骨髓间质干细胞在肿瘤进展和肿瘤微环境中的作用及机制
|
摘要
目的：骨髓间质干细胞(mesenchymal stem cells, MSCs)与肿瘤细胞共同接种或不同部位接种均能促进裸鼠体内肿瘤发生及肿瘤生长明显加快,然而其确切机制并不清楚。本研究旨在探讨MSCs在肿瘤微环境中的作用及促进肿瘤发生、发展的机制,为骨髓MSC在肿瘤生长中的作用提供证据,为基于MSC的肿瘤靶向治疗提供新的靶位。
方法：采用SGC-7901胃癌细胞株与人骨髓MSCs (hMSCs)培养上清液(hMSCs-CM)或hMSCs来源的囊泡(exosomes)共培养48h后,取预处理的SGC-7901细胞以1×106接种于BALB/c裸鼠皮下观察致瘤情况。同时设立SGC-7901与hMSCs混合接种组及SGC-7901细胞单独接种组做为对照。采用MTT法检测hMSCs-CM体外处理SGC-7901细胞前后的增殖作用。通过vWF免疫组织化学染色及核磁共振(MR)分析肿瘤组织的血管分布。RT-PCR及ELISA检测hMSCs-CM作用后SGC-7901细胞VEGF的mRNA和蛋白水平表达,并采用鸡胚绒毛膜尿囊试验(CAM)分析血管新生能力。全基因表达谱芯片及Western-blot检测肿瘤细胞经MSC处理前后ERK1/2、RhoA-GTP活性检测,分析hMSCs处理肿瘤细胞前后的基因表达谱及信号通路改变。采用“纤维蛋白原-凝血酶法”建立人胃癌组织原位移植模型,并从原位移植模型胃癌组织及临床胃癌组织中分离出胃癌MSCs (GC-MSCs)。体外肿瘤组织或SGC-7901细胞与hMSCs Transwell共培养,观察hMSCs向肿瘤相关成纤维母细胞(TAFs)的转化。
结果：在不需要hMSCs长期存在或与肿瘤细胞直接接触的情况下,仅hMSC-CM预处理肿瘤细胞即可产生与hMSCs共接种同样的效果,即导致肿瘤体内生长加快,而且证实这种作用主要是由MSCs分泌可溶性细胞因子所导致的。hMSC-CM预处理肿瘤细胞致瘤组织与未处理组相比新生血管更加丰富,VEGF及基因检测表明hMSC-CM预处理肿瘤细胞VEGF在mRNA及蛋白水平上均显著增高,且其基因表达谱也有很大的改变。SGC-7901细胞经hMSCs-CM处理后N-cadherin、slug、snail等基因表达明显增强,而E-cadherin表达降低,其体内致瘤组织α-SMA表达增高,结果表明hMSCs-CMs可诱导肿瘤细胞上皮-间质化转变(epithelial-mesenchymal transition, EMT)。hMSCs来源的exosomes与肿瘤细胞共接种或体外预处理均可导致肿瘤体内生长加快,肿瘤组织α-SMA、VEGF、CXCR4、PCNA表达及血管密度增加,但是hMSCs来源的exosomes体外对肿瘤细胞的增殖没有明显的促进作用,可导致肿瘤细胞ERK的短暂活化及VEGF和CXCR4基因表达增强,并对exosomes的作用浓度呈剂量依赖效应。在20例临床胃癌组织标本中分离得到13例胃癌间质干细胞(GC-MSCs), GC-MSCs的生物学特性包括形态、表面标志、特异基因表达及多向分化潜能均与骨髓MSCs相似。本研究还成功建立了裸鼠胃癌原位移植模型,其致瘤率为100%,并从原位移植瘤中分离得到MSCs。体外肿瘤细胞或肿瘤组织作用骨髓MSCs一定时间后MSCs可向TAFs转化,表达TAF的特异标志如α-SMA、vimetin等,且具有体内促进肿瘤细胞生长能力,表明MSC是肿瘤微环境的主要成分,对肿瘤的生长起重要作用。
结论：骨髓MSCs分泌信号分子活化肿瘤细胞促进其VEGF自分泌增强及改变肿瘤细胞基因表达,诱导肿瘤细胞EMT发生及肿瘤血管形成,促进肿瘤细胞体内生长及迁移能力增强,并且首次发现MSCs来源的exosomes能促使肿瘤细胞体内生长明显加快,这为MSCs体内促进肿瘤细胞生长提供了一个新的机制,exosomes介导的细胞间的相互作用可成为肿瘤治疗的新靶点。GC-MSCs的分离培养及肿瘤微环境诱导下骨髓MSCs向TAF转化表明MSC是肿瘤微环境的组成部分,骨髓MSCs是TAFs的重要来源,这为骨髓MSCs在肿瘤发生、发展中的作用及肿瘤靶向治疗提供了实验依据。
Objective:Mesenchymal stem cells (MSCs) were injected as cell mixture with tumor cells or were injected separately at different anatomic sites from the site of tumor injection can significantly enhance the growth of tumor xenograft in BALB/C nude mouse model, but the exact mechanism remains unclear. The aim of this study is to investigate the effect of MSCs on tumor microenvironment and the mechanism of MSCs on tumor initiation and progression. It will provide the new evidence that MSCs exert the tumor promoting function and provide a new target of tumor therapy based on MSC.
Methods:We treated SGC-7901 gastric cancer line cells with hMSC-conditioned medium (hMSC-CM) or hMSC derived exosomes for 48 hours, followed by subcutaneously injection of the treated SGC-7901 cells (1x106) into BALB/c nude mice for the development of tumor xenograft. We also injected untreated SGC-7901 cells alone or co-injected with hMSC as control group. We determine in vitro proliferation index of SGC-7901 tumor cells before and after hMSC-CM treatment in culture using MTT assay. We set out to quantitative measure the presence of blood vessels by using immunostaining of vWF and Magnetic Resonance (MR) angiography was performed for analyzing tumor vascularity. We detected the effect hMSC secreted molecules on the expression of VEGF at both mRNA and protein levels in SGC-7901 cells by RT-PCR and ELISA assay, and to test neovascularization functionally in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis observation. The activation of ERK1/2 or RhoA-GTP were performed for gene expression profile analysis on hMSC-CM treated and untreated cells by gene chip and western bolt assay.We established nude mouse orthotopic transplantation models of human stomach cancer constructed using intact tumor tissue by "Fibrinogen-thrombin" paste technique. And gastric cancer-derived MSC-like cells (hGC-MSCs) were isolated from gastric cancer tissue samples. We treated hMSCs with SGC-7901 cells or gastric cancer tissue in vitro to observe whether hMSCs differentiate into tumor associated fibroblast (TAF).
Results:Our results suggest that physical and continuous presence or interaction of MSCs with tumor cell is not required for enhanced tumor growth. Instead, one dose of pretreatment of tumor cells with hMSC conditioned-media is sufficient to recapitulate hMSC co-injection and the hMSCs secreted soluble factors are the major effort if not all tumor growth-promoting potential.The tumor tissue section exhibited a much more robust neovasculization in the xenograft derived from hMSC-CM pretreated tumor cells contrasting to that of untreated control tumor graft. Our data clearly demonstrated that signaling molecules secreted by hMSCs strongly activate VEGF expression of tumor cells at both mRNA and protein levels and the drastic ongoing activation pathways in these tumor cells upon the exposure to hMSC-CM leading to profound alteration in gene expression profiles of the tumor cells. After treatment with hMSCs-CM, the gene expression of SGC-7901 cell for N-cadherin,slug,snail was increased,but the expression of E-cadherin was decreased. The tumor tissue expressed stronger a-SMA in vivo. Our results showed that hMSCs-CM can induced epithelial-mesenchymal transition(EMT) for tumor cell. MSC-exosomes co-injected with tumor cell or pretreatment in vitro can promoted tumor growth, increased the expression of a-SMA、VEGF、CXCR4、PCNA and blood vessels density in tumor tissue. However, the MSC-exosomes did not induce any significant increase in tumor cell proliferation in vitro but a transient activation of ERK and enhanced expression of VEGF and CXCR4 genes were observed. The gastric cancer-derived MSC-like cells (hGC-MSCs) were isolated from 13 out of 20 cancer tissue samples. Their characteristics, including morphology, surface antigens, specific gene expression, and differentiation potential, were similar to those of MSCs derived from human bone marrow (hBM-MSCs). The nude mouse orthotopic transplantation model of human stomach cancer was constructed and 100% successful tumor-take rate was obtained in the model and we have succeed isolated MSCs from the nude mouse orthotopic transplantation model tissue.
After treatment with tumor cell or tumor tissue in vitro, hBM-MSCs may be differentiate into TAF, also they can expression the special mark of TAFs, such as a-SMA,vimetin. Our findings suggest that MSCs are components of the tumor microenvironment, which can promote tumor growth.
Conclusions:In this study, we show that through the action of secreted VEGF, MSCs potentiate tumor cells by activating angiogenic program as well as by altering the expression profile of a broad range of genes. These cells exhibit the ability to induced EMT or neovascularization for tumor. It also can promote tumor cell growth and the ability of migration.To our knowledge, it's the first report to present that MSC-exosomes had a significant acceleration effect on tumor growth in vivo, which offers a new mechanism responsible for the roles of MSCs in promoting tumor growth in vivo and the exosomes-meidated cell-cell interaction may be a new tumor therapeutic target. The existence of MSC-like cells in gastric cancer tissues suggests that MSC is the portion of tumor microenvironment, and the MSCs may be differentiate into TAF under tumor microenvironment in vitro. Taken together, these data suggest that hMSCs are a source of TAFs. This provides an experimental foundation for investigating the role of hMSCs in the initiation and progression of cancers and it may be a potential targets for cancer therapy.
方法：采用SGC-7901胃癌细胞株与人骨髓MSCs (hMSCs)培养上清液(hMSCs-CM)或hMSCs来源的囊泡(exosomes)共培养48h后,取预处理的SGC-7901细胞以1×106接种于BALB/c裸鼠皮下观察致瘤情况。同时设立SGC-7901与hMSCs混合接种组及SGC-7901细胞单独接种组做为对照。采用MTT法检测hMSCs-CM体外处理SGC-7901细胞前后的增殖作用。通过vWF免疫组织化学染色及核磁共振(MR)分析肿瘤组织的血管分布。RT-PCR及ELISA检测hMSCs-CM作用后SGC-7901细胞VEGF的mRNA和蛋白水平表达,并采用鸡胚绒毛膜尿囊试验(CAM)分析血管新生能力。全基因表达谱芯片及Western-blot检测肿瘤细胞经MSC处理前后ERK1/2、RhoA-GTP活性检测,分析hMSCs处理肿瘤细胞前后的基因表达谱及信号通路改变。采用“纤维蛋白原-凝血酶法”建立人胃癌组织原位移植模型,并从原位移植模型胃癌组织及临床胃癌组织中分离出胃癌MSCs (GC-MSCs)。体外肿瘤组织或SGC-7901细胞与hMSCs Transwell共培养,观察hMSCs向肿瘤相关成纤维母细胞(TAFs)的转化。
结果：在不需要hMSCs长期存在或与肿瘤细胞直接接触的情况下,仅hMSC-CM预处理肿瘤细胞即可产生与hMSCs共接种同样的效果,即导致肿瘤体内生长加快,而且证实这种作用主要是由MSCs分泌可溶性细胞因子所导致的。hMSC-CM预处理肿瘤细胞致瘤组织与未处理组相比新生血管更加丰富,VEGF及基因检测表明hMSC-CM预处理肿瘤细胞VEGF在mRNA及蛋白水平上均显著增高,且其基因表达谱也有很大的改变。SGC-7901细胞经hMSCs-CM处理后N-cadherin、slug、snail等基因表达明显增强,而E-cadherin表达降低,其体内致瘤组织α-SMA表达增高,结果表明hMSCs-CMs可诱导肿瘤细胞上皮-间质化转变(epithelial-mesenchymal transition, EMT)。hMSCs来源的exosomes与肿瘤细胞共接种或体外预处理均可导致肿瘤体内生长加快,肿瘤组织α-SMA、VEGF、CXCR4、PCNA表达及血管密度增加,但是hMSCs来源的exosomes体外对肿瘤细胞的增殖没有明显的促进作用,可导致肿瘤细胞ERK的短暂活化及VEGF和CXCR4基因表达增强,并对exosomes的作用浓度呈剂量依赖效应。在20例临床胃癌组织标本中分离得到13例胃癌间质干细胞(GC-MSCs), GC-MSCs的生物学特性包括形态、表面标志、特异基因表达及多向分化潜能均与骨髓MSCs相似。本研究还成功建立了裸鼠胃癌原位移植模型,其致瘤率为100%,并从原位移植瘤中分离得到MSCs。体外肿瘤细胞或肿瘤组织作用骨髓MSCs一定时间后MSCs可向TAFs转化,表达TAF的特异标志如α-SMA、vimetin等,且具有体内促进肿瘤细胞生长能力,表明MSC是肿瘤微环境的主要成分,对肿瘤的生长起重要作用。
结论：骨髓MSCs分泌信号分子活化肿瘤细胞促进其VEGF自分泌增强及改变肿瘤细胞基因表达,诱导肿瘤细胞EMT发生及肿瘤血管形成,促进肿瘤细胞体内生长及迁移能力增强,并且首次发现MSCs来源的exosomes能促使肿瘤细胞体内生长明显加快,这为MSCs体内促进肿瘤细胞生长提供了一个新的机制,exosomes介导的细胞间的相互作用可成为肿瘤治疗的新靶点。GC-MSCs的分离培养及肿瘤微环境诱导下骨髓MSCs向TAF转化表明MSC是肿瘤微环境的组成部分,骨髓MSCs是TAFs的重要来源,这为骨髓MSCs在肿瘤发生、发展中的作用及肿瘤靶向治疗提供了实验依据。
Objective:Mesenchymal stem cells (MSCs) were injected as cell mixture with tumor cells or were injected separately at different anatomic sites from the site of tumor injection can significantly enhance the growth of tumor xenograft in BALB/C nude mouse model, but the exact mechanism remains unclear. The aim of this study is to investigate the effect of MSCs on tumor microenvironment and the mechanism of MSCs on tumor initiation and progression. It will provide the new evidence that MSCs exert the tumor promoting function and provide a new target of tumor therapy based on MSC.
Methods:We treated SGC-7901 gastric cancer line cells with hMSC-conditioned medium (hMSC-CM) or hMSC derived exosomes for 48 hours, followed by subcutaneously injection of the treated SGC-7901 cells (1x106) into BALB/c nude mice for the development of tumor xenograft. We also injected untreated SGC-7901 cells alone or co-injected with hMSC as control group. We determine in vitro proliferation index of SGC-7901 tumor cells before and after hMSC-CM treatment in culture using MTT assay. We set out to quantitative measure the presence of blood vessels by using immunostaining of vWF and Magnetic Resonance (MR) angiography was performed for analyzing tumor vascularity. We detected the effect hMSC secreted molecules on the expression of VEGF at both mRNA and protein levels in SGC-7901 cells by RT-PCR and ELISA assay, and to test neovascularization functionally in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis observation. The activation of ERK1/2 or RhoA-GTP were performed for gene expression profile analysis on hMSC-CM treated and untreated cells by gene chip and western bolt assay.We established nude mouse orthotopic transplantation models of human stomach cancer constructed using intact tumor tissue by "Fibrinogen-thrombin" paste technique. And gastric cancer-derived MSC-like cells (hGC-MSCs) were isolated from gastric cancer tissue samples. We treated hMSCs with SGC-7901 cells or gastric cancer tissue in vitro to observe whether hMSCs differentiate into tumor associated fibroblast (TAF).
Results:Our results suggest that physical and continuous presence or interaction of MSCs with tumor cell is not required for enhanced tumor growth. Instead, one dose of pretreatment of tumor cells with hMSC conditioned-media is sufficient to recapitulate hMSC co-injection and the hMSCs secreted soluble factors are the major effort if not all tumor growth-promoting potential.The tumor tissue section exhibited a much more robust neovasculization in the xenograft derived from hMSC-CM pretreated tumor cells contrasting to that of untreated control tumor graft. Our data clearly demonstrated that signaling molecules secreted by hMSCs strongly activate VEGF expression of tumor cells at both mRNA and protein levels and the drastic ongoing activation pathways in these tumor cells upon the exposure to hMSC-CM leading to profound alteration in gene expression profiles of the tumor cells. After treatment with hMSCs-CM, the gene expression of SGC-7901 cell for N-cadherin,slug,snail was increased,but the expression of E-cadherin was decreased. The tumor tissue expressed stronger a-SMA in vivo. Our results showed that hMSCs-CM can induced epithelial-mesenchymal transition(EMT) for tumor cell. MSC-exosomes co-injected with tumor cell or pretreatment in vitro can promoted tumor growth, increased the expression of a-SMA、VEGF、CXCR4、PCNA and blood vessels density in tumor tissue. However, the MSC-exosomes did not induce any significant increase in tumor cell proliferation in vitro but a transient activation of ERK and enhanced expression of VEGF and CXCR4 genes were observed. The gastric cancer-derived MSC-like cells (hGC-MSCs) were isolated from 13 out of 20 cancer tissue samples. Their characteristics, including morphology, surface antigens, specific gene expression, and differentiation potential, were similar to those of MSCs derived from human bone marrow (hBM-MSCs). The nude mouse orthotopic transplantation model of human stomach cancer was constructed and 100% successful tumor-take rate was obtained in the model and we have succeed isolated MSCs from the nude mouse orthotopic transplantation model tissue.
After treatment with tumor cell or tumor tissue in vitro, hBM-MSCs may be differentiate into TAF, also they can expression the special mark of TAFs, such as a-SMA,vimetin. Our findings suggest that MSCs are components of the tumor microenvironment, which can promote tumor growth.
Conclusions:In this study, we show that through the action of secreted VEGF, MSCs potentiate tumor cells by activating angiogenic program as well as by altering the expression profile of a broad range of genes. These cells exhibit the ability to induced EMT or neovascularization for tumor. It also can promote tumor cell growth and the ability of migration.To our knowledge, it's the first report to present that MSC-exosomes had a significant acceleration effect on tumor growth in vivo, which offers a new mechanism responsible for the roles of MSCs in promoting tumor growth in vivo and the exosomes-meidated cell-cell interaction may be a new tumor therapeutic target. The existence of MSC-like cells in gastric cancer tissues suggests that MSC is the portion of tumor microenvironment, and the MSCs may be differentiate into TAF under tumor microenvironment in vitro. Taken together, these data suggest that hMSCs are a source of TAFs. This provides an experimental foundation for investigating the role of hMSCs in the initiation and progression of cancers and it may be a potential targets for cancer therapy.
引文
[1]Xu W, Zhang X, Qian H, et al. Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp Biol Med 2004;229(7):623-31.
[2]Roorda BD, ter Elst A, Kamps WA, et al. Bone marrow-derived cells and tumor growth:contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells.Crit Rev Oncol Hematol 2009;69(3):187-98.
[3]Schinkothe T, Bloch W, Schmidt A. In vitro secreting profile of human mesenchymal stem cells.Stem Cells Dev 2008;17(1):199-206.
[4]朱伟,许文荣,孙晓春,等.骨髓间质干细胞体外分化为成骨细胞的实验研究.生物医学工程研究2003；22(3)：41-3.
[5]Potapova IA, Gaudette GR, Brink PR, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro.Stem Cells 2007;25(7):1761-8.
[6]Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57(1):11-20.
[7]Spaeth E, Klopp A, Dembinski J, et al. Inflammation and tumor microenvironments:defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008;15(10):730-8.
[8]Cao H, Xu W, Qian H, et al. Mesenchymal stem cell-like cells derived from human gastric cancer tissues.Cancer Lett 2009;274(1):61-71.
[9]Reya T, Morrison SJ, Clarke MF, et al. Stem cells,cancer, and cancer stem cells. Nature 2001; 414(6859):105-11.
[10]单于,陈系古.干细胞与肿瘤发生的关系.中国病理生理杂志2003；19(9)：1272-75.
[11]Serakinci N, Guldberg P, Burns JS, et al. Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene 2004; 23(29):5095-8.
[12]XuW, Qian H, Zhu W, et al. A novel tumor cell line cloned from mutated human embryonic bone marrow mesenchymal stem cells. Oncol Rep 2004; 12(3):501-508.
[13]顾国利,王石林,魏学明.胃肠道间质瘤基础与临床进展.空军总医院学报2004；20(2)：99-105.
[14]Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102 (10):3837-44.
[15]Sato T, Sakai T, Noguchi Y, et al. Tumor-stromal cell contact p romotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases. Gynecol Oncol 2004; 92 (1): 47-56.
[16]Halla BM, Fortney JE, Taylor L, et al. Stromal cells exp ressing elevated VCAM-1 enhance survival of B lineage tumor cells. Cancer Lett 2004; 207(2):229-39.
[17]Zhu W, Xu W, Jiang R, Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol 2006; 80(3):267-74.
[18]Fierro FA, Sierralta WD, Epunan MJ, et al. Marrow-derived mesenchymal stem cells:role in epithelial tumor cell determination. Clin Exp Metastasis 2004; 21(4):313-9.
[19]申通.干细胞与肿瘤血管新生.肿瘤研究与临床2004；16(1)：67-70.
[20]Han C, Zhang X, XuW, et al. Cloning of the nucleostemin gene and its function in transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells. Int J Mol Med 2005; 16 (2):205-13.
[21]Ohlsson LB, Varas L, Kjellman C, et al. Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and vitro in gelatin matrix. Exp Mol Pathol 2003; 75 (3):248-55.
[22]Sohara Y, Shimada H,Minkin C, et al. Bone marrow mesenchymal stem cells provide an altemate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Res 2005; 65 (4):1129-35.
[23]Hall B, Dembinski J, Sasser AK, et al. Mesenchymal stem cells in cancer:Tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007;86(1):8-16.
[24]Kidd S, Spaeth E, Klopp A, et al. The (in) auspicious role of mesenchymal stromal cells in cancer:be it friend or foe. Cytotherapy 2008;10(7):657-67.
[25]Klopp AH, Spaeth EL, Dembinski JL, et al.Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007;67(24):11687-95.
[26]Hamada H, Kobune M,Nakamura K, et al. Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy. Cancer Sci 2005;96(3):149-56.
[27]Nakamura K, Ito Y, Kawano Y, et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 2004; 11 (14):1155-64.
[28]Nakamizo A, Marini F, Amano T, et al. Human bone marrow derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65 (8):3307-18.
[29]Hung SC, Deng WP, Yang WK, et al. Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging. Clin Cancer Res 2005; 11 (21):7749-56.
[30]Studeny M, Marini FC, Dembinski JL, et al. Mesenchymal stem cells potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96 (21):1593-603.
[31]张梁.促血管生成素在肿瘤血管生成中的作用.福建医药杂志2005；27(1)：128-31.
[32]Pandya NM, Dhalla NS, Santani DD. Angiogenesis—a new target for future therapy. Vascul Pharmacol 2006; 44(5):265-74.
[33]Gupta M K, Qin RY. Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol 2003;9(6):1144-55.
[34]Feng Y, vom Hagen F, Pfister F, et al. Impaired pericyte recuitement and abnormal retinal angiogenesis as result of angiopoietin-2 overexpression. Thromb and haemost 2007;97(1):99-108.
[35]Moon WS,Park HS,Yu KH, et al. Expression of angiopoietin 1 and their common receptor Tie2 in human gastric carcinoma:implication for angiogenesis. J Korean Med Sci 2006;21(2):272-8.
[36]蒋凯,程渝.肿瘤的血管生成及调控因子.重庆医学2005；34(3)：456-9.
[37]Lobov IB,Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. PNAS 2002;99(17):11205-10.
[38]Staito M, Watanabe J, Fujisawa T, et al. Angiopoietin-1,2 and Tie2 expressions in endometrial adenocarcinoma—the Ang2 dominant balance up-regulates tumor angiogenesis in the presence of VEGF. Eur J Gynaecol Oncol 2006; 27(2):129-34.
[39]Udani V, Santarelli J, Yung Y, et al. Differential expression of angipoietin-1 and angipoietin-2 may enhance recruitment of bone-marrow-derived endothelial precursor cells into brain tumors. Neurol Res 2005; 27(8):801-6.
[40]Zhu Y, Lee C, Shen F, et al. Angiogenesis in the mature mouse brain angiopoietin-2 facilitates vascular endothelial growth factor-induced. Stroke 2005; 36(7):1533-7.
[41]de Castro Junior G, Puglisi F, Azambuja E, et al. Angiogenesis and cancer:A cross-talk between basic science and clinical trials (the "do ut des" paradigm). Crit Rev Oncol Hematol 2006; 59(1):40-50.
[42]Yoshiji H, Kuriyama S, Noguchi R, et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut 2005; 54(12):1768-75.
[43]Yu JM, Jun ES, Bae YC, et al. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo.Stem Cells Dev 2008; 17(3):463-73
[44]Zeisberg M, Kalluri R. Fibroblast in cancer. Nat Rev Cancer 2006; 6(5):392-401.
[45]乌新林,施琳,董培德.肿瘤相关成纤维细胞：抗肿瘤治疗的新靶点.国际外科学杂志2006；33(2)：154-7.
[46]Bhowmick NA, Neilson EG, Moese HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432(7015):332-7.
[47]Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinoma promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121(3):335-48.
[48]Ishii G, Sangai T, Oda T, et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun 2003; 309(1):232-40.
[49]Direkze NC, Hodivala-Dilke K, Jeffery R, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 2004; 64(23):8492-5.
[50]向明章,蒋耀光.间充质干细胞的恶性转化与肿瘤间质形成.重庆医学2007；36(4)：365-7.
[51]王丽霞,费小明,陆化.骨髓间充质干细胞与肿瘤的关系研究进展.国际输血及血液学杂志2007；30(1)：31-4.
[52]Burger JA, Kipps TJ. CXCR4:a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006; 107(5):1761-7.
[53]Li H, Fan X, Houghton J. Tumor microenvironment:the role of the tumor stroma in cancer. J Cell Biochem 2007; 101(4):805-15.
[54]Bierie B, Moses HL. Tumour microenvironment:TGFbeta:the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006; 6(7):506-20.
[55]Jeon ES, Moon HJ, Lee MJ, et al. Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells. Stem Cells, Stem cells 2008; 26(3):789-97.
[56]Muraoka RS, Dumont N, Ritter CA, et al. Blockade of TGF-beta mammary tumor cell viability, migration, and metastases. J Clin Invest 2002; 109(12): 1551-9.
[57]张晓艳,汤为学.成纤维细胞活化蛋白与肿瘤.国外医学肿瘤学分册2004；31(8)：582-4.
[58]Bhowmick NA, Neilson EG, Moses HL.Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432(7015):332-7.
[59]Zeisberq EM, Potenta S, Xie L, et al. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts.Cancer Res 2007;67(21):10123-8.
[60]Mishra PJ,Merlino G..A traitor in our midst:mesenchymal stem cells contribute to tumor progression and metastasis. Future Oncol 2008;4(6):745-9.
[61]Mishra PJ, Humeniuk R, Medina DJ, et al. Carcinoma-associated fibrolast-like differentiation of human mensenchymal stem cells.Cancer Res 2008;68(11):4331-9.
[62]于清蕊.干细胞与肿瘤干细胞.中国组织工程研究与临床康复2007,11(15)：2948-50.
[63]钱波,蔡寒青,冯洁.干细胞、肿瘤干细胞与肿瘤发生.世界华人消化杂志2007,15(13)：1526-31.
[64]Zhu Y, Sun Z, Han Q, et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009;23(5):925-33.
[65]Qiao L,Xu Z, Zhao Z, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model.Cell Res 2008;18(4):500-7.
[66]邓均,蒲晓允,张春雷,等.K562细胞影响BMSCs生长及M IP21α表达的实验研究.第三军医大学学报2004；26(19)：1720-2.
[67]Reiser J, Zhang XY, Hemenway CS, et al. Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Op in Biol Ther 2005; 5 (12):1571-84.
[68]Kan I, Melamed E, Offen D. Integral therapeutic potential of bone marrow mesenchymal stem cells. Curr Drug Targets 2005; 6 (1):31-41.
[69]Minguell JJ, Erices A. Mesenchymal stem cells and the treatment of cardiac disease. Exp BiolMed 2006; 231 (1):39-49.
[70]Marini F, Dembinski J, StudenyM, et al. Mesenchym stem cells as delivery systems for cancer therapy:evaluation of tropism and efficacy. Molecular Therapy 2005; 11 (Supp lement 1):173.
[71]Xin H, KanehiraM, Mizuguchi H, et al. Tumor targeting innumogene therapy by mesenchymal stem cells expressing CX3CL1. Molecular Therapy 2005; 11(Supp lement 1):28.
[72]Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57(1):11-20.
[73]冯凯,毕冬杰,李渤涛,等.与骨髓MSC共孵育的T淋巴细胞对白血病细胞的杀伤作用.白血病·淋巴瘤2005；14(2)：65-8.
[74]Elzaouk L, Moelling K, Pavlovic J. Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma model. Exp Dermatol 2006; 15 (11)):865-74.
[75]Kucerova L, Altanerova V, Matuskova M, et al. Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res 2007; 67 (13):6304-13.
[76]Stoff-Khalili MA, Rivera AA, Mathis JM, et al. Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat 2007; 105 (2):157-67.
[77]Bader AG, Kang S, Vogt PK. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A 2006; 103(5):1475-9.
[78]Mangieri D, Nico B, Coluccia AM, et al. An alternative in vivo system for testing angiogenic potential of human neuroblastoma cells. Cancer Lett 2009; 18;277(2):199-204..
[79]Chen Y, Wang Y, Yu H, et al. The cross talk between protein kinase A-and RhoA-mediated signaling in cancer cells. Exp Biol Med (Maywood) 2005; 230(10):731-41.
[80]Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449(7162):557-63.
[81]Spaeth EL, Dembinski JL, Sasser AK, et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 2009; 4(4):e4992.
[82]Sasser AK, Mundy BL, Smith KM, et al. Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments. Cancer Lett 2007; 254(2):255-64.
[83]Simons M, Raposo G. Exosomes-vesicular carriers for intercellular communication.Curr Opin Cell Biol 2009; 21(4):575-81.
[84]Cocucci E, Racchetti G, Meldolesi J.Shedding micro vesicles:artefacts no more.Trends Cell Biol 2009; 19(2):43-51.
[85]Hao S, Moyana T, Xiang J. Review:cancer immunotherapy by exosome-based vaccines. Cancer Biother Radiopharm 2007; 22(5):692-703.
[86]Qu JL, Qu XJ, Zhao MF, et al.Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation.Dig Liver Dis 2009;41(12):875-80.
[87]Johnstone RM, Adam M, Hammond JR, et al..Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987; 262(19):9412-20.
[88]Olver C, Vidal M. Proteomic analysis of secreted exosomes. Subcell Biochem 2007;43:99-131.
[89]王兴忠,许文荣,朱伟,等.人骨髓间质干细胞PKH26荧光标记技术.中华检验医学杂志2006；29(9)：834-7.
[90]Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6):654-9.
[91]Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20(5):1053-67.
[92]Timmers L, Lim SK, Arslan F, et al. Reduction of myocardial infract size by human mesenchymal stem cell conditioned medium. Stem cell Res 2007; 1(2):129-37.
[93]Shinagawa K, Kitadai Y, Tanaka M, et al. Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 2010; 127(10):2323-33.
[94]Bouffi C, Djouad F, Mathieu M, et al. Multipotent mesenchymal stromal cells and rheumatoid arthritis:risk or benefit? Rheumatology (Oxford) 2009;48(10):1185-9.
[95]Pap E, Pallinger E, Pasztoi M,et al. Highlights of a new type of intercellular communication:microvesicle-based information transfer. Inflamm Res 2009; 58(1):1-8.
[96]Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4(3):214-22.
[97]Hood JL, Pan H, Lanza GM, et al. Paracrine induction of endothelium by tumor exosomes. Lab Invest 2009; 89(11):1317-28.
[98]Hao L, Zhang C, Qiu Y, et al. Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett 2007; 253(1):34-42.
[99]Liang Z, Brooks J, Willard M, et al. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway.Biochem Biophys Res Commun 2007;359(3):716-22.
[100]Lin TM, Chang HW, Wang KH, et al.Isolation and identification of mesenchymal stem cells from human lipoma tissue.Biochem Biophys Res Commun 2007;361(4)883-9.
[101]Gibbs CP, Kukekov VG, Reith JD, et al, Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 2005; 7(11):967-76.
[102]Houghton J, Stoicov C, Nomura S, et al, Gastric cancer originating from bone marrow-derived cells. Science 2004;306 (5701):1568-71.
[103]Tsai RY, McKay RD. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells, Genes Dev 2002; 16 (23):2991-3003.
[104]Bea S,Tort F, Pinyol M., et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res 2001;61(6):2409-12.
[105]Sleeman JP, Cremers N. New concepts in breast cancer metastasis:tumor initiating cells and the microenvironment. Clin Exp Metastasis 2007; 24 (8):707-15.
[106]Liu Y, Hu T, Shen J, et al. Separation, cultivation and biological characteristics of oral carcinoma-associated fibroblasts. Oral Dis 2006; 12 (4):375-80.
[107]Cao J, Tan MH, Yang P, et al. Effects of adjuvant chemotherapy on bone marrow mesenchymal stem cells of colorectal cancer patients. Cancer Lett 2008; 263 (2):197-203.
[108]Paunescu V, Bojin FM, Tatu CA, et al. Tumor-associated fibroblasts and mesenchymal stem cells:more similarities than differences. J Cell Mol Med 2010; [Epub ahead of print]
[109]Furukawa T, Fu X, Kuboba T, et al. Nude mouse metastatic models of human stomach cancer constructed using orthotopic implantation of histologically intact tissue. Cancer Res 1993; 53(5):1204-8.
[110]陈亚琳,魏品康,许玲,等.采用OB胶粘贴法建立人胃癌裸鼠原位种植转移模型.癌症2005；24(2)：246-8.
[111]Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 1990; 50(19):6130-8.
[112]张晓青,刘炳亚,张明均,等.裸鼠人胃癌转移模型的建立及比较.中华实验外科杂志2005；22(12)：1583.
[113]Illert B, Otto C, Braendlein S, et al. Optimization of a metastasizing human gastric cancer model in nude mice. Microsurgery 2003;23(5):508-12.
[114]Shi J, Wei PK, Zhang S, et al. OB glue paste technique for establishing nude mouse human gastric cancer orthotopic transplantation models. World J Gastroenterol 2008;14(30):4800-4.
[115]王齐敏,金晓明,贺岩,等.胃癌细胞和组织块原位移植模型的建立及评价.肿瘤学杂志2008；14(4)：251-3.
[116]李莹杰,贺岩,王齐敏,等.优化胶粘贴法建立裸鼠胃癌原位种植模型.中国实验动物学报2007；15(5)：369-71.
[117]Ahmed TA, Dare EV, Hincke M. Fibrin:a versatile scaffold for tissue engineering applications.Tissue Eng Part B Rev 2008;[Epub ahead of print]
[118]Hu L, Lee M, Campbell W, et al. Role of endogenous thrombin in tumor implantation,seeding, and spontaneous metastasis. Blood 2004;104(9):2746-51.
[119]孟宇宏,虞积耀,陆应麟.凝血酶与肿瘤转移.中国实验血液学杂2007；15(3)：671-4.
[2]Roorda BD, ter Elst A, Kamps WA, et al. Bone marrow-derived cells and tumor growth:contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells.Crit Rev Oncol Hematol 2009;69(3):187-98.
[3]Schinkothe T, Bloch W, Schmidt A. In vitro secreting profile of human mesenchymal stem cells.Stem Cells Dev 2008;17(1):199-206.
[4]朱伟,许文荣,孙晓春,等.骨髓间质干细胞体外分化为成骨细胞的实验研究.生物医学工程研究2003；22(3)：41-3.
[5]Potapova IA, Gaudette GR, Brink PR, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro.Stem Cells 2007;25(7):1761-8.
[6]Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57(1):11-20.
[7]Spaeth E, Klopp A, Dembinski J, et al. Inflammation and tumor microenvironments:defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008;15(10):730-8.
[8]Cao H, Xu W, Qian H, et al. Mesenchymal stem cell-like cells derived from human gastric cancer tissues.Cancer Lett 2009;274(1):61-71.
[9]Reya T, Morrison SJ, Clarke MF, et al. Stem cells,cancer, and cancer stem cells. Nature 2001; 414(6859):105-11.
[10]单于,陈系古.干细胞与肿瘤发生的关系.中国病理生理杂志2003；19(9)：1272-75.
[11]Serakinci N, Guldberg P, Burns JS, et al. Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene 2004; 23(29):5095-8.
[12]XuW, Qian H, Zhu W, et al. A novel tumor cell line cloned from mutated human embryonic bone marrow mesenchymal stem cells. Oncol Rep 2004; 12(3):501-508.
[13]顾国利,王石林,魏学明.胃肠道间质瘤基础与临床进展.空军总医院学报2004；20(2)：99-105.
[14]Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102 (10):3837-44.
[15]Sato T, Sakai T, Noguchi Y, et al. Tumor-stromal cell contact p romotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases. Gynecol Oncol 2004; 92 (1): 47-56.
[16]Halla BM, Fortney JE, Taylor L, et al. Stromal cells exp ressing elevated VCAM-1 enhance survival of B lineage tumor cells. Cancer Lett 2004; 207(2):229-39.
[17]Zhu W, Xu W, Jiang R, Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol 2006; 80(3):267-74.
[18]Fierro FA, Sierralta WD, Epunan MJ, et al. Marrow-derived mesenchymal stem cells:role in epithelial tumor cell determination. Clin Exp Metastasis 2004; 21(4):313-9.
[19]申通.干细胞与肿瘤血管新生.肿瘤研究与临床2004；16(1)：67-70.
[20]Han C, Zhang X, XuW, et al. Cloning of the nucleostemin gene and its function in transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells. Int J Mol Med 2005; 16 (2):205-13.
[21]Ohlsson LB, Varas L, Kjellman C, et al. Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and vitro in gelatin matrix. Exp Mol Pathol 2003; 75 (3):248-55.
[22]Sohara Y, Shimada H,Minkin C, et al. Bone marrow mesenchymal stem cells provide an altemate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Res 2005; 65 (4):1129-35.
[23]Hall B, Dembinski J, Sasser AK, et al. Mesenchymal stem cells in cancer:Tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007;86(1):8-16.
[24]Kidd S, Spaeth E, Klopp A, et al. The (in) auspicious role of mesenchymal stromal cells in cancer:be it friend or foe. Cytotherapy 2008;10(7):657-67.
[25]Klopp AH, Spaeth EL, Dembinski JL, et al.Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007;67(24):11687-95.
[26]Hamada H, Kobune M,Nakamura K, et al. Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy. Cancer Sci 2005;96(3):149-56.
[27]Nakamura K, Ito Y, Kawano Y, et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 2004; 11 (14):1155-64.
[28]Nakamizo A, Marini F, Amano T, et al. Human bone marrow derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65 (8):3307-18.
[29]Hung SC, Deng WP, Yang WK, et al. Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging. Clin Cancer Res 2005; 11 (21):7749-56.
[30]Studeny M, Marini FC, Dembinski JL, et al. Mesenchymal stem cells potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96 (21):1593-603.
[31]张梁.促血管生成素在肿瘤血管生成中的作用.福建医药杂志2005；27(1)：128-31.
[32]Pandya NM, Dhalla NS, Santani DD. Angiogenesis—a new target for future therapy. Vascul Pharmacol 2006; 44(5):265-74.
[33]Gupta M K, Qin RY. Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol 2003;9(6):1144-55.
[34]Feng Y, vom Hagen F, Pfister F, et al. Impaired pericyte recuitement and abnormal retinal angiogenesis as result of angiopoietin-2 overexpression. Thromb and haemost 2007;97(1):99-108.
[35]Moon WS,Park HS,Yu KH, et al. Expression of angiopoietin 1 and their common receptor Tie2 in human gastric carcinoma:implication for angiogenesis. J Korean Med Sci 2006;21(2):272-8.
[36]蒋凯,程渝.肿瘤的血管生成及调控因子.重庆医学2005；34(3)：456-9.
[37]Lobov IB,Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. PNAS 2002;99(17):11205-10.
[38]Staito M, Watanabe J, Fujisawa T, et al. Angiopoietin-1,2 and Tie2 expressions in endometrial adenocarcinoma—the Ang2 dominant balance up-regulates tumor angiogenesis in the presence of VEGF. Eur J Gynaecol Oncol 2006; 27(2):129-34.
[39]Udani V, Santarelli J, Yung Y, et al. Differential expression of angipoietin-1 and angipoietin-2 may enhance recruitment of bone-marrow-derived endothelial precursor cells into brain tumors. Neurol Res 2005; 27(8):801-6.
[40]Zhu Y, Lee C, Shen F, et al. Angiogenesis in the mature mouse brain angiopoietin-2 facilitates vascular endothelial growth factor-induced. Stroke 2005; 36(7):1533-7.
[41]de Castro Junior G, Puglisi F, Azambuja E, et al. Angiogenesis and cancer:A cross-talk between basic science and clinical trials (the "do ut des" paradigm). Crit Rev Oncol Hematol 2006; 59(1):40-50.
[42]Yoshiji H, Kuriyama S, Noguchi R, et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut 2005; 54(12):1768-75.
[43]Yu JM, Jun ES, Bae YC, et al. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo.Stem Cells Dev 2008; 17(3):463-73
[44]Zeisberg M, Kalluri R. Fibroblast in cancer. Nat Rev Cancer 2006; 6(5):392-401.
[45]乌新林,施琳,董培德.肿瘤相关成纤维细胞：抗肿瘤治疗的新靶点.国际外科学杂志2006；33(2)：154-7.
[46]Bhowmick NA, Neilson EG, Moese HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432(7015):332-7.
[47]Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinoma promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121(3):335-48.
[48]Ishii G, Sangai T, Oda T, et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun 2003; 309(1):232-40.
[49]Direkze NC, Hodivala-Dilke K, Jeffery R, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 2004; 64(23):8492-5.
[50]向明章,蒋耀光.间充质干细胞的恶性转化与肿瘤间质形成.重庆医学2007；36(4)：365-7.
[51]王丽霞,费小明,陆化.骨髓间充质干细胞与肿瘤的关系研究进展.国际输血及血液学杂志2007；30(1)：31-4.
[52]Burger JA, Kipps TJ. CXCR4:a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006; 107(5):1761-7.
[53]Li H, Fan X, Houghton J. Tumor microenvironment:the role of the tumor stroma in cancer. J Cell Biochem 2007; 101(4):805-15.
[54]Bierie B, Moses HL. Tumour microenvironment:TGFbeta:the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006; 6(7):506-20.
[55]Jeon ES, Moon HJ, Lee MJ, et al. Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells. Stem Cells, Stem cells 2008; 26(3):789-97.
[56]Muraoka RS, Dumont N, Ritter CA, et al. Blockade of TGF-beta mammary tumor cell viability, migration, and metastases. J Clin Invest 2002; 109(12): 1551-9.
[57]张晓艳,汤为学.成纤维细胞活化蛋白与肿瘤.国外医学肿瘤学分册2004；31(8)：582-4.
[58]Bhowmick NA, Neilson EG, Moses HL.Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432(7015):332-7.
[59]Zeisberq EM, Potenta S, Xie L, et al. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts.Cancer Res 2007;67(21):10123-8.
[60]Mishra PJ,Merlino G..A traitor in our midst:mesenchymal stem cells contribute to tumor progression and metastasis. Future Oncol 2008;4(6):745-9.
[61]Mishra PJ, Humeniuk R, Medina DJ, et al. Carcinoma-associated fibrolast-like differentiation of human mensenchymal stem cells.Cancer Res 2008;68(11):4331-9.
[62]于清蕊.干细胞与肿瘤干细胞.中国组织工程研究与临床康复2007,11(15)：2948-50.
[63]钱波,蔡寒青,冯洁.干细胞、肿瘤干细胞与肿瘤发生.世界华人消化杂志2007,15(13)：1526-31.
[64]Zhu Y, Sun Z, Han Q, et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009;23(5):925-33.
[65]Qiao L,Xu Z, Zhao Z, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model.Cell Res 2008;18(4):500-7.
[66]邓均,蒲晓允,张春雷,等.K562细胞影响BMSCs生长及M IP21α表达的实验研究.第三军医大学学报2004；26(19)：1720-2.
[67]Reiser J, Zhang XY, Hemenway CS, et al. Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Op in Biol Ther 2005; 5 (12):1571-84.
[68]Kan I, Melamed E, Offen D. Integral therapeutic potential of bone marrow mesenchymal stem cells. Curr Drug Targets 2005; 6 (1):31-41.
[69]Minguell JJ, Erices A. Mesenchymal stem cells and the treatment of cardiac disease. Exp BiolMed 2006; 231 (1):39-49.
[70]Marini F, Dembinski J, StudenyM, et al. Mesenchym stem cells as delivery systems for cancer therapy:evaluation of tropism and efficacy. Molecular Therapy 2005; 11 (Supp lement 1):173.
[71]Xin H, KanehiraM, Mizuguchi H, et al. Tumor targeting innumogene therapy by mesenchymal stem cells expressing CX3CL1. Molecular Therapy 2005; 11(Supp lement 1):28.
[72]Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57(1):11-20.
[73]冯凯,毕冬杰,李渤涛,等.与骨髓MSC共孵育的T淋巴细胞对白血病细胞的杀伤作用.白血病·淋巴瘤2005；14(2)：65-8.
[74]Elzaouk L, Moelling K, Pavlovic J. Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma model. Exp Dermatol 2006; 15 (11)):865-74.
[75]Kucerova L, Altanerova V, Matuskova M, et al. Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res 2007; 67 (13):6304-13.
[76]Stoff-Khalili MA, Rivera AA, Mathis JM, et al. Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat 2007; 105 (2):157-67.
[77]Bader AG, Kang S, Vogt PK. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A 2006; 103(5):1475-9.
[78]Mangieri D, Nico B, Coluccia AM, et al. An alternative in vivo system for testing angiogenic potential of human neuroblastoma cells. Cancer Lett 2009; 18;277(2):199-204..
[79]Chen Y, Wang Y, Yu H, et al. The cross talk between protein kinase A-and RhoA-mediated signaling in cancer cells. Exp Biol Med (Maywood) 2005; 230(10):731-41.
[80]Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449(7162):557-63.
[81]Spaeth EL, Dembinski JL, Sasser AK, et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 2009; 4(4):e4992.
[82]Sasser AK, Mundy BL, Smith KM, et al. Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments. Cancer Lett 2007; 254(2):255-64.
[83]Simons M, Raposo G. Exosomes-vesicular carriers for intercellular communication.Curr Opin Cell Biol 2009; 21(4):575-81.
[84]Cocucci E, Racchetti G, Meldolesi J.Shedding micro vesicles:artefacts no more.Trends Cell Biol 2009; 19(2):43-51.
[85]Hao S, Moyana T, Xiang J. Review:cancer immunotherapy by exosome-based vaccines. Cancer Biother Radiopharm 2007; 22(5):692-703.
[86]Qu JL, Qu XJ, Zhao MF, et al.Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation.Dig Liver Dis 2009;41(12):875-80.
[87]Johnstone RM, Adam M, Hammond JR, et al..Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987; 262(19):9412-20.
[88]Olver C, Vidal M. Proteomic analysis of secreted exosomes. Subcell Biochem 2007;43:99-131.
[89]王兴忠,许文荣,朱伟,等.人骨髓间质干细胞PKH26荧光标记技术.中华检验医学杂志2006；29(9)：834-7.
[90]Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6):654-9.
[91]Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20(5):1053-67.
[92]Timmers L, Lim SK, Arslan F, et al. Reduction of myocardial infract size by human mesenchymal stem cell conditioned medium. Stem cell Res 2007; 1(2):129-37.
[93]Shinagawa K, Kitadai Y, Tanaka M, et al. Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 2010; 127(10):2323-33.
[94]Bouffi C, Djouad F, Mathieu M, et al. Multipotent mesenchymal stromal cells and rheumatoid arthritis:risk or benefit? Rheumatology (Oxford) 2009;48(10):1185-9.
[95]Pap E, Pallinger E, Pasztoi M,et al. Highlights of a new type of intercellular communication:microvesicle-based information transfer. Inflamm Res 2009; 58(1):1-8.
[96]Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4(3):214-22.
[97]Hood JL, Pan H, Lanza GM, et al. Paracrine induction of endothelium by tumor exosomes. Lab Invest 2009; 89(11):1317-28.
[98]Hao L, Zhang C, Qiu Y, et al. Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett 2007; 253(1):34-42.
[99]Liang Z, Brooks J, Willard M, et al. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway.Biochem Biophys Res Commun 2007;359(3):716-22.
[100]Lin TM, Chang HW, Wang KH, et al.Isolation and identification of mesenchymal stem cells from human lipoma tissue.Biochem Biophys Res Commun 2007;361(4)883-9.
[101]Gibbs CP, Kukekov VG, Reith JD, et al, Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 2005; 7(11):967-76.
[102]Houghton J, Stoicov C, Nomura S, et al, Gastric cancer originating from bone marrow-derived cells. Science 2004;306 (5701):1568-71.
[103]Tsai RY, McKay RD. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells, Genes Dev 2002; 16 (23):2991-3003.
[104]Bea S,Tort F, Pinyol M., et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res 2001;61(6):2409-12.
[105]Sleeman JP, Cremers N. New concepts in breast cancer metastasis:tumor initiating cells and the microenvironment. Clin Exp Metastasis 2007; 24 (8):707-15.
[106]Liu Y, Hu T, Shen J, et al. Separation, cultivation and biological characteristics of oral carcinoma-associated fibroblasts. Oral Dis 2006; 12 (4):375-80.
[107]Cao J, Tan MH, Yang P, et al. Effects of adjuvant chemotherapy on bone marrow mesenchymal stem cells of colorectal cancer patients. Cancer Lett 2008; 263 (2):197-203.
[108]Paunescu V, Bojin FM, Tatu CA, et al. Tumor-associated fibroblasts and mesenchymal stem cells:more similarities than differences. J Cell Mol Med 2010; [Epub ahead of print]
[109]Furukawa T, Fu X, Kuboba T, et al. Nude mouse metastatic models of human stomach cancer constructed using orthotopic implantation of histologically intact tissue. Cancer Res 1993; 53(5):1204-8.
[110]陈亚琳,魏品康,许玲,等.采用OB胶粘贴法建立人胃癌裸鼠原位种植转移模型.癌症2005；24(2)：246-8.
[111]Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 1990; 50(19):6130-8.
[112]张晓青,刘炳亚,张明均,等.裸鼠人胃癌转移模型的建立及比较.中华实验外科杂志2005；22(12)：1583.
[113]Illert B, Otto C, Braendlein S, et al. Optimization of a metastasizing human gastric cancer model in nude mice. Microsurgery 2003;23(5):508-12.
[114]Shi J, Wei PK, Zhang S, et al. OB glue paste technique for establishing nude mouse human gastric cancer orthotopic transplantation models. World J Gastroenterol 2008;14(30):4800-4.
[115]王齐敏,金晓明,贺岩,等.胃癌细胞和组织块原位移植模型的建立及评价.肿瘤学杂志2008；14(4)：251-3.
[116]李莹杰,贺岩,王齐敏,等.优化胶粘贴法建立裸鼠胃癌原位种植模型.中国实验动物学报2007；15(5)：369-71.
[117]Ahmed TA, Dare EV, Hincke M. Fibrin:a versatile scaffold for tissue engineering applications.Tissue Eng Part B Rev 2008;[Epub ahead of print]
[118]Hu L, Lee M, Campbell W, et al. Role of endogenous thrombin in tumor implantation,seeding, and spontaneous metastasis. Blood 2004;104(9):2746-51.
[119]孟宇宏,虞积耀,陆应麟.凝血酶与肿瘤转移.中国实验血液学杂2007；15(3)：671-4.