The identification of the origin and molecular characteristics of prostate cancer(PCa)has crucial implications for personalized treatment.The development of effective treatments for PCa has been limited;however,the re...The identification of the origin and molecular characteristics of prostate cancer(PCa)has crucial implications for personalized treatment.The development of effective treatments for PCa has been limited;however,the recent establishment of several transgenicmouse lines and/or xenografting models is better reflecting the disease in vivo.With appropriate models,valuable tools for elucidating the functions of specific genes have gone deep into prostate development and carcinogenesis.In the present review,we summarize a number of important PCa research models established in our laboratories(PSA-Cre-ERT2/PTEN transgenic mouse models,AP-OX model,tissue recombination-xenografting models and PDX models),which represent advances of translational models from transgenic mouse lines to human tumor xenografting.Better understanding of the developments of these models will offer new insights into tumor progression and may help explain the functional significance of genetic variations in PCa.Additionally,this understanding could lead to new modes for curing PCa based on their particular biological phenotypes.展开更多
AIM: To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral treatment.METHODS: We developed a stable S3-green fluorescence protein (GFP) c...AIM: To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral treatment.METHODS: We developed a stable S3-green fluorescence protein (GFP) cell line that replicated the GFP-tagged HCV sub-genomic RNA derived from a highly efficient JFH1 virus. S3-GFP replicon cell line was injected subcutaneously into γ-irradiated SCID mice. We showed that the S3-GFP replicon cell line formed human HCC xenografts in SCID mice. Cells were isolated from subcutaneous tumors and then serially passaged multiple times in SCID mice by culturing in growth medium supplemented with G-418. The mouse-adapted S3-GFP replicon cells were implanted subcutaneously and also into the liver of SCID mice via intrasplenic infusion to study the replication of HCV in the HCC xenografts. The tumor model was validated for antiviral testing after intraperitoneal injection of interferon-α (IFN-α). RESULTS: A highly tumorigenic S3-GFP replicon cell line was developed that formed subcutaneous tumors within 2 wk and diffuse liver metastasis within 4 wk in SCID mice. Replication of HCV in the subcutaneous and liver tumors was confirmed by cell colony assay, detection of the viral RNA by ribonuclease protection assay and real-time quantitative reverse transcription polymerase chain reaction. High-level replication of HCV sub-genomic RNA in the tumor could be visualized by GFP expression using fluorescence microscopy. IFN-α cleared HCV RNA replication in the subcutaneous tumors within 2 wk and 4 wk in the liver tumor model. CONCLUSION: A non-infectious mouse model allows us to study replication of HCV in subcutaneous and metastatic liver tumors. Clearance of HCV by IFN-α supports use of this model to test other anti-HCV drugs.展开更多
Boanmycin (bleomycin A6 . BM) . an antitumor antibiotic, was conjugated to monoclonal antibodies including R19, H 111 and CCT2. The immunoconjugates exhibited selective cytotoxicity to related target cells including c...Boanmycin (bleomycin A6 . BM) . an antitumor antibiotic, was conjugated to monoclonal antibodies including R19, H 111 and CCT2. The immunoconjugates exhibited selective cytotoxicity to related target cells including cecum cancer Hce-8693 cells, liver cancer BEL-7402 cells and leukemia CEM cells. They were highly effective against related human tumor xenografts in nude mice, and the inhibition rates by the conjugates were much higher than those by free BM. The inhibition rate by R19-BM conjugate against human cecum cancer xenografts reached 90%. BY immunoelectron microscopy, CCT2-BM conjugate showed specific binding and internalization in leukemia CEM cells. The results indicate that boanmycin-monoclonal antibody immunoconjugates are highly active both in vitro and in vivo.展开更多
Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor...Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor, normalsaline （NS） 100 μL/d], drug control group （did not burden tumor, rh-endostatin 400 μg/d）, model group （mice burdened tumor, NS 100 μL/d） and treatment group （mice burdened tumor, rh-endostatin 400 μg/d）, administration was given during d1-d28. The volume of tumor and the weight of mouse were measured before and after administration. The expression of CD34, MMP-2, MMP-9, HIF-la and VEGF in myocardium and tumor were detected by immunohistochemistry. The structure of vasculature was observed by immunoenzymatic double staining with CD34 and Masson. Results： The tumor volume increase of treatment group （48.18 mm3） was less than the model group （113.80 mm3）, the change of weight was not significant among the four groups. After treated with endotar, the expression of MMP-9 and VEGF in tumor were obviously down-regulated, but the same results was not found in MMP-2, HIF-la of tumor. MVD in tumor of treatment group decreased significantly compared with model group. Proportion of tumor vessels covered by collagen in treatment group increased compared with model group. However, MVD and microvasculature in myocardium did not change significantly. Conclusion： Rh-endostatin can decrease the expression of MMP-9, VEGF and MVD to inhibit growth of tumor and normalize micrangium in tumor but cannot weaken MMPs and MVD of mature micrangium in myocardium.展开更多
Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsat...Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsatisfactory. The utility of traditional cancer cell lines in translational research is limited by their poor correspondence to the genomic alterations and expression profiles that occur in actual patient tumors. In the last decade, increasing attention has been given to patient-derived tumor xenografts(PDTXs), which can faithfully recapitulate the histopathology, molecular characteristics, and therapeutic responses of the patient's tumor. However, the widespread development and utilization of PDTXs is restricted by factors such as the timeframe of establishment, lymphoma transformation during passaging, the immunodeficient microenvironment, and pharmacokinetic differences between mice and humans. In this review, we summarize the establishment and characterization of PDTX models for gastric cancer(GC). We then weigh the advantages and limitations of PDTXs when used to evaluate novel compounds, identify effective biomarkers, demonstrate resistance mechanisms, and predict clinical outcomes.展开更多
目的:基于肿瘤蛋白53(tumor protein 53,p53)/溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11/xCT)/谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)通路探讨疏肝祛瘀解毒方(SGQYJDF)诱导铁死亡抑制裸鼠肝癌增殖...目的:基于肿瘤蛋白53(tumor protein 53,p53)/溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11/xCT)/谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)通路探讨疏肝祛瘀解毒方(SGQYJDF)诱导铁死亡抑制裸鼠肝癌增殖。方法:通过将人肝癌细胞株SK-Hep-1注射于裸鼠右腋皮下,建立异种皮下移植瘤模型,成模后分为模型对照组、SGQYJDF低、中、高剂量组和SGQYJDF中剂量联合Sorafenib组,按分组连续灌胃14 d,期间观察裸鼠肿瘤体积;灌胃14 d后,测量肿瘤质量并计算生长抑制率,采用HE染色观察各组肿瘤组织病理学变化;比色法检测各组肿瘤组织内丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH)和亚铁离子(ferrous ions,Fe^(2+))水平;免疫组织化学法(immunohistochemistry,IHC)检测各组肿瘤组织内增殖标志物(Kiel 67 antigen,Ki-67)及GPX4表达;免疫荧光法(immunofluorescence,IF)检测肿瘤组织内p53和xCT的表达;Western blot法检测p53、xCT和GPX4的表达水平。结果:(1)在肿瘤增殖方面,通过观察裸鼠肿瘤体积及质量并计算生长抑制率,与模型对照组比较,SGQYJDF能够呈剂量相关性的降低肿瘤体积(P<0.01),抑制肿瘤质量增长(P<0.01),各组肿瘤组织均未见明显浸润,同时通过IHC观察计算肿瘤组织内Ki-67阳性细胞率可知,与模型对照组比较,SGQYJDF能够呈剂量相关性降低肿瘤组织Ki-67阳性细胞率(P<0.01),抑制其增殖能力;(2)在铁死亡生化指标方面,通过检测计算相对含量,与模型对照组比较,SGQYJDF能够呈剂量依赖性提高肿瘤组织内Fe^(2+)含量和MDA含量,同时降低GSH的含量(P<0.01);(3)在蛋白表达方面,通过IHC、IF与Western blot实验,与模型对照组比较,SGQYJDF能够呈剂量相关性地上调p53(P<0.05)的表达,同时抑制xCT(P<0.05)和GPX4(P<0.01)的表达。此外,在实验结果中,我们发现人体等效量的SGQYJDF与Sorafenib联用,其效应高于两倍人体等效量的SGQYJDF。结论:提示SGQYJDF可能通过上调裸鼠皮下移植瘤p53的表达、抑制xCT和GPX4的表达从而诱导其发生铁死亡,抑制其增殖。展开更多
Patient derived xenograft (PDX) is defined as a growth of patients’ tumor in the xenograft setting. The evolution of cancer model in animal has a century old history. The most single reason that exerted the pressure ...Patient derived xenograft (PDX) is defined as a growth of patients’ tumor in the xenograft setting. The evolution of cancer model in animal has a century old history. The most single reason that exerted the pressure on the traditional animal model of cancer to evolve to PDX is that the traditional models have not delivered as expected and traditional models have not predicted clinical success. In spite of well above 50 drugs developed and approved for oncology over the last several decades, there remains a nirking paucity of clinical success as a reminder that this war on cancer riding on the animal model is far from won. In a backbreaking attempt to analyze the failure, the limitation of the “model” system appeared to be the most rational cause of this shortcoming. It was more of a failure to test a drug rather than a failure to make a drug that stunted our collective growth and success in cancer research. PDX is the product of this age-old failure and its fitness is currently tested in virtually all organ-type solid tumors. This review will present and appraise PDX model in the context of its evolution, its future promise, its limitations and more specifically, the current content of PDX in different solid tumors including breast, lung, colorectal, prostrate, GBM, pancreatic, hepatocellular carcinoma and melanoma.展开更多
基金The study was supported by funding from the NIDDK(DK098277)to Douglas W.Strandfrom the National Nature Scientific Foundation of China(NSFC No.81372772)to Dr.Ming Jiang,the Scientific Research Foundation for Jiangsu Specially-Appointed Professor(Sujiaoshi[2012]No.34),to Dr.Ming Jiang,Department of Education in Jiangsu Province,China and the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),China.
文摘The identification of the origin and molecular characteristics of prostate cancer(PCa)has crucial implications for personalized treatment.The development of effective treatments for PCa has been limited;however,the recent establishment of several transgenicmouse lines and/or xenografting models is better reflecting the disease in vivo.With appropriate models,valuable tools for elucidating the functions of specific genes have gone deep into prostate development and carcinogenesis.In the present review,we summarize a number of important PCa research models established in our laboratories(PSA-Cre-ERT2/PTEN transgenic mouse models,AP-OX model,tissue recombination-xenografting models and PDX models),which represent advances of translational models from transgenic mouse lines to human tumor xenografting.Better understanding of the developments of these models will offer new insights into tumor progression and may help explain the functional significance of genetic variations in PCa.Additionally,this understanding could lead to new modes for curing PCa based on their particular biological phenotypes.
基金Supported by Funds received from the National Cancer Institute (CA127481,CA129776)Geyer Foundation,New York,Louisiana Cancer Research Consortium and Tulane Cancer Center
文摘AIM: To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral treatment.METHODS: We developed a stable S3-green fluorescence protein (GFP) cell line that replicated the GFP-tagged HCV sub-genomic RNA derived from a highly efficient JFH1 virus. S3-GFP replicon cell line was injected subcutaneously into γ-irradiated SCID mice. We showed that the S3-GFP replicon cell line formed human HCC xenografts in SCID mice. Cells were isolated from subcutaneous tumors and then serially passaged multiple times in SCID mice by culturing in growth medium supplemented with G-418. The mouse-adapted S3-GFP replicon cells were implanted subcutaneously and also into the liver of SCID mice via intrasplenic infusion to study the replication of HCV in the HCC xenografts. The tumor model was validated for antiviral testing after intraperitoneal injection of interferon-α (IFN-α). RESULTS: A highly tumorigenic S3-GFP replicon cell line was developed that formed subcutaneous tumors within 2 wk and diffuse liver metastasis within 4 wk in SCID mice. Replication of HCV in the subcutaneous and liver tumors was confirmed by cell colony assay, detection of the viral RNA by ribonuclease protection assay and real-time quantitative reverse transcription polymerase chain reaction. High-level replication of HCV sub-genomic RNA in the tumor could be visualized by GFP expression using fluorescence microscopy. IFN-α cleared HCV RNA replication in the subcutaneous tumors within 2 wk and 4 wk in the liver tumor model. CONCLUSION: A non-infectious mouse model allows us to study replication of HCV in subcutaneous and metastatic liver tumors. Clearance of HCV by IFN-α supports use of this model to test other anti-HCV drugs.
文摘Boanmycin (bleomycin A6 . BM) . an antitumor antibiotic, was conjugated to monoclonal antibodies including R19, H 111 and CCT2. The immunoconjugates exhibited selective cytotoxicity to related target cells including cecum cancer Hce-8693 cells, liver cancer BEL-7402 cells and leukemia CEM cells. They were highly effective against related human tumor xenografts in nude mice, and the inhibition rates by the conjugates were much higher than those by free BM. The inhibition rate by R19-BM conjugate against human cecum cancer xenografts reached 90%. BY immunoelectron microscopy, CCT2-BM conjugate showed specific binding and internalization in leukemia CEM cells. The results indicate that boanmycin-monoclonal antibody immunoconjugates are highly active both in vitro and in vivo.
基金Supported by grants from the Tianjin Medical University Research Projects(2009KY37)CSCO Vascular Target Fund Research Projects of Roche(Y-X2011-001)
文摘Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor, normalsaline （NS） 100 μL/d], drug control group （did not burden tumor, rh-endostatin 400 μg/d）, model group （mice burdened tumor, NS 100 μL/d） and treatment group （mice burdened tumor, rh-endostatin 400 μg/d）, administration was given during d1-d28. The volume of tumor and the weight of mouse were measured before and after administration. The expression of CD34, MMP-2, MMP-9, HIF-la and VEGF in myocardium and tumor were detected by immunohistochemistry. The structure of vasculature was observed by immunoenzymatic double staining with CD34 and Masson. Results： The tumor volume increase of treatment group （48.18 mm3） was less than the model group （113.80 mm3）, the change of weight was not significant among the four groups. After treated with endotar, the expression of MMP-9 and VEGF in tumor were obviously down-regulated, but the same results was not found in MMP-2, HIF-la of tumor. MVD in tumor of treatment group decreased significantly compared with model group. Proportion of tumor vessels covered by collagen in treatment group increased compared with model group. However, MVD and microvasculature in myocardium did not change significantly. Conclusion： Rh-endostatin can decrease the expression of MMP-9, VEGF and MVD to inhibit growth of tumor and normalize micrangium in tumor but cannot weaken MMPs and MVD of mature micrangium in myocardium.
文摘Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsatisfactory. The utility of traditional cancer cell lines in translational research is limited by their poor correspondence to the genomic alterations and expression profiles that occur in actual patient tumors. In the last decade, increasing attention has been given to patient-derived tumor xenografts(PDTXs), which can faithfully recapitulate the histopathology, molecular characteristics, and therapeutic responses of the patient's tumor. However, the widespread development and utilization of PDTXs is restricted by factors such as the timeframe of establishment, lymphoma transformation during passaging, the immunodeficient microenvironment, and pharmacokinetic differences between mice and humans. In this review, we summarize the establishment and characterization of PDTX models for gastric cancer(GC). We then weigh the advantages and limitations of PDTXs when used to evaluate novel compounds, identify effective biomarkers, demonstrate resistance mechanisms, and predict clinical outcomes.
文摘Patient derived xenograft (PDX) is defined as a growth of patients’ tumor in the xenograft setting. The evolution of cancer model in animal has a century old history. The most single reason that exerted the pressure on the traditional animal model of cancer to evolve to PDX is that the traditional models have not delivered as expected and traditional models have not predicted clinical success. In spite of well above 50 drugs developed and approved for oncology over the last several decades, there remains a nirking paucity of clinical success as a reminder that this war on cancer riding on the animal model is far from won. In a backbreaking attempt to analyze the failure, the limitation of the “model” system appeared to be the most rational cause of this shortcoming. It was more of a failure to test a drug rather than a failure to make a drug that stunted our collective growth and success in cancer research. PDX is the product of this age-old failure and its fitness is currently tested in virtually all organ-type solid tumors. This review will present and appraise PDX model in the context of its evolution, its future promise, its limitations and more specifically, the current content of PDX in different solid tumors including breast, lung, colorectal, prostrate, GBM, pancreatic, hepatocellular carcinoma and melanoma.
