Interleukin-11 Overexpression and M2 Macrophage Density are Associated with Angiogenic Activity in Proliferative Diabetic Retinopathy

ABSTRACT

Purpose

To investigate the expression of IL-11 and its receptor IL-11Rα and to quantify density of CD163⁺ M2 macrophages in proliferative diabetic retinopathy (PDR).     

胰腺导管癌中血管生成、细胞增殖指数、DNA倍性检测的临床意义

目的:探讨血管生成、细胞增殖指数、DNA倍性在胰腺导管癌发生、发展中的作用及临床意义。方法:对29例胰腺导管癌和7例慢性胰腺炎患者的石蜡包埋标本作苏木精鄄伊红(HE)染色,CD34、Ki67免疫组织化学染色,镜下计算微血管密度(MVD)及Ki67阳性细胞比例,同时用流式细胞仪(FCM)检测细胞核DNA倍性,计算异倍体出现率及S期比例,并结合临床病理资料对各项指标作相关分析。结果:胰腺导管癌和慢性胰腺炎都有较多的新生血管。MVD值在胰腺导管癌高、中、低分化3组之间差异无显著性。按肿瘤直径分为≤1.5cm、1.6～2.9cm、≥3cm3组,此3组间MVD值、Ki67阳性细胞百分率、DNA异倍体出现率及肿瘤周围有无浸润的差异都非常显著(P<0.01)。肿瘤越大,MVD值、Ki67阳性细胞百分率及DNA异倍体出现率越高。结论:胰腺导管癌的发生、发展伴血管生成和DNA合成增加,联合测定MVD、Ki67阳性细胞百分率、DNA倍型可能为胰腺导管癌临床预后预测提供辅助参考指标。     

L-arginine对局灶脑缺血脑细胞凋亡和微血管密度的影响

目的探讨NO合成底物左旋-精氨酸(L-Arg)对兔局灶脑缺血后血管再生和脑细胞凋亡的影响。方法兔局灶脑缺血后应用L-Arg,流式细胞仪定量分析细胞凋亡率的变化,CD34免疫组织化学测脑组织微血管密度(MVD),脑组织含水率评价脑水肿。结果与对照组比较,L-Arg组脑细胞凋亡率明显减少(8.72±2.62 vs 16.62±2.82,P<0.01),同时脑组织MVD却明显增加(1.21±0.43 vs 0.69±0.22,P<0.01)。结论外源性L-Arg可减少缺血后脑细胞凋亡并促进缺血后血管再生,对局灶脑缺血具有重要的神经保护作用。     

RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

Association of Vascular Endothelial Growth Factor Expression with Tumor Angiogenesis and with Early Relapse in Primary Breast Cancer

Angiogenesis is an independent prognostic indicator in breast cancer. In this report, the relationship between expression of vascular endothclial growth factor (VEGF; a selective mitogen for endothelial cells) and the microvessel density was examined in 103 primary breast cancers. The expression of VEGF was evaluated by immunocytochemical staining using anti-VEGF antibody. The microvessel density, which was determined by immunostaining for factor VIII antigen, in VEGF-rich tumors was clearly higher than that in VEGF-poor tumors ( P <0.01). There was a good correlation between VEGF expression and the increment of microvessel density. Furthermore, postoperative survey demonstrated that the relapse-free survival rate of VEGF-rich tumors was significantly worse than that of VEGF-poor tumors. It was suggested that the expression of VEGF is closely associated with the promotion of angiogenesis and with early relapse in primary breast cancer.     

Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis

Human lymphoproliferative diseases can be hypothesized to invade locally and to metastatize via mechanisms similar to those developed by a variety of solid tumors, i.e., the secretion of extracellular matrix-degrading enzymes and stimulation of angiogenesis. To assess this hypothesis, Namalwa, Raji, and Daudi cell lines (Burkitt’s lymphoma), LIK and SB cell lines (B-cell lymphoblastic leukemia), CEM and Jurkat cell lines (T-cell lymphoblastic leukemia), and U266 cell line (multiple myeloma) were evaluated for their capacity to produce matrix metalloproteinase-2 and -9, and urokinase-type plasminogen activator. These cell lines were also assessed for their ability: (1) to produce the angiogenic basic fibroblast growth factor and vascular endothelial growth factor; (2) to induce an angiogenic phenotype in cultured endothelial cells, represented by cell proliferation, chemotaxis, and morphogensis; (3) to stimulate angiogenesis in different in vivo experimental models. All cell lines expressed the mRNA for one or both metalloproteinases. Namalwa, Raji, LIK, SB, and U266 cells secreted the active form of both metalloproteinases, while Daudi, CEM, and Jurkat cells produced metalloproteinase-2 but not -9. In contrast, urokinase-type plasminogen activator was secreted only by SB cells. While Raji, LIK, SB, CEM, and Jurkat cells secreted both basic fibroblast growth factor and vascular endothelial growth factor, Daudi and U266 cells produced only the former, and Namalwa cells only the latter. Accordingly, the conditioned medium of all cell lines stimulated cell proliferation and/or chemotaxis in cultured endothelial cells, with the exception of that of Namalwa cells which was ineffective. The conditioned medium of CEM and Jurkat cells induced morphogenesis in cultured endothelial cells grown on a reconstituted basement membrane (Matrigel). Lastly, Namalwa, Raji, LIK, SB, U266, CEM, and Jurkat cells induced angiogenesis and mononuclear cell recruitment in the murine Matrigel sponge model and in a chick embryo chorioallantoic membrane assay. The extent of angiogenesis in both models was strictly correlated with the density of the mononuclear cell infiltrate. The results indicate that human lymphoproliferative disease cells possess both local and remote invasive ability via the secretion of matrix-degrading enzymes and the induction of angiogenesis which is fostered by host inflammatory cells and by an intervening ensemble of angiogenic factors.     

血管生成素-2在食管鳞癌中的表达及意义

目的初步探讨血管生成素-2(Angiopoietin-2,Ang-2)在食管鳞状细胞癌组织中的表达及其与肿瘤病理分级、浸润和转移的关系。方法采用S-P免疫组织化学方法,对85例食管鳞癌及22例正常食管组织中的Ang-2表达水平进行检测,并与肿瘤病理分级、浸润深度及淋巴结转移情况进行统计学分析。结果85例食管鳞癌组织中,57例Ang-2表达呈阳性,阳性率为67.06%,显著高于Ang-2在正常食管组织中的表达(P<0.05)。Ang-2表达与肿瘤病理分级和淋巴结转移显著相关(P<0.05)。结论Ang-2的表达与食管鳞癌的临床分期及病理分级呈正相关,提示Ang-2促进肿瘤新生血管形成,参与食管鳞癌的发生和发展,可作为反映食管癌进展的生物学指标。     

环氧合酶-2和血管内皮生长因子共表达与肝细胞癌血管形成的关系

目的　探讨环氧合酶 (COX) 2与肝细胞癌血管形成的关系。方法　利用免疫组织化学、Westernblot方法检测 48例肝癌组织中COX 2和血管内皮生长因子 (VEGF)蛋白及逆转录 聚合酶链反应法 (RT PCR)检测COX 2和VEGFmRNA的共表达 ,对共表达COX 2和VEGF蛋白和mRNA的肝癌组织进行微血管记数。结果　免疫组织化学检测中 ,48例肝癌组织 3 6例共表达COX 2和VEGF蛋白。类似结果见于蛋白电泳分析。RT PCR显示 ,48例肝癌组织 3 6例共表达COX 2mRNA和VEGFmRNA。两者之间的表达明显相关 (γ =0 .845 )。共表达COX 2和VEGF蛋白和mRNA的肝癌组织中 ,平均微血管数 (5 6.8± 17.5 )个 ,明显高于阴性表达组。结论　COX 2可能与肝细胞癌的血管形成有关 ,且其作用之一可能是通过上调VEGF通道来发挥的     

sVE‐cadherin and sCD146 serum levels in patients with multiple myeloma

The role of angiogenesis in multiple myeloma (MM) pathogenesis is well established. Angiogenesis is linked to the functional state of endothelial junctions that are modulated by the growth and activation of endothelial cells. CD146 and vascular endothelial‐cadherin (VE‐cadherin) are cell adhesion molecules localized at the endothelial junction. The aim of the study was to assess sVE‐cadherin and sCD146 serum levels in MM patients. Forty‐six untreated patients with MM were included in this study. In addition, 23 of 46 patients were analyzed again in partial remission after initial chemotherapy. Twenty‐two samples from healthy volunteers were evaluated as the control. There was no significant difference in sCD146 level between MM patients and the control (511 ± 177.2 vs. 460.9 ± 156.9 ng/ml respectively). In untreated MM patients, sVE‐cadherin level was significantly higher than in the control (1.36 ± 0.55 vs. 0.63 ± 0.56 ng/ml respectively; P < 0.05). In untreated MM patients, sVE‐cadherin level was significantly higher than in MM patients in partial remission (1.36 ± 0.55 vs. 0.5 ± 0.33 respectively; P < 0.05). sVE‐cadherin but not sCD146 serum level was increased in untreated MM patients and decreases after chemotherapy in patients in partial remission. VE‐cadherin may reflect intensity of angiogenesis in MM and may be useful in prognosis of response to treatment.     

Genetically modified fibroblasts induce angiogenesis in the rat epigastric island flap

Methods: Gene therapy was tested for inducing functional angiogenesis in the superficial rat epigastric island flap to allow earlier pedicle division. Autologous rat fibroblasts were grown, harvested, cultured and retrovirally transfected to produce platelet-derived growth factor AA (PDGF-AA), an angiogenetically active protein. Stable gene expression was monitored by PDGF-AA enzyme-linked immunosorbent assay (ELISA). One hundred and eighty animals were divided into three groups (I–III) and a bilateral flap created in each animal. In all experiments, the right-sided flap was subjected to experimental treatment and the left-sided flap served as control (1 ml saline 0.9%). During flap elevation, group I received 5×10⁶ GMFB (genetically modified fibroblasts) plus 1 ml Dul-becco's modified Eagle's medium. Group II was treated with 5×10⁶ NMFB (non-modified fibroblasts) plus 1 ml medium and group III received 1 ml medium only. The flaps were sutured back and the vascular pedicle was bilaterally ligated and divided in each of ten animals during the following 6 days. After 7 days, the flaps were harvested, the amount of necrosis measured and histologically examined. Results: The GMFB produced up to 560 times more PDGF-AA than the NMFB, measured by ELISA. The GMFB-treated flaps tolerated surgical division of the vascular pedicle significantly earlier than groups II and III. Histologically, fibroblasts persisted in all flaps of groups I and II, without major inflammatory reaction. In all GMFB-treated flaps, massive angiogenesis could be demonstrated. Conclusion: By means of retroviral gene transfer, autologous rat fibroblasts can be genetically modified for stable expression of the PDGF-A gene to produce high amounts of PDGF-AA, which is angiogenetically active. After injection into the panniculus carnosus, these cells induce functional angiogenesis to permit earlier division of the vascular pedicle in this flap model. Received: 5 January 1998 / Accepted: 17 June 1998