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ABSTRACT: Abstract Colorectal cancer is an aggressive malignancy with a high mortality rate; however, effective therapies are currently lacking. Cancer-targeting gene-virotherapy (CTGVT) has been proposed to be a promising strategy for cancer therapy. The purpose of this study was to investigate the antitumor activity of the oncolytic adenovirus harboring Lipocalin-2 (ZD55-Lipocalin-2, an example of CTGVT) in colorectal cancer. ZD55-Lipocalin-2 was generated by deleting E1B55-KD and inserting the Lipocalin-2 gene. Its cytopathic effects and cell growth inhibition were detected in vitro, and antitumor effects were examined in a nude mouse model of human colorectal cancer xenografts. Results showed that ZD55-Lipocalin-2 significantly inhibited the colorectal cancer growth by selective cytolysis, inducing apoptosis and decreasing the microvessel density in tumors. The anticancer potential of ZD55-Lipocalin-2 showed stronger than that of the isolated Lipocalin-2 gene therapy or isolated ZD55 oncolytic adenovirus therapy. ZD55-Lipocalin-2 may serve as a potential anticancer agent for colorectal cancer treatment.
Cancer Biotherapy & Radiopharmaceuticals 03/2013; · 1.44 Impact Factor
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ABSTRACT: The occurrence of multiple primary malignancies (MPM) in one patient is a rare but increasingly frequent event, partly due to medical advances in diagnosis and therapy. A number of theories have been proposed to explain MPM, but none have been proven. A key risk factor appears to be family history. We present the case of a 43-year-old male with multiple cancers who was first admitted to the hospital for an undifferentiated pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma (pG2T2bN0Mx stage III) of the right scapula in May 2009. The patient underwent three tumor resections in situ due to tumor recurrence. During the period of chemotherapy and radiotherapy, computed tomography (CT) revealed a 10x10-cm enhancing soft mass of the ascending colon, which was diagnosed as mucinous adenocarcinoma in a pathological report. Laboratory data showed elevated serum levels of carcinoembryonic antigen (CEA, 20.0 μg/l; normal range, 0.0-10.0 μg/l). Certain family members of the patient had been diagnosed with endometrial, colon and pancreatic cancer. None of the family had a smoking history or presented with familial adenomatous polyposis (FAP). The patient with hereditary non-polyposis colorectal cancer (HNPCC), whose family fulfilled Amsterdam Criteria I (AC I), has remained free of disease for 15 months. Family history may be a key risk factor for MPM and HNPCC, the detailed molecular mechanisms of which remain to be elucidated. This case report with an investigation of family history may improve the clinical recognition of HNPCC and MPM.
Oncology letters 11/2012; 4(5):931-934. · 0.11 Impact Factor
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ABSTRACT: To investigate the effects of lentivirus mediated siRNA targeting human metastasis suppressor 1 (MTSS1, MIM-B gene) gene on the invasive and metastatic potentials of hepatocellular carcinoma (HCC) MHCC97H cells.
The siRNA targeting MTSS1 was cloned into one lentivirus work vector. The work vector and three package plasmids were co-transfected into 293T cells with the help of lipefeetamine 2000. Lentivirus was collected in 72 hours and was added to the cultured MHCC97H cells. The total cell MIM-B mRNA and MIM-B protein were extracted and underwent real-time PCR and western-blot test respectively. Boden chamber assay was used to evaluate the invasive potential of MHCC97H cells. Gelatin zymography was used to detect matrix metalloproteinase-2 (MMP2) activity. Metastatic human HCC nude mice models were established by orthotopic implantation with a high metastatic potential human HCC cell line MHCC97H. Twenty-four nude mice bearing orthotopic xenografts were randomized into black control group, Lenti-GFP group and intervention group (Lenti-MTSS1 group) 14 days after orthotopic implantation (8 per group). The ultrasound-guided multi-point injection was performed on mice with borate buffered saline, Lenti-GFP and Lenti-MTSS1 respectively. Mice were sacrificed on day 35 for the examination of pulmonary metastasis. The SPSS 13.0 soft ware was applied to data analysis.
The small interfering RNA targeting MTSS1 was constructed successfully with a transfection efficiency of 97.0%, which produced a marked inhibition of invasive ability of MHCC97H cells through Matrigel, being 37.9+/-4.4, 37.4+/-5.3 and 26.6+/-4.6 in the black control group, Lenti-GFP group and Lenti-MTSS1 group (F = 26.695, P value is less than 0.01), respectively. MIM-B expression and MMP2 activity of intervention group were also significantly down-regulated as compared to the control group. The results of in vivo studies showed that the numbers of lung metastatic nodules were 6.5+/-2.6, 6.4+/-2.7 and 3.8+/-1.3 in the black control group, Lenti-GFP group and intervention group respectively with significant statistical difference (F = 3.637, P value is less than 0.05), accorded with tumor tissue MIM-B mRNA expression of 0.39+/-0.19, 0.38+/-0.10 and 0.16+/-0.11 respectively (F = 11.644, P value is less than 0.01) when comparison was made between control group and therapy group.
Small interfering RNA mediated by lentivirus inhibited MIM-B expression and resulted in inhibition of the invasive and metastatic potentials of MHCC97H cells, which may attributed, in part, the down regulation of MMP2 activity, and thus may provide a new molecular targeted therapy for HCC patients in the future.
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 12/2010; 18(12):915-9.
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ABSTRACT: Liver resection is a widely accepted treatment for hepatocellular carcinoma (HCC). Our previous clinical study showed that the rate of palliative resection was 34.0% (1958-2008, 2754 of 8107). However, the influence of palliative resection on tumor metastasis remains controversial. The present study was conducted to evaluate the effect of palliative resection on residual HCC and to explore interventional approaches.
Palliative resection was done in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Tumor growth, invasion, metastasis, lifespan, and some molecular alterations were examined in vivo and in vitro. Mice that underwent palliative resection were treated with the Chinese herbal compound "Songyou Yin," interferon-alfa-1b (IFN-α), or their combination to assess their effects.
In the palliative resection group, the number of lung metastatic nodules increased markedly as compared to the sham operation group (14.3 ± 4.7 versus 8.7 ± 3.6, P < 0.05); tumor matrix metalloproteinase 2 (MMP2) activity was elevated by 1.4-fold, with up-regulation of vascular endothelial growth factor (VEGF) and down-regulation of tissue inhibitor of metalloproteinase 2 (TIMP2). The sera of mice undergoing palliative resection significantly enhanced cell invasiveness by 1.3-fold. After treatment, tumor volume was 1205.2 ± 581.3 mm3, 724.9 ± 337.6 mm3, 507.6 ± 367.0 mm3, and 245.3 ± 181.2 mm3 in the control, "Songyou Yin," IFN-α, and combination groups, respectively. The combined therapy noticeably decreased the MMP2/TIMP2 ratio and prolonged the lifespan by 42.2%. Moreover, a significant (P < 0.001) reduction of microvessel density was found: 43.6 ± 8.5, 34.5 ± 5.9, 23.5 ± 5.6, and 18.2 ± 8.0 in the control and treatment groups, respectively.
Palliative resection-stimulated HCC metastasis may occur, in part, by up-regulation of VEGF and MMP2/TIMP2. "Songyou Yin" reinforced the ability of IFN-α to inhibit the metastasis-enhancing potential induced by palliative resection, which indicated its potential postoperative use in patients with HCC.
BMC Cancer 10/2010; 10:580. · 3.01 Impact Factor
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ABSTRACT: To investigate the effects of palliative liver resection on metastatic potential and its gene function net of residual hepatocellular carcinoma (HCC) in nude mice model.
Orthotopic HCC model was established by implantation of human HCC cell line MHCC97H xenografts with a high metastatic potential. Thirty-six HCC-bearing nude mice were randomized into 3 groups at 14 days post-operation, including palliative resection group (HCC samples A, B), control group 1 (sham operation, HCC sample C1) and control group 2 (without intervention, HCC sample C2). Six mice in each group were sacrificed by cervical dislocation at 14 days after palliative resection. Oligo tumor metastasis microarray and GEArray expression analysis suite software were employed for gene analysis. The methods of support vector machine (SVM), gene significance analysis and gene correlation degree analysis were used to search the markers capable of differentiating the metastatic potential of HCC. Gene function net was constructed based on special gene clustering analysis and multi-dimensional scale. Real-time PCR was applied to detect the mRNA expression. The remaining mice were sacrificed at 35 days after palliative resection for the examination of pulmonary metastasis. SAS 8.2 software was used for statistical analysis.
Gene analysis showed that for different gene expression among groups, the density of gene net in palliative group (B, 0.0670) were higher than those in control groups (A, 0.0145; C1, 0.0210; C2, 0.0146), the condensation degree of gene net in residual HCC (B, 0.1940) was higher than that in its own control group (A, 0.0098). Human gene metastasis suppressor 1 (MTSS1) that encodes a protein of missing in metastasis B (MIM-B) was situated in the central position of gene function net of residual HCC. The relative MIM-B mRNA expression examined by Real-time PCR was significantly up-regulated in residual HCC (B, 0.283 +/- 0.023) as comparison was made among groups (A, 0.142 +/- 0.018; C1, 0.177 +/- 0.054; C2, 0.156 +/- 0.017, all P < 0.05). The number of lung metastatic nodules in the palliative group (14.3 +/- 4.7) was more than that in the sham group (8.7 +/- 3.6) at 35 days post-resection (P < 0.01).
Palliative liver resection enhances the pulmonary metastatic potential of residual HCC in nude mice model. MIM-B may be one of the key therapeutic targets for HCC patients.
Zhonghua yi xue za zhi 05/2010; 90(18):1278-82.
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ABSTRACT: Chinese herbs have become a focus of interest in cancer treatment. This study evaluates the effect of the herbal compound extract "Songyou Yin" (containing Salvia miltiorrhiza Bge.-danshen and other four herbs) on hepatocellular carcinoma (HCC).
Human HCC cell line MHCC97H with high-metastatic potential was employed for in vitro study. In vivo study was conducted in nude mice bearing HCC orthotopic xenograft with MHCC97H.
In vitro, "Songyou Yin" caused dramatic attenuation of tumor proliferation by induction of apoptosis that was associated with caspase-3 activation, and inhibit invasiveness of MHCC97H via reducing matrix metalloproteinase-2 (MMP2) activity. In vivo, "Songyou Yin" minimized cancer-related body weight loss of mice bearing tumors without distinct toxicity, and inhibited tumor growth with stepwise increased dosage of "Songyou Yin" and accorded with the expression of proliferating cell nuclear antigen. Moreover, "Songyou Yin" inhibited tumor growth was associated with an increased TUNEL-positive apoptosis as well as a decreased microvessel density and vascular endothelial growth factor (VEGF) abundance, and inhibited tumor invasion via down-regulation of MMP2. The lung metastatic extent was decreased (p < 0.01, compared with control). The life span of nude mice bearing xenografts was 75.0 +/- 3.9 days in "Songyou Yin" group, whereas it was 52.0 +/- 2.3 days in the control (p < 0.001).
Nontoxic herbal compound extract "Songyou Yin" inhibited tumor growth and prolonged survival, via inducing apoptosis and down-regulation of MMP2 and VEGF, which indicated its potential use in patients with advanced HCC.
Journal of Cancer Research and Clinical Oncology 03/2009; 135(9):1245-55. · 2.56 Impact Factor
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Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 05/2008; 16(4):309-10.
