F=694.54, P<0.01); H-E stained biopsy revealed that the largest tumor necrosis was in the UCBMSC-TNF-α treatment group. Conclusion: Transgenic UCBMSCs can paracrine TNF-α, which has an inhibitory effect on gastric cancer.
2012, 19(6):609-614.
DOI: 10.3872/j.issn.1007-385X.2012.6.008
Abstract:
Objective:To investigate the effect and mechanism of CXC chemokine receptor-4 (CXCR4) in the proliferation and migration of breast cancer MDA-MB-231SA-rfp cells in vitro and in vivo by a specific small CXCR4 inhibitor, AMD3100. Methods:MDA-MB-231SA-rfp cells were treated with AMD3100, and the proliferation and migration were detected by CCK-8 and Transwell assay. MDA-MB-231SA-rfp cells were inoculated into nude mice to establish a model of breast cancer bone etastasis xenograft. AMD3100 at different final concentrations were delivered to mice. X-ray was taken to observe breast cancer bone metastasis and MicroPET was used to perform a semiquatitative analysis of breast cancer bone metastasis. H-E staining was used to further determine the location of breast cancer bone metastasis. Western blotting was performed to determine CXCR4 protein expression in MDA-MB-231SA-rfp cells as well as in xenograft tissues before and after AMD3100 administration. Results: The cell proliferation and migration of MDA-MB-231SA-rfp cells line induced by SDF-1 were gnificantly inhibited by AMD3100 (P＜0.05) and 2 000 ng/ml AMD3100 showed much more significant inhibition of the cell proliferation and migration (P＜0.01). The model of breast cancer bone metastasis xenograft was successfully established. Bone erosion of the lower limb found by X-ray was decreased after AMD3100 treatment of different concentrations . MicroPET images demonstrated that SUVmax values of the control group, low concentration AMD3100 group and high concentration AMD3100 group were respectively 9.44±0.53, 5.70±0.25 and 2.18±0.47 (P<0.01). H-E staining detection confirmed the bone metastasis of breast cancer. No significant difference was found in CXCR4 protein expression in MDA-MB-231SA-rfp cells and bone metastasis tissues before and after AMD3100 administration. Conclusion: Blocking the CXCR4 activity by AMD3100 can inhibit the proliferation and migration capacity of breast cancer MDA-MB-231SA-rfp cells in vitro, and also the bone metastasis in xenograft in vivo in nude mice.
Objective:To investigate the effect and mechanism of CXC chemokine receptor-4 (CXCR4) in the proliferation and migration of breast cancer MDA-MB-231SA-rfp cells in vitro and in vivo by a specific small CXCR4 inhibitor, AMD3100. Methods:MDA-MB-231SA-rfp cells were treated with AMD3100, and the proliferation and migration were detected by CCK-8 and Transwell assay. MDA-MB-231SA-rfp cells were inoculated into nude mice to establish a model of breast cancer bone etastasis xenograft. AMD3100 at different final concentrations were delivered to mice. X-ray was taken to observe breast cancer bone metastasis and MicroPET was used to perform a semiquatitative analysis of breast cancer bone metastasis. H-E staining was used to further determine the location of breast cancer bone metastasis. Western blotting was performed to determine CXCR4 protein expression in MDA-MB-231SA-rfp cells as well as in xenograft tissues before and after AMD3100 administration. Results: The cell proliferation and migration of MDA-MB-231SA-rfp cells line induced by SDF-1 were gnificantly inhibited by AMD3100 (P＜0.05) and 2 000 ng/ml AMD3100 showed much more significant inhibition of the cell proliferation and migration (P＜0.01). The model of breast cancer bone metastasis xenograft was successfully established. Bone erosion of the lower limb found by X-ray was decreased after AMD3100 treatment of different concentrations . MicroPET images demonstrated that SUVmax values of the control group, low concentration AMD3100 group and high concentration AMD3100 group were respectively 9.44±0.53, 5.70±0.25 and 2.18±0.47 (P<0.01). H-E staining detection confirmed the bone metastasis of breast cancer. No significant difference was found in CXCR4 protein expression in MDA-MB-231SA-rfp cells and bone metastasis tissues before and after AMD3100 administration. Conclusion: Blocking the CXCR4 activity by AMD3100 can inhibit the proliferation and migration capacity of breast cancer MDA-MB-231SA-rfp cells in vitro, and also the bone metastasis in xenograft in vivo in nude mice.
9 Effect of lentivirus-mediated silence of RhoA gene on invasion and migration of ovarian cancer cells
2012, 19(6):615-620.
DOI: 10.3872/j.issn.1007-385X.2012.6.009
Abstract:
Objective:To construct a ovary cancer cell line HO8910 with a stable knockdown of RhoA gene by lentiviral vectors; and to investigate the effect of RhoA gene on invasion and migration of HO8910 cells. Methods: Lenti-U6-shRhoA lentivirus targeting silence RhoA gene expression was constructed and infected into HO8910 cells. HO8910 cells stable knockdown RhoA gene expression were obtained by puromycin selection. The expression of RhoA mRNA in HO8910 cells was detected by real-time PCR; the proliferation of HO8910 cells was detected by MTT assay; and Transwell migration assay and Matrigel invasion assay were used to measure the effect of RhoA gene silence on invasion and migration of HO8910 cells. Results: The lentiviral vector Lenti-U6-shRhoA targeting RhoA gene was constructed successfully and a stable RhoA knockdown HO8910 cell line was established. The RhoA gene expression was efficiently suppressed by Lenti-U6-shRhoA with a expression rate of (30.7±5.4)%, compared with the control Lenti-U6-NC group (95.9±6.53)% (P<0.05). The knockdown of RhoA gene inhibited the survival rate of HO8910 cells (\[51.16±741\]% vs \[95.67±214\]%, P<0.05); Compared with the Lenti-U6-NC group, the capabilities of the invasion (97±12 vs 689±23, P<0.05), migration (31±6 vs 84±13, P<0.05) and adhesion rate (\[68.16±6.53\]% vs \[9871±492\]%, P<005) were also obviously suppressed in the RhoA stable knockdown HO8910 cell line. Conclusion: The lentivirus-mediated RhoA gene silence can suppress the invasion and migration of ovary cancer HO8910 cells.
Objective:To construct a ovary cancer cell line HO8910 with a stable knockdown of RhoA gene by lentiviral vectors; and to investigate the effect of RhoA gene on invasion and migration of HO8910 cells. Methods: Lenti-U6-shRhoA lentivirus targeting silence RhoA gene expression was constructed and infected into HO8910 cells. HO8910 cells stable knockdown RhoA gene expression were obtained by puromycin selection. The expression of RhoA mRNA in HO8910 cells was detected by real-time PCR; the proliferation of HO8910 cells was detected by MTT assay; and Transwell migration assay and Matrigel invasion assay were used to measure the effect of RhoA gene silence on invasion and migration of HO8910 cells. Results: The lentiviral vector Lenti-U6-shRhoA targeting RhoA gene was constructed successfully and a stable RhoA knockdown HO8910 cell line was established. The RhoA gene expression was efficiently suppressed by Lenti-U6-shRhoA with a expression rate of (30.7±5.4)%, compared with the control Lenti-U6-NC group (95.9±6.53)% (P<0.05). The knockdown of RhoA gene inhibited the survival rate of HO8910 cells (\[51.16±741\]% vs \[95.67±214\]%, P<0.05); Compared with the Lenti-U6-NC group, the capabilities of the invasion (97±12 vs 689±23, P<0.05), migration (31±6 vs 84±13, P<0.05) and adhesion rate (\[68.16±6.53\]% vs \[9871±492\]%, P<005) were also obviously suppressed in the RhoA stable knockdown HO8910 cell line. Conclusion: The lentivirus-mediated RhoA gene silence can suppress the invasion and migration of ovary cancer HO8910 cells.
2012, 19(6):621-627.
DOI: 10.3872/j.issn.1007-385X.2012.6.010
Abstract:
Objective:To study the characterization of the cell-in-cell structure formed between heterotypic cells and its biological significance. Methods:By establishing flow cytometry-based analysis and sorting methodology, the formation of heterotypic cell-in-cell structures between human liver cancer PLC/PRF/5 cells and peripheral blood mononuclear cells (PBMCs) was characterized. Based on this step, a method of sorting the cell-in-cell structures and obtaining the cell-in-cell structures formed between mouse splenocytes and PLC/PRF/5 cells was established. Further analysis of the biological characteristic changes of the PLC/PRF/5 cells via plate colony formation assay showed the effect of the cell-in-cell structure formation on PLC/PRF/5 cells. Results: At 4 h and 8 h, the ratio of the cell-in-cell structures formed by activated PBMCs to PLC/PRF/5 tumor cells were apparently higher than that in the inactivated PBMC group (4 h:\[15.75±128\]% vs \[10.56±0.57\]%, P<0.05; 8 h: \[13.49±1.23\]% vs \[11.38±0.97\]%, P<0.05). Besides, the ratio of activated PBMC group at 4 h was still significantly higher than that in the inactivated PBMC group at 8 h (P<005). The colony formation ratio of the sorted cell-in-cell structures formed by mouse splenocytes into PLC/PRF/5 cells was significantly higher than that of PLC/PRF/5 cells (\[32.25±2.32\]% vs \[21.92±2.02\]%, P<0.05). Conclusion: The ratio of cell-in-cell structures formed between activated PBMCs and PLC/PRF/5 cells is higher than that of the inactivated PBMCs, reaching the highest ratio in shorter time. Meanwhile, tumor cells in cell-in-cell structures show an increased colony formation ability in vitro.
Objective:To study the characterization of the cell-in-cell structure formed between heterotypic cells and its biological significance. Methods:By establishing flow cytometry-based analysis and sorting methodology, the formation of heterotypic cell-in-cell structures between human liver cancer PLC/PRF/5 cells and peripheral blood mononuclear cells (PBMCs) was characterized. Based on this step, a method of sorting the cell-in-cell structures and obtaining the cell-in-cell structures formed between mouse splenocytes and PLC/PRF/5 cells was established. Further analysis of the biological characteristic changes of the PLC/PRF/5 cells via plate colony formation assay showed the effect of the cell-in-cell structure formation on PLC/PRF/5 cells. Results: At 4 h and 8 h, the ratio of the cell-in-cell structures formed by activated PBMCs to PLC/PRF/5 tumor cells were apparently higher than that in the inactivated PBMC group (4 h:\[15.75±128\]% vs \[10.56±0.57\]%, P<0.05; 8 h: \[13.49±1.23\]% vs \[11.38±0.97\]%, P<0.05). Besides, the ratio of activated PBMC group at 4 h was still significantly higher than that in the inactivated PBMC group at 8 h (P<005). The colony formation ratio of the sorted cell-in-cell structures formed by mouse splenocytes into PLC/PRF/5 cells was significantly higher than that of PLC/PRF/5 cells (\[32.25±2.32\]% vs \[21.92±2.02\]%, P<0.05). Conclusion: The ratio of cell-in-cell structures formed between activated PBMCs and PLC/PRF/5 cells is higher than that of the inactivated PBMCs, reaching the highest ratio in shorter time. Meanwhile, tumor cells in cell-in-cell structures show an increased colony formation ability in vitro.
2012, 19(6):628-631.
DOI: 10.3872/j.issn.1007-385X.2012.6.011
Abstract:
Objective: To observe the co-expressions of human glioma tumor stem cell marker (CD133) and epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) in the glioma tissues and their clinical significance. Methods: Forty glioma samples (17 with grade Ⅱ, 12 with grade Ⅲ, 11 with grade IV) were obtained from patients with glioma (who had been diagnosed in the People’s Hospital, Zhengzhou University, from Jan. 2011 to Jun. 2011) receiving surgery. The percentages of CD133+, EGFRvⅢ+ and CD133+/EGFRvⅢ+ cells in the glioma tissues in different grades were analyzed by flow cytometry and the clinical features were compared. Results: The expression of CD133 and EGFRvⅢ in human glioma increased gradually with the pathologic grade of glioma tissue. The double positive CD133+/EGFRvⅢ+ cells were found in the glioma tissues of different grades. The percentage of CD133+/EGFRvⅢ+ cells was between （4.75±126)% to (18.26±3.45)% in different grades of gliomas, with the percentages of CD133+/EGFRvⅢ+ cells in grade Ⅲ and Ⅳ being higher significantly than that in grade Ⅱ (P<0.05). CD133+/EGFRvⅢ+ cells exerted much more influence than did cells expressing CD133+ or EGFRvⅢ+ on survival time of the gliomas patients, and the median survival time of the patients with double positive CD133+/EGFRvⅢ+ was shorter.Conclusion: The co-expressions of CD133 and EGFRvⅢ exist in human gliomas, which are related with the degree of malignant glioma and the survival rate. Our study provides a new potential target for the treatment of glioma.
Objective: To observe the co-expressions of human glioma tumor stem cell marker (CD133) and epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) in the glioma tissues and their clinical significance. Methods: Forty glioma samples (17 with grade Ⅱ, 12 with grade Ⅲ, 11 with grade IV) were obtained from patients with glioma (who had been diagnosed in the People’s Hospital, Zhengzhou University, from Jan. 2011 to Jun. 2011) receiving surgery. The percentages of CD133+, EGFRvⅢ+ and CD133+/EGFRvⅢ+ cells in the glioma tissues in different grades were analyzed by flow cytometry and the clinical features were compared. Results: The expression of CD133 and EGFRvⅢ in human glioma increased gradually with the pathologic grade of glioma tissue. The double positive CD133+/EGFRvⅢ+ cells were found in the glioma tissues of different grades. The percentage of CD133+/EGFRvⅢ+ cells was between （4.75±126)% to (18.26±3.45)% in different grades of gliomas, with the percentages of CD133+/EGFRvⅢ+ cells in grade Ⅲ and Ⅳ being higher significantly than that in grade Ⅱ (P<0.05). CD133+/EGFRvⅢ+ cells exerted much more influence than did cells expressing CD133+ or EGFRvⅢ+ on survival time of the gliomas patients, and the median survival time of the patients with double positive CD133+/EGFRvⅢ+ was shorter.Conclusion: The co-expressions of CD133 and EGFRvⅢ exist in human gliomas, which are related with the degree of malignant glioma and the survival rate. Our study provides a new potential target for the treatment of glioma.
2012, 19(6):632-638.
DOI: 10.3872/j.issn.1007-385X.2012.6.012
Abstract:
Objective:To investigate the promoter and exon1 methylation of insulin-like growth factor binding protein 7 ( IGFBP7 ) gene and its correlation with the expression of IGFBP7 protein in gastric cardia adenocarcinoma (GCA) tissues. Methods: Eighty-five GCA samples and 67 paracancerous tissues from GCA patients (who had been diagnosed in the Forth Hospital of Hebei Medical University, from April, 2009 to December, 2011) were included in the present study. Methylation specific polymerase chain reaction (MSP), RT-PCR and immunohistochchemistry methods were respectively used to examine the methylation status, mRNA and protein expressions of IGFBP7 in GCA tissues and paracancerous tissues. Results: For the promoter site, the methylation frequency of IGFBP7 gene in the GCA specimens (52.9%, 45/85) was significantly higher than that in the paracancerous tissues (35.8%, 24/67) (P<005). For the 5′ UTR of exon1, the methylation frequency of IGFBP7 gene in the GCA specimens (35.3%, 30/85) was significantly higher than that in the paracancerous tissues (19.4%, 13/67) (P<0.05). The methylation frequency of IGFBP7 gene in the promoter site was significantly higher than that in the 5′ UTR of exon1 (P<0.05). The mRNA and protein expressions of IGFBP7 in the GCA tissues were significantly higher than those in the paracancerous tissues (P<0.05) and were inversely correlated with the methylation status of promoter. Conclusion: Compared to the exon1, IGFBP7 promoter site is more likely to be methylated in GCA tissues and may play an important role in the down-regulation of IGFBP7 in GCA tumorigenesis. Hypermethylation of IGFBP7 in promoter site may be one of the mechanisms leading to the occurrence of GCA.
Objective:To investigate the promoter and exon1 methylation of insulin-like growth factor binding protein 7 ( IGFBP7 ) gene and its correlation with the expression of IGFBP7 protein in gastric cardia adenocarcinoma (GCA) tissues. Methods: Eighty-five GCA samples and 67 paracancerous tissues from GCA patients (who had been diagnosed in the Forth Hospital of Hebei Medical University, from April, 2009 to December, 2011) were included in the present study. Methylation specific polymerase chain reaction (MSP), RT-PCR and immunohistochchemistry methods were respectively used to examine the methylation status, mRNA and protein expressions of IGFBP7 in GCA tissues and paracancerous tissues. Results: For the promoter site, the methylation frequency of IGFBP7 gene in the GCA specimens (52.9%, 45/85) was significantly higher than that in the paracancerous tissues (35.8%, 24/67) (P<005). For the 5′ UTR of exon1, the methylation frequency of IGFBP7 gene in the GCA specimens (35.3%, 30/85) was significantly higher than that in the paracancerous tissues (19.4%, 13/67) (P<0.05). The methylation frequency of IGFBP7 gene in the promoter site was significantly higher than that in the 5′ UTR of exon1 (P<0.05). The mRNA and protein expressions of IGFBP7 in the GCA tissues were significantly higher than those in the paracancerous tissues (P<0.05) and were inversely correlated with the methylation status of promoter. Conclusion: Compared to the exon1, IGFBP7 promoter site is more likely to be methylated in GCA tissues and may play an important role in the down-regulation of IGFBP7 in GCA tumorigenesis. Hypermethylation of IGFBP7 in promoter site may be one of the mechanisms leading to the occurrence of GCA.
2012, 19(6):639-642.
DOI: 10.3872/j.issn.1007-385X.2012.6.013
Abstract:
Objective: To study the expression of glutathione S-transferase (GST) in colorectal mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (non-MC) and analyze its clinical significance. Methods: The expressions of GST, nm23 and cytokeratin 7 (CK7) in 109 MC and 441 non-MC specimens (from Colorectal Surgery Department, Xinhua Hospital Affiliated to Shanghai Jiaotong University) were detected by using an immunohistochemical method to explore the clinical significance. Results: The positive rates of GST and nm23 in the MC tissues were 52.3% and 57.8% respectively, which were significantly lower than those in the non-MC tissues (64.7%, 73.0%; P<0.05); while the positive rate of CK7 in the MC tissues was 27.5%, which was significantly higher than that in the non-MC tissues (18.4%, P=0.033). The expression of GST was correlated with differentiation and lymph node metastasis of MC; however, no correlation was found between the expressions of CK7 and nm23 and clinical pathological features of MC. Conclusion: GST is abnormally expressed in MC and non-MC tissues, and GST expression might be used as a biomarker of differentiation and lymph node metastasis in MC.
Objective: To study the expression of glutathione S-transferase (GST) in colorectal mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (non-MC) and analyze its clinical significance. Methods: The expressions of GST, nm23 and cytokeratin 7 (CK7) in 109 MC and 441 non-MC specimens (from Colorectal Surgery Department, Xinhua Hospital Affiliated to Shanghai Jiaotong University) were detected by using an immunohistochemical method to explore the clinical significance. Results: The positive rates of GST and nm23 in the MC tissues were 52.3% and 57.8% respectively, which were significantly lower than those in the non-MC tissues (64.7%, 73.0%; P<0.05); while the positive rate of CK7 in the MC tissues was 27.5%, which was significantly higher than that in the non-MC tissues (18.4%, P=0.033). The expression of GST was correlated with differentiation and lymph node metastasis of MC; however, no correlation was found between the expressions of CK7 and nm23 and clinical pathological features of MC. Conclusion: GST is abnormally expressed in MC and non-MC tissues, and GST expression might be used as a biomarker of differentiation and lymph node metastasis in MC.
2012, 19(6):643-647.
DOI: 10.3872/j.issn.1007-385X.2012.6.014
Abstract:
Objective: To explore the expansion method of autologous NK cells from renal cell carcinoma (RCC) patients based on IL-15- and 4-1BBL-modified K562 cells (modi-K562 cells) combined with IL-2 and to investigate their cytotoxicity against RCC 786-O cell lines. Methods: Peripheral blood mononuclear cells (PBMCs) from 10 RCC patients were co-cultured with modi-K562 cells in medium containing various concentrations of IL-2 for 14 d. The expansion, immune phenotype and cytotoxicity against 786-O cells were analyzed by flow cytometry and Calcein-AM release assay. Results: modi-K562 combined with IL-2 effectively amplified NK cells in vitro. The number of NK cells from 300 IU/mL IL-2 co-culture system for 14 d had amplified on an average of （202.4±12.8) fold. Moreover, the expanded NK cells significantly increased cytotoxicity against 786-O cells. At an effect/target (E∶T) ratio of 20∶1, (72.0±4.3)% of the targets were killed by the expanded NK cells, whereas unexpanded ones killed only (34.2±3.6)% of targets (P<0.01). Conclusion: modi-K562 cells combined with IL-2 can effectively stimulate the expansion of RCC patients’ NK cells in vitro, which significantly augment the cytotoxicity against RCC 786-O cells.
Objective: To explore the expansion method of autologous NK cells from renal cell carcinoma (RCC) patients based on IL-15- and 4-1BBL-modified K562 cells (modi-K562 cells) combined with IL-2 and to investigate their cytotoxicity against RCC 786-O cell lines. Methods: Peripheral blood mononuclear cells (PBMCs) from 10 RCC patients were co-cultured with modi-K562 cells in medium containing various concentrations of IL-2 for 14 d. The expansion, immune phenotype and cytotoxicity against 786-O cells were analyzed by flow cytometry and Calcein-AM release assay. Results: modi-K562 combined with IL-2 effectively amplified NK cells in vitro. The number of NK cells from 300 IU/mL IL-2 co-culture system for 14 d had amplified on an average of （202.4±12.8) fold. Moreover, the expanded NK cells significantly increased cytotoxicity against 786-O cells. At an effect/target (E∶T) ratio of 20∶1, (72.0±4.3)% of the targets were killed by the expanded NK cells, whereas unexpanded ones killed only (34.2±3.6)% of targets (P<0.01). Conclusion: modi-K562 cells combined with IL-2 can effectively stimulate the expansion of RCC patients’ NK cells in vitro, which significantly augment the cytotoxicity against RCC 786-O cells.
2012, 19(6):648-651.
DOI: 10.3872/j.issn.1007-385X.2012.6.015
Abstract:
以嵌合抗原受体（chimeric antigen receptor，CAR）修饰T细胞为基础的肿瘤过继细胞免疫治疗近年来取得了很大的进步，它赋予T细胞靶向杀伤活性，并可克服肿瘤局部免疫抑制微环境和打破宿主免疫耐受状态。CAR以单链抗体-共刺激分子-免疫受体酪氨酸活化基序的嵌合模式修饰T细胞显示出良好的抗肿瘤作用，Ⅰ/Ⅱ期临床试验在白血病、淋巴瘤等恶性肿瘤中取得了令人鼓舞的治疗效果；CAR修饰T细胞临床治疗也带来了挑战，比如脱靶效应、细胞因子风暴、移植物抗宿主病样损伤等。研究者正在通过安装人工基因调控系统、优化共刺激分子、筛选最佳治疗潜质的T细胞亚群来提高CAR修饰T细胞的有效性和安全性，相信随着研究的不段深入，基于CAR的免疫治疗新策略会给肿瘤患者带来新的希望。
以嵌合抗原受体（chimeric antigen receptor，CAR）修饰T细胞为基础的肿瘤过继细胞免疫治疗近年来取得了很大的进步，它赋予T细胞靶向杀伤活性，并可克服肿瘤局部免疫抑制微环境和打破宿主免疫耐受状态。CAR以单链抗体-共刺激分子-免疫受体酪氨酸活化基序的嵌合模式修饰T细胞显示出良好的抗肿瘤作用，Ⅰ/Ⅱ期临床试验在白血病、淋巴瘤等恶性肿瘤中取得了令人鼓舞的治疗效果；CAR修饰T细胞临床治疗也带来了挑战，比如脱靶效应、细胞因子风暴、移植物抗宿主病样损伤等。研究者正在通过安装人工基因调控系统、优化共刺激分子、筛选最佳治疗潜质的T细胞亚群来提高CAR修饰T细胞的有效性和安全性，相信随着研究的不段深入，基于CAR的免疫治疗新策略会给肿瘤患者带来新的希望。
2012, 19(6):652-655.
DOI: 10.3872/j.issn.1007-385X.2012.6.016
Abstract:
趋化因子受体7（CC chemokine receptor 7，CCR7），主要表达于树突状细胞、淋巴细胞和各种肿瘤细胞表面，在树突状细胞抗肿瘤免疫应答和促进肿瘤侵袭和淋巴转移过程中发挥着不容忽视的作用。一方面，CCR7使活化的成熟DC通过输入淋巴管进入淋巴结，引导负载抗原的（dendritic cell，DC）从肿瘤部位迁移至淋巴组织，在诱导DC的抗肿瘤免疫反应中起重要作用；另一方面，CCR7在多种肿瘤如乳腺癌、非小细胞肺癌、结肠癌、胃癌等中表达，而淋巴结中丰富的CCL21则能趋化CCR7阳性的肿瘤细胞向淋巴结转移，直接导致肿瘤的扩散。CCR7在免疫细胞和肿瘤细胞共同表达的这一特点决定了其很有可能成为DC疫苗免疫效果和DC功能评价，以及某些实体瘤淋巴结转移评价乃至治疗的新靶点。
趋化因子受体7（CC chemokine receptor 7，CCR7），主要表达于树突状细胞、淋巴细胞和各种肿瘤细胞表面，在树突状细胞抗肿瘤免疫应答和促进肿瘤侵袭和淋巴转移过程中发挥着不容忽视的作用。一方面，CCR7使活化的成熟DC通过输入淋巴管进入淋巴结，引导负载抗原的（dendritic cell，DC）从肿瘤部位迁移至淋巴组织，在诱导DC的抗肿瘤免疫反应中起重要作用；另一方面，CCR7在多种肿瘤如乳腺癌、非小细胞肺癌、结肠癌、胃癌等中表达，而淋巴结中丰富的CCL21则能趋化CCR7阳性的肿瘤细胞向淋巴结转移，直接导致肿瘤的扩散。CCR7在免疫细胞和肿瘤细胞共同表达的这一特点决定了其很有可能成为DC疫苗免疫效果和DC功能评价，以及某些实体瘤淋巴结转移评价乃至治疗的新靶点。
2012, 19(6):656-661.
DOI: 10.3872/j.issn.1007-385X.2012.6.017
Abstract:
幽门螺杆菌（Helicobacter pylori，Hp）是人类胃癌的Ⅰ类致癌原，Hp感染与胃癌的发生和预后密切相关。树突状细胞（dendritic cell，DC）是机体功能最强的专职抗原提呈细胞，可启动并调节免疫应答。胃癌组织中DC的状态及浸润程度与胃癌TNM分期和淋巴结转移密切相关。Hp阳性者胃黏膜中DC数量和活性高于Hp阴性者。近年来研究发现，Hp可诱导DC成熟，上调DC表面成熟标志分子如CD80、CD83、CD86和MHCⅡ等的表达，促进细胞因子IL-6、IL-8及IL-12等的分泌，但主要诱导DC分泌Th1 细胞因子，促使Th0细胞增殖分化为Th1细胞，介导细胞免疫反应，促进DC和效应T细胞产生IFN-γ，增强抗肿瘤活性。研究还显示，Hp对DC成熟状态和活化水平的影响与Hp刺激时间、Hp感染复数、Hp成分及Hp制备方法密切相关，Hp刺激DC成熟和活化的机制可能与MyD88和转录因子E2F1相关。
幽门螺杆菌（Helicobacter pylori，Hp）是人类胃癌的Ⅰ类致癌原，Hp感染与胃癌的发生和预后密切相关。树突状细胞（dendritic cell，DC）是机体功能最强的专职抗原提呈细胞，可启动并调节免疫应答。胃癌组织中DC的状态及浸润程度与胃癌TNM分期和淋巴结转移密切相关。Hp阳性者胃黏膜中DC数量和活性高于Hp阴性者。近年来研究发现，Hp可诱导DC成熟，上调DC表面成熟标志分子如CD80、CD83、CD86和MHCⅡ等的表达，促进细胞因子IL-6、IL-8及IL-12等的分泌，但主要诱导DC分泌Th1 细胞因子，促使Th0细胞增殖分化为Th1细胞，介导细胞免疫反应，促进DC和效应T细胞产生IFN-γ，增强抗肿瘤活性。研究还显示，Hp对DC成熟状态和活化水平的影响与Hp刺激时间、Hp感染复数、Hp成分及Hp制备方法密切相关，Hp刺激DC成熟和活化的机制可能与MyD88和转录因子E2F1相关。
2012, 19(6):662-667.
DOI: 10.3872/j.issn.1007-385X.2012.6.018
Abstract:
利妥昔单抗是针对B细胞表面标志CD20抗原的单克隆抗体，利妥昔单抗联合化疗显著改善了B细胞淋巴瘤患者的预后。但是仍有部分患者对利妥昔单抗治疗无效或在治疗有效后短期内复发，说明利妥昔单抗联合化疗不足以彻底清除淋巴瘤细胞，提示存在着一定的耐药性肿瘤细胞。补体依赖细胞毒作用（complement-dependent cytotoxicity，CDC）是利妥昔单抗对淋巴瘤细胞的主要杀伤机制之一，CDC作用通路中的任何一个环节异常都有可能影响利妥昔单抗的疗效。CD20抗原是利妥昔单抗发挥作用的基础，CD20抗原的表达强度、其编码基因的多态性以及其在细胞膜上的承载结构——脂质筏均可能影响CDC作用；此外，补体的基因多态性（如 C1q、CD11b）、血清补体水平及补体调节蛋白的水平均可能影响着CDC作用通路中的不同环节，从而影响利妥昔单抗作用的发挥。随着利妥昔单抗的广泛应用，对其耐药机制的研究日益深入。本文将对目前关于利妥昔单抗CDC作用通路中可能影响其疗效的主要因素进行综述。
利妥昔单抗是针对B细胞表面标志CD20抗原的单克隆抗体，利妥昔单抗联合化疗显著改善了B细胞淋巴瘤患者的预后。但是仍有部分患者对利妥昔单抗治疗无效或在治疗有效后短期内复发，说明利妥昔单抗联合化疗不足以彻底清除淋巴瘤细胞，提示存在着一定的耐药性肿瘤细胞。补体依赖细胞毒作用（complement-dependent cytotoxicity，CDC）是利妥昔单抗对淋巴瘤细胞的主要杀伤机制之一，CDC作用通路中的任何一个环节异常都有可能影响利妥昔单抗的疗效。CD20抗原是利妥昔单抗发挥作用的基础，CD20抗原的表达强度、其编码基因的多态性以及其在细胞膜上的承载结构——脂质筏均可能影响CDC作用；此外，补体的基因多态性（如 C1q、CD11b）、血清补体水平及补体调节蛋白的水平均可能影响着CDC作用通路中的不同环节，从而影响利妥昔单抗作用的发挥。随着利妥昔单抗的广泛应用，对其耐药机制的研究日益深入。本文将对目前关于利妥昔单抗CDC作用通路中可能影响其疗效的主要因素进行综述。
2012, 19(6):668-672.
DOI: 10.3872/j.issn.1007-385X.2012.6.019
Abstract:
肿瘤浸润性淋巴细胞（tumor infiltrating lymphocyte，TIL）是从肿瘤组织中分离出的CD4+、CD8+T细胞，在体外经白介素2（interleukin-2，IL-2）的刺激、活化、扩增后可应用于临床肿瘤过继细胞治疗（adoptive cell therapy，ACT）。为避免IL-2在扩增中的大量使用使得TIL中CD4+CD25+Treg数量增加所产生的免疫耐受现象，现在研究集中于改进TIL的体外扩增方法；研究显示，“年轻”型 TIL（young TIL）靶向肿瘤的特异性更高，故其是潜在的扩增对象。临床使用TIL过继治疗前需对肿瘤患者进行全身放疗处理；TIL过继治疗联合化疗药物（如环磷酰胺，氟达拉滨等）对自体淋巴清除（lymphodepletion）的肿瘤患者疗效显著，将成为以后肿瘤免疫治疗的主要方向；除化疗药物外，还可开发肿瘤疫苗、单克隆抗体等联合TIL过继治疗。本文主要介绍TIL培养体系、功能改进的研究以及TIL过继治疗联合化疗药物在临床恶性肿瘤治疗中的应用，讨论其可能存在的问题并展望未来的发展方向。
肿瘤浸润性淋巴细胞（tumor infiltrating lymphocyte，TIL）是从肿瘤组织中分离出的CD4+、CD8+T细胞，在体外经白介素2（interleukin-2，IL-2）的刺激、活化、扩增后可应用于临床肿瘤过继细胞治疗（adoptive cell therapy，ACT）。为避免IL-2在扩增中的大量使用使得TIL中CD4+CD25+Treg数量增加所产生的免疫耐受现象，现在研究集中于改进TIL的体外扩增方法；研究显示，“年轻”型 TIL（young TIL）靶向肿瘤的特异性更高，故其是潜在的扩增对象。临床使用TIL过继治疗前需对肿瘤患者进行全身放疗处理；TIL过继治疗联合化疗药物（如环磷酰胺，氟达拉滨等）对自体淋巴清除（lymphodepletion）的肿瘤患者疗效显著，将成为以后肿瘤免疫治疗的主要方向；除化疗药物外，还可开发肿瘤疫苗、单克隆抗体等联合TIL过继治疗。本文主要介绍TIL培养体系、功能改进的研究以及TIL过继治疗联合化疗药物在临床恶性肿瘤治疗中的应用，讨论其可能存在的问题并展望未来的发展方向。
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- 《中国肿瘤生物治疗杂志》
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Supported by:Beijing E-Tiller Technology Development Co., Ltd.