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单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination,invasion,and metastasis in a zebrafish tumor model,HypoxiaVEGFAngiogenesisMetastasis,概要,Mechanisms,underlying pathological angiogenesis in relation to hypoxia in tumor invasion and metastasis,remain elusive,.,Tumor microvascular networks,possess several,unique pathological features,including extremely high densities of leaky,tortuous,and primitive microvessels that usually lack pericyte coverage,base-ment membrane,and arteriole-venule distinctions.,Although hypoxia often results in necrosis of the central core of a fast-growing tumor,it could potentially persuade tumor cells to invade neighboring healthy vasculatures for,survival,eventually leading to metastasis,which is one of the hallmarks for cancer therapy.,A,clinical detectable metastatic,mass often represents an ultimate consequence of several distinctive steps of the metastatic cascade,including dissemination of malignant cells from the primary site,transport of tumor cells via the circulation or lymphatic system,adhesion of tumor cells in distal tissues/organs,and re-growth of tumor cells into a detectable mass.,Clinical detection of a metastasis,does not reveal early events,of tumor cell dissemination and intimate interactions between tumor cells and microvessels.So the the cancer therapy is difficult.,We have developed a zebrash tumor model that allows us to study the role of pathological angiogenesis under normoxia and hypoxia in arbitrating early events of the metastatic cascade at the single cell level.,Hypoxia and,VEGF signaling pathway,significantly contribute to early events of the metastatic cascade.The ndings also shed light on molecular mechanisms of benecial effects of clinically available anti-VEGF drugs for cancer therapy.,方法和结果,1,Hypoxic Metastasis Model in Zebrafish,The,Tg(fli1:EGFP)zebrafish,embryos Murine T241 tumor cells were labeled with DiI dye in vitro and labeled cells were injected into the perivitelline cavity of,48 h,post-fertilization embryos.,Tumor-bearing zebrafish embryos were placed in either,normoxic or hypoxic water,(7.5%air saturation),and,monitor daily in living zebrafish embryos.,At day 3 after implantation,murine T241 tumor cells under hypoxia were significantly disseminated away from primary sites.the,sizes,of primary tumors in both groups,remained similar,.The border of primary tumors under hypoxia was irregular and invasive fronts were often present.,A substantial number of tumor cells under hypoxia were disseminated to distal parts of the fish body,including,the head and tail regions.,Consistent with increase of tumor cell dissemination,hypoxia significantly stimulated,neovascularization and tortuosity,of the tumor vasculature.,we also studied hypoxia induced tumor cell dissemination and metastasis in another murine tumor cell line,Lewis lung carcinoma,(LLC).,Increasing of tumor dissemination was well correlated with enhanced tumor neovascularization,2 Dissemination and Metastasis of Human Tumor Cells,we selected,highly,metastatic MDAMB-231 breast cancer and,lowly,metastaticOVCAR8 ovarian cancer cell lines.,Implantation of MDA MB-231breast cancer cells in zebrafish embryos resulted in widespread tumor cell dissemination and metastasis at,day 6,post-injection.all MDA MB-231 tumor cells were spread away from the primary site.,The difference of metastatic potentials between these two cell lines is due to,their different capacities of dissemination,.,Thus,this zebrafish model might be used to discriminate,highly and lowly,metastatic potentials of human cancers and to,predict prognosis,.,3 Tumor-Derived VEGF Facilitates Dissemination and Metastasis,T241 tumor cells were stably,transfected to express VEGF at a high level.,Total,numbers,of disseminated tumor cells and the maximal distance of metastasis in the T241-VEGF group were significantly,greater,than those in controls.,Microvessel density,in T241-VEGF tumors was significantly higher relative to control tumors.,At,day 2,after implantation,a significant number of tumor cells,invaded,the neighboring tissues around primary tumors.,At,day 4,increasing numbers of invasive tumor cells were detected and were disseminated to,distal parts of the fish body,.,To generalize these findings to other tumor types,murine LLC,were also stably transfected with VEGF.,Similar to T241 fibrosarcoma,implantation of LLC-VEGF tumors resulted in marked increase of tumor cell dissemination,invasion and distal metastasis compared with vector controls.,4 VEGF Blockade Inhibits VEGF-Tumor Cell Invasion,Dissemination,and Metastasis,T241-VEGF tumor-bearing embryos were treated with sunitinib,a known,VEGFR,blockade,It showed that tumor cell dissemination,metastasis and vessel density in primary tumors were significantly,inhibited,by sunitinib in a dose-dependent manner.,the average,size,of primary tumors was also significantly,reduced,by sunitinib treatment.,sunitinib effectiv
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