肝癌组织中环氧合酶-2血管内皮生长因子表达与肿瘤血管生成的关系

目的观察肝癌（HCC）组织中环氧合酶-2（COX-2）、血管内皮生长因子（VEGF）的表达水平及和肿瘤血管形成的关系。方法应用免疫组织化学方法检测40例肝癌患者手术切除标本的COX-2、VEGF的表达．抗CD34单克隆抗体显示血管内皮细胞，根据CD34阳性的血管内皮细胞计数来测定肿瘤微血管密度（MVD）。结果高分化HCC中COX-2蛋白表达显著高于中分化和低分化HCC（P〈0.05）；转移组COX-2表达显著高于无转移组（P〈0.01）。转移组VEGF蛋白表达显著高于无转移组（P〈0．01）；无包膜HCC中VEGF蛋白表达显著高于有包膜HCC（P〈0．05）。转移组MVD显著高于无转移组（P〈0．01）。COX-2和VEGF及VEGF和MVD之间表达的强弱呈正相关（分别r=0．6261，r=0．6097，均P〈0．001）。结论COX-2的过度表达可能与高分化HCC有关。     

ANGPTL4基因表达和血管生成与胃癌发展的关系

目的探讨ANGPTL4 mRNA的表达和血管生成与胃癌发展的关系。方法选择50例胃癌患者组织标本作为实验组,10例正常胃黏膜标本作为对照组,采用原位杂交技术检测ANGPTL4 mRNA表达,免疫组化染色法检验微血管密度,并分析其与胃癌临床病理学特征的关系。结果 ANGPTL4 mRNA阳性率及微血管密度MVD计数均为胃癌组织〉癌旁组织〉正常胃黏膜,差异有统计学意义（P〈0.01）。经Pearson相关分析,ANGPTL4mRNA阳性率与MVD计数呈正相关（P〈0.05）。胃癌组织中ANGPTL4阳性表达率与MVD计数与年龄、性别无关,与组织病理分级、TNM分期、浸润深度及淋巴结转移密切相关（P〈0.05）,分别与组织病理分级、TNM分期、浸润深度呈正相关（P〈0.05）。结论胃癌组织中ANGPTL4mRNA高表达可能促进新生血管形成,肿瘤细胞浸润和转移。     

Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy

Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway, but it also recognizes and inactivates various anti-cancer chemotherapeutic agents. Moreover, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), an angiogenic factor with anti-apoptotic properties. Increased expression of PD-ECGF/TP is found in many tumor and stromal cells, and elevated TP levels are associated with aggressive disease and/or poor prognosis. Thus, progression and metastasis of TP-expressing tumors might be abrogated by TP inhibitors that are used as single agents or in combination with (TP-sensitive) nucleoside analogues. On the other hand, increased TP activity in tumors may be exploited for the tumor-specific activation of fluoropyrimidine prodrugs, such as capecitabine. This review will focus on the different biological activities of PD-ECGF/TP and their implications for cancer progression and treatment.     

转化生长因子β1和VEGF在甲状腺癌组织中的表达及其与血管生成的关系

目的探讨转化生长因子(TGF)β1和血管内皮生长因子(VEGF)在甲状腺癌组织中的表达及其与肿瘤血管生成的关系.方法采用免疫组织化学方法,检测46例甲状腺癌组织中TGFβ1与VEGF表达及肿瘤微血管计数(MVC).结果 46例甲状腺癌组织中TGFβ1阳性表达率为63.04%(29/46),TGFβ1阳性表达者MVC值(26.18±4.05)显著大于阴性表达者(20.13±4.29),VEGF阳性表达者35例,阳性表达率为79.06%,VEGF阳性表达者MVC值(25.82±3.61)亦显著大于阴性表达者(19.65±6.32)(均P＜0.05),TGFβ1、VEGF阳性表达率在乳头状癌、滤泡癌、髓样癌及未分化癌中两两比较差异均无统计学意义(P＞0.05),在Ⅰ、Ⅱ、Ⅲ、Ⅳ期甲状腺癌中两两比较差异也均无统计学意义(P＞0.05).结论 TGFβ1与VEGF表达与甲状腺癌组织学分型、临床分期无关,但参与甲状腺癌肿瘤血管生成过程.     

垂体腺瘤中VEGF表达、血管生成与腺瘤侵袭性的关系

目的:探讨垂体腺瘤中血管生成的程度及其与肿瘤侵袭性的关系.方法:采用免疫组化SP法对47例垂体腺瘤(侵袭性25例、非侵袭性22例)病理标本和4例正常脑垂体标本检测血管内皮细胞生长因子(VEGF)的表达和第Ⅷ因子相关抗原(F8-RA)组化染色行微血管记数(MVC)并作统计学分析.结果:侵袭性垂体腺瘤中VEGF表达及MVC均显著大于非侵袭性腺瘤(P＜0.05),VEGF表达强度与MVC两者在垂体腺瘤血管生成中呈正相关(r=0.7625, P＜0.01).结论:腺瘤组织中的VEGF的异常表达和MVC能够准确地反映垂体腺瘤血管的生成程度与腺瘤侵袭密切相关,可为临床上评价垂体腺瘤侵袭性及预后提供生物学上的参考指标.     

一氧化氮与子宫颈癌可能关系的探讨

目的　探讨一氧化氮 (NO)与子宫颈癌的关系。方法　采用一氧化氮代谢量测定法及分光光度计在 5 40 nm波长下测定 32例子宫颈癌及 2 4例慢性子宫颈炎患者组织中的 NO- 2 / NO- 3 含量。结果　子宫颈癌组织中 NO含量 (2 31± 2 4)明显高于子宫颈炎组织中 NO含量 (194± 2 1)。随子宫颈癌临床分期增高 ,NO含量虽有增高趋势 ,但无统计学差异。结论　子宫颈癌组织中 NO含量明显升高 ,可能与子宫颈癌的发生发展有一定关系。     

Bradykinin promotes vascular endothelial growth factor expression and increases angiogenesis in human prostate cancer cells

Prostate cancer is the most commonly diagnosed malignancy in men and shows a tendency for metastasis to distant organs. Angiogenesis is required for metastasis. Bradykinin (BK) is an inflammatory mediator involved in tumor growth and metastasis, but its role in vascular endothelial growth factor (VEGF) expression and angiogenesis in human prostate cancer remains unknown. The aim of this study was to examine whether BK promotes prostate cancer angiogenesis via VEGF expression. We found that exogenous BK increased VEGF expression in prostate cancer cells and further promoted tube formation in endothelial progenitor cells and human umbilical vein endothelial cells. Pretreatment of prostate cancer with B2 receptor antagonist or small interfering RNA (siRNA) reduced BK-mediated VEGF production. The Akt and mammalian target of rapamycin (mTOR) pathways were activated after BK treatment, and BK-induced VEGF expression was abolished by the specific inhibitor and siRNA of the Akt and mTOR cascades. BK also promoted nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) activity. Importantly, BK knockdown reduced VEGF expression and abolished prostate cancer cell conditional medium-mediated angiogenesis. Taken together, these results indicate that BK operates through the B2 receptor, Akt, and mTOR, which in turn activate NF-κB and AP-1, activating VEGF expression and contributing to angiogenesis in human prostate cancer cells.     

Enhancement of gastric mucosal epidermal growth factor and platelet-derived growth factor receptor expression by sucralfate.

1. The effect of an anti-ulcer agent, sucralfate, on the expression of gastric mucosal epidermal growth factor (EGF) and platelet derived growth factor (PDGF) receptors was investigated. 2. Gastric mucosal cell membranes, isolated from the stomach of groups of rats, one receiving twice daily for 3 consecutive days a dose of 100 mg/kg sucralfate, and the other only the vehicle, were used as source for EGF and PDGF receptors. 3. Binding assays revealed the presence of both types of receptors, activation of which led to the elevation of tyrosine kinase activity as evidenced by a marked increase in membrane protein tyrosine phosphorylation patterns. 4. The specific receptor binding in the control group was 2.46 fmol/mg protein for EGF and 1.46 fmol/mg protein for PDGF, whereas the respective binding values in the sucralfate treated group increased by 61 and 65%. 5. The results suggest that sucralfate is capable of enhancement of epithelial proliferative activities through the stimulation of gastric mucosal EGF and PDGF receptors.     

Investigational platelet-derived growth factor receptor kinase inhibitors in breast cancer therapy

Introduction: Aberrant regulation of platelet-derived growth factors (PDGFs) and their receptors (PDGFR) has been shown to be involved in many solid tumors, including breast cancer. PDGFR-α and PDGFR-β expressions were documented in breast cancer and are correlated with tumor aggressiveness and metastasis. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake.

Areas covered: This review summarizes the present understanding of PDGF signaling in breast cancer based on experimental studies and available clinical trials. It also provides a critical discussion of selected ongoing clinical trials in patients with breast cancer involving PDGFR inhibition with tyrosine kinase inhibitors, specifically in endocrine responsive breast cancer.

Expert opinion: An increased molecular understanding of response and resistance mechanisms to endocrine therapy will be essential for therapeutic advances in PDGFR-directed cancer therapy. Future developments in the field will rely on clinical studies where prospective analyses of target expression in breast cancer cells and in the tumor stroma are included. More selective PDGFR inhibitors with reduced side effects will be crucial for combinatorial therapies. Development of sensitive diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.     

端粒酶与bcl-2及bax蛋白在宫颈癌中表达的相关性研究

目的:探讨端粒酶检测在宫颈癌诊断中的作用及其在宫颈癌发生中与bcl-2和bax蛋白表达的相关性.方法:用原位杂交方法检测端粒酶的表达及其活性,采用免疫组织化学Envision法检测bcl-2和bax.结果:端粒酶在宫颈癌中的表达率明显高于癌前病变(P＜0.01)和宫颈良性肿瘤.端粒酶活性与bcl-2表达呈负相关,与bax表达呈显著负相关,与bcl-2/bax比值明显正相关.结论:bcl-2/bax表达失衡(比值增大)可能是端粒酶激活的重要途径之一.     

米非司酮对子宫腺肌病组织中血小板源性生长因子表达及对月经的影响

目的探讨米非司酮对子宫腺肌病患者在位内膜组织中血小板源性生长因子(PDGF)表达及对月经的影响的可能机制。方法 2006年1月至2011年8月在山西医科大学第一医院妇科因子宫腺肌病行子宫切除术者为研究组,因宫颈上皮内瘤变(CIN)Ⅲ行子宫切除术者为对照组,采用组织芯片和免疫组织化学SP法,检测试验组、对照组在位子宫内膜组织中PDGF的表达水平以及对月经的影响,并比较其差异。结果 PDGF主要表达在子宫内膜腺细胞胞质内,对照组(17%)与试验组在位内膜(37%)阳性率差异有统计学意义(P<0.05);PDGF阳性表达率用米非司酮干预组(27%)与未用米非司酮组(70%)之间差异有统计学意义(P<0.05);月经量改变与PDGF阳性表达率差异有统计学意义。小剂量米非司酮有抑制子宫出血的作用,无不良反应。结论 PDGF参与子宫腺肌病的发病过程;米非司酮对PDGF有抑制作用。PDGF在月经改变中可能起一定的作用。小剂量、短时间应用米非司酮可抑制子宫出血。     

人类表皮生长因子受体-2阳性乳腺癌患者甲状腺激素与血管内皮生长因子的关系分析

目的探析人类表皮生长因子受体-2(HER-2)阳性乳腺癌患者甲状腺激素与血管内皮生长因子(VEGF)表达情况。方法随机数字表法选取天津医科大学附属肿瘤医院乳腺科2011年9月至2014年9月收治的50例HER-2阳性乳腺癌患者纳入A组,另随机数字表法抽取同期收治的HER-2阴性乳腺癌患者(B组)、乳腺良性病变患者(C组)各50例。检测3组甲状腺激素水平[三碘甲腺原氨酸(T3)、甲状腺素(T4)、游离三碘甲腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺素(TSH)]、比较A组与B组的VEGF表达情况、比较A组与B组VEGF阳性表达患者CD31与CD105标记的微血管密度(MVD)。结果 3组FT3、FT4及TSH的差异无统计学意义(P>0.05);A组与B组T3、T4水平的差异无统计学意义(P>0.05),但均高于C组(P<0.05)。A组患者的VEGF mRNA阳性率与VEGF蛋白阳性率分别为66%、62%,均高于B组(P<0.05)。A组VEGF mRNA(+)患者CD31、CD105标记的MVD分别为(20±6)/mm~2、(25±7)/mm~2,均高于B组(P<0.05);A组VEGF蛋白(+)患者CD31、CD105标记的MVD分别为(20±6)/mm~2、(26±5)/mm~2,均高于B组(P<0.05)。结论较之乳腺良性病变患者,乳腺癌患者化疗前T3与T4水平明显偏低,HER-2阳性乳腺癌患者的血管内皮生长因子表达强于HER-2阴性患者。     

The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis

Introduction: Fibroblast growth factors (FGFs) are endowed with a potent pro-angiogenic activity. Activation of the FGF/FGF receptor (FGFR) system occurs in a variety of human tumors. This may lead to neovascularization, supporting tumor progression and metastatic dissemination. Thus, a compelling biologic rationale exists for the development of anti-FGF/FGFR agents for the inhibition of tumor angiogenesis in cancer therapy.

Areas covered: A comprehensive search on PubMed was performed to identify studies on the role of the FGF/FGFR system in angiogenesis. Endothelial FGFR signaling, the pro-angiogenic function of canonical FGFs, and their role in human tumors are described. In addition, experimental approaches aimed at the identification and characterization of nonselective and selective FGF/FGFR inhibitors and their evaluation in clinical trials are summarized.

Expert opinion: Different approaches can be envisaged to inhibit the FGF/FGFR system, a target for the development of ‘two-compartment’ anti-angiogenic/anti-tumor agents, including FGFR selective and nonselective small-molecule tyrosine kinase inhibitors, anti-FGFR antibodies, and FGF ligand traps. Further studies are required to define the correlation between tumor vascularization and activation of the FGF/FGFR system and for the identification of cancer patients more likely to benefit from anti-FGF/FGFR treatments. In addition, advantages and disadvantages about the use of selective versus non-selective FGF inhibitors remain to be elucidated.     

Vascular endothelial growth factor and angiogenesis

Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of pro- and antiangiogenic molecules have already been discovered. Vascular endothelial growth factor (VEGF) is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF in physiological and pathological processes is reviewed. We also discuss how modulation of VEGF expression creates new therapeutic possibilities and describe recent developments in this field.     

Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer

The treatment of advanced non ? small cell lung cancer (NSCLC) increasingly involves the use of molecularly targeted therapy with activity against either the tumor directly, or indirectly, through activity against host-derived mechanisms of tumor support such as angiogenesis. The most well studied signaling pathway associated with angiogenesis is the vascular endothelial growth factor (VEGF) pathway, and the only antiangiogenic agent currently approved for the treatment of NSCLC is bevacizumab, an antibody targeted against VEGF. More recently, preclinical data supporting the role of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) signaling in angiogenesis have been reported. The platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways may also stimulate tumor growth directly through activation of downstream mitogenic signaling cascades. In addition, 1 or both of these pathways have been associated with resistance to agents targeting the epidermal growth factor receptor (EGFR) and VEGF. A number of agents that target FGF and/or PDGF signaling are now in development for the treatment of NSCLC. This review will summarize the potential molecular roles of PDGFR and FGFR in tumor growth and angiogenesis, as well as discuss the current clinical status of PDGFR and FGFR inhibitors in clinical development.     

血管内皮生长因子在大肠癌中的表达及其与病理特征的关系探讨

目的 探讨血管内皮生长因子（VEGF）在大肠癌中的表达与病理特征的关系。方法 对99例大肠癌标本进行免疫组织化学染色（SP法），采用单克隆抗体VEGF进行标记。结果 VEGF阳性率：结肠癌51．16％（22／43），直肠癌67-86％（38／56）；高中分化腺癌组62．50％（45／72），其他组55．56％（15／27）；浸肌层组42．86％（12／28），浸浆膜组67．61％（48／71）；有转移组72．00％（36／50），无转移组48．99％（24／49）。VEGF的表达与大肠癌的发生部位、组织学分型无明显关系，与大肠癌浸润深度及淋巴结转移明显相关。结论 VEGF可作为判断大肠癌复发及预后的一个重要指标。     

Ghrelin和MMP-9在结直肠癌组织中的表达及意义

目的：观察生长激素释放肤（growth hormone releasing peptide,Ghrelin）和基质金属蛋白酶-9（Matrix metalloproteinases,MMP-9）在结直肠癌组织中的表达水平及意义。方法：应用免疫组织化学方法检测Ghrelin和MMP-9在67例结直肠癌组织及62例癌旁正常黏膜组织中的表达,分析Ghrelin和MMP-9与结直肠癌临床病理特征的关系及两者的相关性。结果：Ghrelin在结直肠癌组织中的阳性表达率为59．70％,高于癌旁正常黏膜组织（24．39％,P〈0．05）;MMP-9在结直肠癌组织中的阳性表达率为83．58％,显著高于癌旁正常黏膜组织（18．39％,P〈0．05）;Ghrelin和MMP-9的高表达与肿瘤浸润深度、分化程度、淋巴结转移和肝转移相关（P〈0．05）;Ghrelin与MMP-9的阳性表达呈正相关（K=0．832,P〈0．001）。结论：Ghrelin和MMP-9表达升高可能与结直肠癌的恶性程度相关,联合检测Ghrelin和MMP-9可能对结直肠癌恶性程度及患者预后评估具有重要意义。     

Sustained release of platelet-derived growth factor and vascular endothelial growth factor from silk/calcium phosphate/PLGA based nanocomposite scaffold

To exploit the therapeutic potential of growth factors in tissue regeneration, it is necessary to design a porous scaffold in order to concurrently accommodate cells and release angiogenic factors in a controlled manner. In an attempt to address these issues, we developed a nanocomposite scaffold based on silk/calcium phosphate/PLGA by freeze-drying and electrospinning in order to control the release of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). The highly porous scaffold possessed appropriate chemical and physical structure as confirmed by FTIR, XRD, SEM, and Zeta potential analysis. Furthermore, the incorporation of PDGF and VEGF in the scaffold was confirmed using Raman spectroscopy while their bioactivity was maintained by 82% and 89% for up to 28 days, respectively. The release of PDGF was slower than VEGF as respected. Additionally, the scaffold could promote proliferation, alkaline phosphatase production and attachment of human osteoblast cells. Histological examination established new bone matrix formation with neovascularization in the angiogenic factors loaded scaffold after 10 weeks of implantation in rabbit model. Finally, it was considered that the fabricated nanocomposite could be useful for bone tissue engineering applications.