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目的研究血管内皮生长因子（VEGF）及其受体2（VEGFR2）在实验性左侧精索静脉曲张（ELV）大鼠附睾中的表达和定位，探讨VEGF、VEGFR2在精索静脉曲张（VC）致男性不育中的作用。方法通过部分结扎左肾静脉建立大鼠ELV模型，于术后2周和4周取材，采用免疫组化法检测VEGF、VEGFR2在附睾中的表达变化。结果ELV大鼠两侧附睾中VEGF蛋白表达均上调，但ELV 4周组表达明显少于2周组；ELV2周组大鼠附睾中VEGFR2蛋白的表达比对照组有所增加，而ELV4周组相比对照组和ELV2周组均显著下降。结论ELV对VEGF、VEGFR2蛋白的表达有影响，说明VC所致男性不育可能与VEGF及VEGFR2的表达变化有关。

目的观察血管内皮生长因子C（VEGF-C）及其受体3（VEGFR-3）和肾小球上皮细胞整合膜蛋白（podoplanin）在食管癌组织中的表达，分析其与肿瘤淋巴结转移的关系。方法免疫组织化学SP法检测76例食管癌组织中VEGF-C、VEGFR-3和podoplanin的表达及淋巴管密度（LVD）。结果食管癌VEGF-C表达阳性率为63．1％，VEGF-C的表达与食管癌的淋巴结转移、TNM分期有统计学意义（P〈0．01，P〈0．05），但与患者年龄、肿瘤大小及分化程度无关；癌旁组织淋巴管密度同淋巴结转移、VEGF-C阳性表达间有统计学意义（P〈0．01，P〈0．05），podoplanin LVD值与VEGFR-3 LVD值相比，具有统计学意义（P〈0．01）。结论食管癌组织中VEGF-C表达与肿瘤TNM分期、淋巴管密度和淋巴结转移有关，VEGF-C表达越高，淋巴管密度越大，淋巴结转移可能性越高。癌旁组织LVD同VEGF-C的高表达及淋巴结转移密切相关，食管癌组织中podoplanin标记的淋巴管密度较VEGFR-3标记的淋巴管密度更为精确，是一种更为满意的淋巴管内皮特异性标志物。

背景与目的 血管内皮生长因子（VEGF）及其受体与肺癌血管生成关系密切，但与肺癌患者预后的关系尚不明确。本研究的目的是对VEGF及其受体KDR、Flt1的表达与肺癌患者预后的关系进行探讨。方法 应用免疫组织化学PV-9000法检测75例具有完整随访资料的肺癌标本中VEGF及其受体KDR、Flt1的表达。结果 VEGF、KDR、Flt1在肺癌组织中的表达较为广泛，主要位于肿瘤细胞、血管内皮细胞、纤维母细胞胞质中，且其表达呈异质性，肺癌组织周边部及坏死区周围的肺癌细胞中表达较强，三者在肿瘤细胞中的阳性率均高于间质纤维母细胞（P〈0．01，P〈0．02，P〈0．02）。肺癌细胞及纤维母细胞VEGF、KDR和Flt1的阳性表达率在术后不同生存时间的三组间差异均具统计学意义（P〈0．01，P〈0．01，P〈0．01；P〈0．01，P〈0．01，P〈0．05）；肺癌细胞VEGF、KDR、Flt1阳性组患者的生存时间均显著低于各相应指标阴性者（P〈0．0001，P〈0．0005，P〈0．0005）。肺癌细胞中VEGF与Flt1受体的表达呈正相关（P〈0．01），纤维母细胞中VEGF与肺癌细胞中Flt1受体的表达呈正相关（P〈0．01），纤维母细胞中VEGF与KDR、Flt1表达分别呈正相关（P〈0．01，P〈0．01）。结论 VEGF可能是促进肺癌细胞生长的重要因子，主要以自分泌途径并附以旁分泌途径通过Flt1发挥作用；VEGF及受体KDR、Flt1对肺癌患者的预后有重要的影响作用。

Vascular endothelial growth factor （VEGF） is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors （VEGFRs）, they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells （DCs）, macrophages, and lymphocytes further express certain types of VEGF receptors. VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness. This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.

Aim： Targeting the VEGF/VEGF receptor （VEGFR） pathway has proved to be an effective antiangiogenic approach for cancer treatment. Here, we identified 6-（（2-（（3-acetamidophenyl）amino）pyrimidin-4-yl）oxy）-N-phenyl-l-naphthamide （designated herein as DW10075） as a novel and highly selective inhibitor of VEGFRs. Methods： In vitro tyrosine kinase activity was measured using ELISA, and intracellular signaling pathway proteins were detected by Western blot analysis. Endothelial cell proliferation was examined with CCK-8 assays, and tumor cell proliferation was determined with SRB assays. Cell,migration, tube formation and rat aortic ring assays were used to detect antiangiogenic activity. Antitumor efficacy was further evaluated in U87-MG human glioblastoma xenograft tumors in nude mice receiving DW10075 （500 mg.kg-1.d-1, po） for two weeks. Results： Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 （the IC50 values were 6.4, 0.69 and 5.5 nmol/L, respectively）, but did not affect 18 other kinases including FGFR and PDGFR at 10 pmol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilical vein endothelial cells （HUVECs）, thus inhibited VEGF-induced HUVEC proliferation. DW10075 （1-100 nmol/L） dose-dependently inhibited VEGF-induced HUVEC migration and tube formation and suppressed angiogenesis in both the rat aortic ring model and the chicken chorioallantoic membrane model. Furthermore, DW10075 exhibited anti-proliferative activity against 22 different human cancer cell lines with IC5o values ranging from 2.2 pmol/L （for U87-MG human glioblastoma cells） to 22.2 pmol/L （for A375 melanoma cells）. In U87-MG xenograft tumors in nude mice, oral administration of DW10075 significantly suppressed tumor growth, and reduced the expression of CD31 and Ki67 in the tumor tissues. Conclusion： DW10075 is a potent and highly selective inhibitor of VEGFR that deserves further development.Aim： Targeting the VEGF/VEGF receptor （VEGFR） pathway has proved to be an effective antiangiogenic approach for cancer treatment. Here, we identified 6-（（2-（（3-acetamidophenyl）amino）pyrimidin-4-yl）oxy）-N-phenyl-l-naphthamide （designated herein as DW10075） as a novel and highly selective inhibitor of VEGFRs. Methods： In vitro tyrosine kinase activity was measured using ELISA, and intracellular signaling pathway proteins were detected by Western blot analysis. Endothelial cell proliferation was examined with CCK-8 assays, and tumor cell proliferation was determined with SRB assays. Cell,migration, tube formation and rat aortic ring assays were used to detect antiangiogenic activity. Antitumor efficacy was further evaluated in U87-MG human glioblastoma xenograft tumors in nude mice receiving DW10075 （500 mg.kg-1.d-1, pc） for two weeks. Results： Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 （the ICso values were 6.4, 0.69 and 5.5 nmol/L, respectively）, but did not affect 18 other kinases including FGFR and PDGFR at 10 pmol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilica vein endothelial cells （HUVECs）, thus inhibited VEGF-induced HUVEC proliferation. DW10075 （1-100 nmol/L） dose-dependently inhibited VEGF-induced HUVEC migration and tube formation and suppressed angiogenesis in both the rat aortic ring model and the chicken chorioallantoic membrane model. Furthermore, DW10075 exhibited anti-proliferative activity against 22 different human cancer cell lines with IC5o values ranging from 2.2 pmol/L （for U87-MG human glioblastoma cells） to 22.2 pmol/L （for A375 melanoma cells）. In U87-MG xenograft tumors in nude mice, oral administration of DW10075 significantly suppressed tumor growth, and reduced the expression of CD31 and Ki67 in the tumor tissues. Conclusion： DW10075 is a potent and highly selective inhibitor of VEGFR that deserves further development.

Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines （HPV7 and RWPE1） and prostate cancer cell lines （DU 145 and PC3）. Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β1 type I receptor （ALK5） kinase inhibitor partially blocked hypoxia-mediated VEGFA16s secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor （VEGFR） 1 （Fit-l） and 2 （FIk-I/KDR）. Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERKI/2） in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.

We previously showed that the repair of bone defects is regulated by neural and vascular signals. In the present study, we examined the effect of topically applied β-nerve growth factor（β-NGF） on neurogenesis and angiogenesis in critical-sized bone defects filled with collagen bone substitute. We created two symmetrical defects, 2.5 mm in diameter, on either side of the parietal bone of the skull, and filled them with bone substitute. Subcutaneously implanted osmotic pumps were used to infuse 10 μgβ-NGF in PBS（β-NGF ＋ PBS） into the right-hand side defect, and PBS into the left（control） defect, over the 7 days following surgery. Immunohistochemical staining and hematoxylin-eosin staining were carried out at 3, 7, 14, 21 and 28 days postoperatively. On day 7, expression of β III-tubulin was lower on the β-NGF ＋ PBS side than on the control side, and that of neurofilament 160 was greater. On day 14, β III-tubulin and protein gene product 9.5 were greater on the β-NGF ＋ PBS side than on the control side. Vascular endothelial growth factor expression was greater on the experimental side than the control side at 7 days, and vascular endothelial growth factor receptor 2 expression was elevated on days 14 and 21, but lower than control levels on day 28. However, no difference in the number of blood vessels was observed between sides. Our results indicate that topical application of β-NGF promoted neurogenesis, and may modulate angiogenesis by promoting nerve regeneration in collagen bone substitute-filled defects.

Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 （VEGFR2） inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-（N-pyrrolidylacetyl）-9-（4-bromobenzyl）-l,3,4,9-tetrahydro-~-carboline （YF-452）, which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells （HUVECs） with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation ofmicrovascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane （CAM） and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase （ERK）, focal adhesion kinase （FAK） and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.

Background： Cerebral arteriovenous malformation （cAVM） is a type of vascular malformation associated with vascular remodeling, hemodynamic imbalance, and inflammation. We detected four angioarchitecture-related cytokines to make a better understanding of the potential aberrant signaling in the pathogenesis of cAVM and found useful proteins in predicting the risk of cerebral hemorrhage. Methods： lmmunohistochemical analysis was conducted on specimens from twenty patients with cAVM diagnosed via magnetic resonance imaging and digital subtraction angiography and twenty primary epilepsy controls using antibodies against vascular endothelial growth factor receptor-2 （VEGFR-2）, matrix metalloproteinase-9 （MMP-9）, vascular cell adhesion molecule （VCAM- 1 ）, and endothelial nitric oxide synthase （eNOS）. Western blotting and real-time fluorescent quantitative polymerase chain reaction （PCR） were performed to determine protein and mRNA expression levels. Student＇s t-test was used for statistical analysis. Results： VEGFR-2, MMP-9, VCAM-1, and eNOS expression levels increased in patients with cAVM compared with those in normal cerebral vascular tissue, as determined by immunohistochemical analysis. In addition, Western blotting and real-time PCR showed that the protein and mRNA expression levels ofVEGFR-2, MMP-9, VCAM-1, and eNOS were higher in the cAVM group than in the control group, all the differences mentioned were statistically significant （P 〈 0,05）. Conclusions： VEGFR-2, MMP-9, VCAM-1, and eNOS are upregulated in patients with cAVM and might play important roles in angiogenesis, vascular remodeling, and migration in patients with cAVM. MMP-9, VEGFR-2, VCAM-1, and eNOS might be potential excellent group proteins in predicting the risk of cerebral hemorrhage at arteriovenous malformation.

Background：Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma （ccRCC）,but biomarkers of activity are lacking.The aim of this study was to investigate the association of Von Hippel-Lindau （VHL） gene status,vascular endothelial growth factor receptor （VEGFR） or stem cell factor receptor （KIT） expression,and their relationships with characteristics and clinical outcome of advanced ccRCC.Methods：A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute,Chinese Academy of Medical Sciences between January 2010 and November 2012.Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry.Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival （PFS） and ovcrall survival （OS） were calculated and then compared based on expression status.The Chi-square test,the KaplanMeier method,and the Lon-rank test were used for statistical analyses.Results：Of 59 patients,objective responses were observed in 28 patients （47.5%）.The median PFS was 13.8 months and median OS was 39.9 months.There was an improved PFS in patients with the following clinical features：Male gender,number of metastatic sites 2 or less,VEGFR-2 positive or KIT positive.Eleven patients （18.6%） had evidence of VHL mutation,with an objective response rate of 45.5%,which showed no difference with patients with no VHL mutation （47.9%）.VHL mutation status did not correlate with either overall response rate （P =0.938） or PFS （P =0.277）.The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients,respectively,which was significantly longer than that of VEGFR-2 or KIT negative patients （P =0.026 and P =0.043）.Conclusion：VHL mutation status could not predict the efficacy of sunitinib or pazopanib.Further investigation of VHL/VEGFR pathway components is needed.