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Progress in tumor vascular normalization for anticancer therapy:challenges and perspectives

Frontiers of Medicine 2012年第1期6卷 67-78页

作者： Bingxue Shang Zhifei Cao Quansheng Zhou Cyrus Tang Hematology Center Jiangsu Institute of Hematologythe First Affiliated Hospital of Soochow UniversitySuzhou 215123China Key Laboratory of Thrombosis and Hemostasis Ministry of HealthSoochow UniversitySuzhou 215123China

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004.Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment,recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy,resulting in tumor recurrence in patients after several months of treatment.Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues,which fosters tumor cells to become more aggressive and metastatic.In 2001,Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers.At present,normalizing the disorganized tumor vasculature,rather than disrupting or blocking them,has emerged as a new option for anticancer therapy.Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies,proteins,peptides,small molecules,and pericytes resulted in decreased tumor size and reduced metastasis.However,current tumor vascular normalizing drugs display moderate anticancer efficacy.Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization,growth,and metastasis.Therefore,multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization.To this end,the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics,as well as the integration ofWestern medicine with traditional Chinese medicine,may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

关键词： angiogenesis vasculogenesis neovascularization tumor vasculature normalization traditional Chinese medicine

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Preoperative evaluation and outcome of corneal transplantation for limbal dermoids：aten-yearfollow-up study

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International Journal of Ophthalmology(English edition) 2016年第12期9卷 1756-1760页

作者： Meng Xin Yue-Rong Gong Shan-Hao Jiang Chun-Hua Dai Su-Xia Li Wei-Yun Shi Shandong University Jinan 250012 Shandong ProvinceChina Department of Ophthalmology Yantai Affiliated Hospital of Binzhou Medical University Yantai 264100 Shandong Province China Department of Ophthalmology Binzhou Medical University Hospital Binzhou 256603 Shandong Province China Shandong Eye Hospital Shandong Eye Institute Shandong Academy of Medical Sciences Jinan 250021 Shandong Province China

AIM： To summarize preoperative evaluation and outcome of corneal transplantation for limbal dermoids for ten years.METHODS： Eighty-five patients diagnosed with limbal dermoids and treated with corneal transplantation were analyzed retrospectively. All patients were further divided into two groups according to absence or presence of neovascularization surrounding the dermoids in the corneal stroma. Eighty-two eyes were treated with tumor excision combined with partial lamellar sclerokeratoplasty, and the other three eyes were performed by penetrating keratoplasty. The size and location of the tumor, the associated ocular and systemic anomalies, the depth of the corneal penetration of tumor tissues, the preoperative and postoperative best-corrected visual acuity （BCVA）, graft survival and cosmetic outcome, and surgical complications were recorded respectively.RESULTS： The average age at surgery was 5.3y （range, 3mo-36y）. The mean size of dermoids was 6.1±1.6 mm. The 43.5% of eyes （37/85） were present with hair at the surface of the dermoid and 72.9% of dermoids were located inferotemporal of the eye. Amplyopia was present in 34.1% of patients （29/85） and 9.4% of patients （8/85） had lipodermoids. Eighteen patients suffered from Goldenhar’s syndrome with an accessory ear. The 75% of patients in group 1 had involvement of the corneal deep stroma down to Descemet’s membrane without involving it, but 71.4% of patients had Descemet’s membrane involvement in group 2. Preoperative BCVA ranged from counting fingers to 20/20. Postoperatively 81.1% had a BCVA of 20/800 or better. There was no significant difference between the post-surgical BCVA of the two groups （t=1.584, P〉0.05）. The grafts of 70.5% patients were present as 1＋ opacity, 21.1% as 2＋ opacity, 8.2% as 3＋ opacity and none as 4＋ opacity. Surgical complications included graft rejection, microperforation, prolonged reepithelialization, steroid glaucoma, interface neovascularization, and interface hemorrhage.CONCLUSION： The dermoids with neovascularization surroundi

关键词： limbal dermoids corneal transplantation neovascularization

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The biology of bone morphogenetic protein signaling pathway in cerebrovascular system

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Chinese Neurosurgical Journal 2021年第4期7卷 281-288页

作者： Haishuang Tang Xiaoxi Zhang Gaici Xue Fengfeng Xu Qingsong Wang Pengfei Yang Bo Hong Yi Xu Qinghai Huang Jianmin Liu Qiao Zuo Department of Neurosurgery Changhai HospitalNaval Military Medical University168 Changhai RoadShanghai 200433People’s Republic of China Naval Medical Center of PLA Naval Military Medical UniversityShanghai 200050People’s Republic of China Department of Cardiology the First Medical CentreChinese PLA General HospitalBeijing 100853People’s Republic of China

Bone morphogenetic protein belongs to transcription growth factor superfamilyβ;bone morphogenetic protein signal pathway regulates cell proliferation,differentiation,and apoptosis among different tissues.Cerebrovascular system supplies sufficient oxygen and blood into brain to maintain its normal function.The disorder of cerebrovascular system will result into serious cerebrovascular diseases,which is gradually becoming a major threat to human health in modern society.In recent decades,many studies have revealed the underlying biology and mechanism of bone morphogenetic protein signal pathway played in cerebrovascular system.This review will discuss the relationship between the two aspects,aiming to provide new perspective for non-invasive treatment and basic research of cerebrovascular diseases.

关键词： Bone morphogenetic protein Hemodynamic neovascularization Cerebrovascular diseases

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Expression of cyclinD1 in a rat model of oxygen-induced retinopathy

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Neural Regeneration Research 2011年第21期6卷 1651-1655页

作者： You Li Yuqiang Zhang Shaoyang Shi Xiaolong Chen Department of Ophthalmology Shengjing Hospital China Medical University Shenyang 110004 Liaoning Province China Department of Orthopedics First Affiliated Hospital China Medical University Shenyang 110001 Liaoning Province China

This study sought to elucidate the correlation between cyclinD1 expression and the emergence of neovascularization in oxygen-induced retinopathy （OIR）. OIR was induced in Sprague-Dawley 7-day-old neonatal rats exposed to hyperoxia （75% O2） for 5 days, and then returned to room air. Adenosine diphosphatase staining showed that the neovascularization started to emerge at rat age of day 14, and reached a peak at day 17, then gradually decreased and resolved by day 26. Immunohistochemical and immunofluorescence staining revealed that cyclinD1 protein expression was seen in the OIR rats at the age of day 12, then gradually increased and returned to normal levels by day 26. These experimental findings demonstrated that the temporal pattern of cyclinD1 protein expression is consistent with the emergence of retinal neovascularization.

关键词： oxygen-induced retinopathy cyclinD1 neovascularization rat

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Efficacy of the nucleotide-binding oligomerization domain 1 inhibitor Nodinhibit-1 on corneal alkali burns in rats

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International Journal of Ophthalmology(English edition) 2015年第5期8卷 860-865页

作者： Xu Huang Yun Han Yi Shao Jing-Lin Yi Affiliated Eye Hospital of Nanchang University Fujian Provincial Key Laboratory of Ophthalmology and Visual Science Eye Institute of Xiamen University Department of Ophthalmology the First Affiliated Hospital of Nanchang University

AIM: To evaluate the therapeutic effect of Nodinhibit-1 on alkali-burn-induced corneal neovascularization (CNV) and inflammation. The nucleotide-binding oligomerzation domain 1 (NOD1) is a potent angiogenic gene. METHODS: The alkali -burned rat corneas (32 right eyes) were treated with eye drops containing Nodinhibit-1 or phosphate buffered solution (PBS, pH 7.4) only, four times per day. CNV and inflammation were monitored using slit lamp microscopy, and the area of CNV was measured by formula. Vascular endothelial growth factor (VEGF) and pigment epithelium -derived factor (PEDF) was determined by Western blot analysis. The TUNEL assay was used to assess the corneal apoptosis cells. RESULTS: Alkali-burn-induced progressive CNV and inflammation in the cornea. After treatment for 7d and 14d, there were statistically significant differences in the CNV areas and inflammatory index on that between two group(P<0.05, respectively). Epithelial defect quantification showed a significant difference between the two groups at days 4 and 7 after the alkali burns (P<0.05). The apoptotic. cells on days 1, 4, and 7 between the two groups showed significant differences at all time points (P<0.05, respectively). Compared to that in control group, the protein level of VEGF expression was significantly reduced whereas the PEDF expression was increase in the Nodinhibit-1 groups on day 14(P<0.05, respectively). CONCLUSION: Topical application of 10.0 mu g/mL Nodinhibit -1 may have potential effect for the alkali burn -induced CNV and inflammation. The effect of Nodinhibit -1 on CNV may be by regulation the equilibrium of VEGF and PEDF in the wounded cornea.

关键词： Nodinhibit-1 inflammation alkali burn cornea neovascularization

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Effect of octreotide on angiogenesis induced by hepatocellular carcinoma in vivo

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Hepatobiliary & Pancreatic Diseases International 2003年第3期2卷 404-409页

作者： WeiDong Jia GeLiang Xu HuiChuan Sun Lu Wang RongNang Xu Qiong Xue Department of General Surgery Anhui Provincial Hospital Hefei 230001 China. jwd@***

OBJECTIVE: To investigate the effect of somatostatin analogue octreotide on angiogenesis induced byhepatocellular carcinoma (HCC) in vivo.METHODS: LCI-D20 corneal micropocket model in nude mouse was used to dynamically observeangiogenesis under a stereoscopic zoom microscope and a digital camera system and to evaluate the effectof octreotide on angiogenesis. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissuesfor tumor xenograft studies. Microvessel density in CD34-stained tumor sections was analyzed byimmunohistochemical SP method.RESULTS: Tumor tissues from LCI-D20 implanted into the corneal micropocket induced angiogenesis.When animals received systemic octreotide treatment, angiogenesis response in the cornea of mice wasmoderate, the appearance of vascular buds was delayed, and the new capillaries were sparse and grewslowly. Compared with the control group, the neovascularization induced by HCC in the cornea of micewas markedly inhibited on day 7, 9, 12, 15, 18 and 21 after implantation in the octreotide-treated group(P<0.05). Systemic administration of octreotide produced a significant suppression of the growth ofLCI-D20. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in theoctreotide-treated animals as compared with the controls (21.7±4.27 versus 31.8±3.87, P<0. 01).CONCLUSION: Somatostatin analogue octreotide is able to inhibit angiogenesis induced by HCC invivo and may provide a new approach to the treatment of HCC.

关键词： liver neoplasms neovascularization angiogenesis octreotide

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Evaluation of carotid plaque neovascularization in patients with coronary heart disease using contrast-enhanced ultrasonography

Evaluation of carotid plaque neovascularization in patients ...

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中国超声医学工程学会第十四届全国超声心动图学术会议

作者： Chuan Qin Li Zhang Xinfang Wang Yilian Duan Zhou Ye MingxingXie Department of Ultrasound Union HospitalTongji Medical CollegeHuazhong University of Science and Technology Hubei Province Key Lab of Molecular Imaging

Objective:To examine the the repeatability of the TIC quantitative analysis software in the micro blood perfusion of neovascularization within carotid plaques by contrast-enhanced ultrasonography(CEUS).To investigate carotid plaque neovascularization in patients with coronary heart disease(CHD) using CEUS,and the correlation between the risk factors and acute coronary syndrome(ACS).Method:A total of 60 ACS patients and 60 stablecoronary artery disease(SCAD) patients were selected to undergo conventional carotid ultrasonography and CEUS,and the plaque enhancement was observed and analyzed quantitatively.The inclusive criteria were matched with 2003 American Heart Association criteria for ACS.Carotid CEUS was performed in relation to the ACS occur within one month.CEUS using a II-generation contrast agent,SonoVue(sulphur hexafluoride microbubbles surrounded by a phospholipid shell).Interobserver and intraobserver variability of the measurements was assessed.A is the maximum number of microbubblesthat local tissues could accumulate,reflecting the local microvascular density and representing the capillary volume.Results:The ACS group presented higher low-density lipoprotein cholesterol(LDL-C)(3.21±0.75 &2.53±0.71,P<0.05) and high-sensitivity C-reactive protein(hs-CRP)(3.76±0.19 & 2.93±0.15,P<0.05)than the SCAD group.The proportion of soft plaques in the ACS group(72%) was higher than that in the SCAD group.The proportion of plaque enhancement,intensity of plaque enhancement(A) and ratio of enhancement intensity in the plaque to that in the carotid lumen in the ACS group were higher than those in SCAD group.The A value was correlated with the hs-CRP value;the sensitivity and specificity of A value were80.0%and 88.3%,respectively.Logistics regression analyses indicated that age(65-74 years),hs-CRP and A were correlated with the occurrence of ACS.The sensitivity and specificity of the A value of carotid plaques were 80.0%and 88.3%,respectively,(the cut-off valuewas 9.97 dB and the AUC was0.865).The measurements using qu

关键词： contrast-enhanced ultrasoungraphy carotid plaque neovascularization acute coronary syndrome

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Angiogenesis Inhibitor Endostar Prevents Vasa Vasorum neovascularization in the Swine Atherosclerosis Model

Angiogenesis Inhibitor Endostar Prevents Vasa Vasorum Neovas...

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2016年浙江省医学会心电生理与起搏学术年会

作者： Xiaoming XU Wei MAO Zhejiang Traditional Chinese Medical Hospital

Aim:Vasa vasorum neovascularization is a key feature of atherosclerosis and is strongly associated with inflammatory infiltration,lipid deposition,intraplaque hemorrhage,and hemosiderin deposit.Here we investigate the effects of Endostar,a strong anti-angiogenic drug,on vasa vasorum neovascularization in the experimental porcine model of early atherosclerosis.Methods:Eighteen adult male Ba-Ma mini pigs were randomly divided into three groups,with six animals in each group.The pigs in the normal(N) group were fed a normal diet for 18 weeks without balloon injury surgery.The animals in the atherosclerotic(AS) control group and theAS+Endostar group were fed a hypercholesterolemic diet for12 weeks after balloon injury surgery,and received either saline or Endostar treatment for an additional six weeks,while remaining on the hypercholesterolemic diet.The atherosclerotic abdominal aorta and levels of serum lipids,TNF-alpha,IL-6 and hs-CRP were analyzed at 18 weeks.Results:The AS group had significantly higher body weight and serum lipid concentration levels than the N group(p<0.05),attesting to the success of the hypercholesterolemic diet.However,no statistical differences were noted between the AS and AS+Endostar groups.Histopathology results revealedthat vasa vasorum density and intima-media thickness(IMT) had also increased in the AS group,as compared with the N group(p<0.05).Endostar treatment significantly alleviated atherosclerosis with decreased vasa vasorum density and IMT(AS vs.AS+Endostar,p<0.05).The results from western blot analysis indicated that the expression of VEGF,β-catenin and TNF-alpha in the atherosclerotic abdominal aorta was considerably reduced by the Endostar treatment.In addition,immunohistochemistry results showed that the angiogenesis markers VEGF and β-catenin were predominately localized in endothelial cells of adventitial vasa vasorum.The levels of serum inflammatory markers TNF-alpha,hsCRPandIL-6 were significantly higher in the AS groupcompared with the N group(p<0.05),but showed no sig

关键词： atherosclerosis vasa vasorum neovascularization Endostar swine

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Cathepsin K effects Ischemia-Induced neovascularization in old Mice

Cathepsin K effects Ischemia-Induced Neovascularization in o...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：姜海英 Xianwu Cheng Yanhua Bing Qinghua Jin Department of Community Healthcare & Geriatrics Nagoya University Graduate School of Medicine Department of Physiology and Pathophysiology Yanbian University Medical College

Cysteinyl cathepsins(Cats)have been implicated in the process of angiogenesis.we investigated the role of Cat K in ischemia-induced neovascularization with a special focus on Notch1 activation in old mice.Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in Cat K Deficient old mice remained impaired throughout the follow-up period.On the operative day14,Cat K deficiency also impaired capillary and collateral vessel formation.Cat K deficiency reduced the levels of cleaved Notch-1,p-Akt proteins in the ischemic muscles,and reduced circulating numbers of EPC-like CD31+/c-Kit+cells than young mice.This study demonstrated that Cat K deficiency impairs ischemia-induced neovascularization through a reduction of EPC angiogenic functions and it associated impairment of Notch1 signaling.

关键词： Cathepsin K neovascularization Ischemia old

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Interleukin (IL)-17A promotes angiogenesis in an experimental corneal neovascularization model

Interleukin (IL)-17A promotes angiogenesis in an experimenta...

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第十二届全国免疫学学术大会

作者： Liu Gaoqin Lu Peirong Department of Ophthalmology the First Affiliated Hospital of Soochow University

Aim and scope:To explore the roles of interleukin(IL)-17 A in alkali-induced corneal neovascularization(CRNV).Material and Method:Induction of CRNV by alkali injury was performed and compared in recombinant mouse IL-17 A protein or anti-mouse IL-17 A neutralizing antibody(Ab)-treated mice.The expression of IL-17 A,IL-17 A receptor(IL-17 RA),vascular endothelial growth factor(VEGF),IL-6,IL-8 and monocyte chemoattractant protein-1(MCP-1) in burned corneas or other cells was examined by RT-PCR and western blot.The infiltration of macrophages,neutrophils and c-Kit positive progenitor cells into burned corneas was detected by flow cytometry(FCM).The Raw264.7 cell line and mouse corneal fibroblasts were stimulated by mouse recombinant IL-17 A or anti-mouse IL-17 A neutralizing Ab in vitro,and the expression of IL-6 and VEGF in culture supernatant was determined by ELISA assay.Results:The alkali-induced CRNV peaked 2 weeks after the alkali burn.Compared to the vehicle-treated group,mouse recombinant IL-17 A administration significantly increased the amount of corneal neovascularization,and it decreased in mice treated with neutralizing anti-mouse IL-17 A Ab.RT-PCR and western blot confirmed that the IL-17 A up-regulated intracomeal VEGF,IL-6,IL-8,MCP-1 and phosphorylated focal adhesion kinase(pFAK) expression.FCM revealed that the infiltration of intracomeal progenitor cells,macrophages and neutrophils were also augmented in IL-17 A-treated mice.The ELISA assay showed that IL-17 A markedly induced VEGF and IL-6 expression in the Raw264.7 murine macrophage cell line and in the mouse corneal fibroblasts.Conclusion:IL-17 A-treated mice exhibited enhanced alkali-induced CRNV through enhanced intracomeal progenitor cell and inflammatory cell infiltration,and increased VEGF and IL-6 expression by fibroblasts and macrophages.

关键词： IL-17A neovascularization corneal chemokine inflammation

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