血管内皮生长因子和微血管密度在食管癌组织中的意义

目的 :探讨血管内皮生长因子 (VEGF)蛋白表达和微血管密度 (MVD)与食管癌临床病理的关系。方法 :应用免疫组织化学SABC法 ,以鼠抗VEGF、兔抗FⅧRAg、UEA 1抗体标记 5 2例食管癌和 5例正常食管黏膜 ,观察其在不同分化程度、浸润深度和有无淋巴结转移食管癌中的表达及MVD情况。结果 :癌组织VEGF阳性 2 8例 (5 3 9% ) ,MVD平均为 5 1 3± 14 8。VEGF蛋白表达和MVD与癌组织分化程度、淋巴结转移有关 (P <0 0 5 ,P <0 0 1) ;与癌组织浸润深度无关 (P >0 0 5 )。结论 :提示VEGF与癌组织血管发生密切相关 ,VEGF蛋白表达和MVD可作为判断食管癌的恶性程度和预后的生物学指标     

Prognostic significance of microvessel density and vascular endothelial growth factor expression in sinonasal carcinomas

The prognostic significance of microvessel density and proliferative activity of the neoplastic cells, evaluated respectively by CD31 and Ki-67 positivity, and immunohistochemical expression of vascular endothelial growth factor (VEGF) was retrospectively investigated in 105 cases of sinonasal carcinoma (80 surgical specimens and 25 biopsies). The most represented histologic types were intestinal-type adenocarcinoma found in 36 patients (34.3%), squamous cell carcinoma (SCC) in 34 (32.4%), mucinous adenocarcinoma (mainly made up of signet-ring cell patterns) in 15 (14.3%), and adenoid cystic carcinoma in 7 (6.7%). Microvessel density values (in vessels per square millimeter), VEGF, and Ki-67 were not dependent on histologic type but were rather correlated to the histologic grading in SCC. Clinical data were available for 92 (87.6%) of 105 patients, with minimum follow-up of 48 months. Most of the patients (81.5%) were at an advanced stage (T3-T4) at diagnosis. The values of all markers were correlated to tumor stage (P = .03). Multivariate analysis showed that both microvessel density and proliferative activity of the neoplastic cells were independent prognostic parameters (mortality hazard ratio, 1.33 and 1.60, respectively). Although VEGF expression was not correlated to prognosis on the whole series (P = .06), it was a powerful prognostic marker when the analysis was restricted to the group of SCCs (hazard ratio, 3.02; 90% confidence interval, 1.58-5.80). These results show that tumor neoangiogenesis, expressed by microvessel density, together with proliferative activity, is a pathologic marker with a strong prognostic impact in sinonasal carcinomas. Therefore, it may be a useful tool in this field so as to carry out therapeutic protocol planning, which may be further enhanced by the adoption of the more recent antiangiogenic molecules.     

血管内皮生长因子-D、 微血管密度及微淋巴管密度的表达与乳腺癌临床病理特征的相关性

目的 探讨乳腺癌中血管内皮生长因子D(vascular endothelial growth factor-D,VEGF-D)及微血管密度(microvessel density,MVD)、微淋巴管密度(Lymphatic vessel density,MLD)表达情况及意义.方法 收集2009年1月至2016年5月在临沂市肿瘤医院病理科存档病例,其中乳腺癌61例,乳腺增生症23例.采用免疫组化法检测各组织VEGF-D、MVD和MLD表达.结果 乳腺癌组织中VEGF-D蛋白阳性率为62.30%,明显高于乳腺增生组织,差异有统计学意义(χ2=16.215,P<0.05);乳腺癌组织中MVD和MLD分别为(17.70±7.10)和(2.41±0.85),明显高于乳腺增生组织,差异有统计学意义(t=10.900、t=8.795,P<0.05);VEGF-D表达与乳腺癌患者年龄、肿瘤大小以及淋巴结转移无明显关系(χ2=0.394、0.032、0.244,P>0.05);MVD和MLD密度与乳腺癌患者年龄和肿瘤大小无明显差异(χ2=0.081,0.126,0.219,0.196,P>0.05);VEGF-D、MVD和MLD密度与乳腺癌组织学分级相关(χ2=13.076、23.892、10.082,P<0.05),随着组织学分级递增,VEGF-D、MVD和MLD密度明显增高;MVD和MLD在乳腺癌伴淋巴结转移中密度明显高于无淋巴结转移(t=2.481、5.791,P<0.05).结论 VEGF-D在乳腺癌组织中呈高表达,可能在乳腺癌的发生发展中起重要作用,而MVD和MLD与乳腺癌肿瘤分化、转移有一定的关系.     

The correlation of angiogenesis with metastasis in primary cutaneous melanoma: a comparative analysis of microvessel density, expression of vascular endothelial growth factor and basic fibroblastic growth factor

AIM: To establish whether there is a correlation between angiogenesis and metastasis in primary cutaneous melanoma (PCMM). METHODS: We studied the microvessel density and the expression of vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) in 22 cases of PCMM with metastasis at presentation (metastatic group) and 28 cases of PCMM without metastasis for 24 months or more (non-metastatic group). Microvessels were stained with CD31/PECAM-1 antibody and counted. We assessed the proportion of VEGF expression in tumour cells, lymphocytes infiltrating the tumour (TIL) and lymphocytes at the periphery of the tumour, as well as the proportion of bFGF expression in tumour cell cytoplasms, nuclei and intra- and peritumoral vessels. RESULTS: An increased microvessel density was detected in the metastatic group (15-33 [24.09 +/- 5.55] versus 2-24 [12.96 +/- 6.02]). Moreover, enhanced expression of VEGF in tumour cells and peritumoral lymphocytes (Chi-square p = 0.038 and p = 0.018) and bFGF in peritumoral vessels (chi(2) p = 0.013) correlated with the simultaneous presence of melanoma metastasis in PCMM. Furthermore, microvessel density was correlated with the expression of bFGF in peritumoral vessels (rs = 0.53, p = 0.049) and VEGF in tumour cells (rs = 0.37, p = 0.019). CONCLUSION: Microvessel density as well as the expression of both VEGF and bFGF might be informative concerning the progression of melanoma.     

Stromal expression of vascular endothelial growth factor correlates with tumor grade and microvessel density in mammary phyllodes tumors: a multicenter study of 185 cases

A retrospective review of 185 mammary phyllodes tumors (105 benign, 51 borderline, 29 malignant) from 4 centers was performed by immunohistochemistry to investigate the expression of vascular endothelial growth factor in the epithelial and stromal cells of mammary phyllodes tumors. The correlation of vascular endothelial growth factor with tumor grade, stromal cell nuclear pleomorphism, cellularity, mitotic rate, margin histomorphology, and the stromal microvessel density was evaluated. Vascular endothelial growth factor expression was found in the epithelium in 29% and in the stromal cells in 31% of cases. There was significant increase of vascular endothelial growth factor expression in the stromal cells with increasing degree of malignancy, but not the epithelium. Microvessel density in the stroma also showed significant correlation with tumor malignancy, and a correlation was shown with the stromal vascular endothelial growth factor expression. Statistical overlap of stromal vascular endothelial growth factor and microvessel density in predicting malignancy suggests that angiogenesis may be an effector mechanism for vascular endothelial growth factor. Assessment of stromal VEGF may be useful as an adjunctive diagnostic criterion in the histologic assessment of malignancy in phyllodes tumors.     

胶原诱导性关节炎大鼠滑膜血管内皮生长因子与微血管密度

背景：目前发现的促进血管增生活性最强的是血管内皮生长因子,其在类风湿关节炎滑膜细胞呈现强表达。 目的：观察对胶原诱导性关节炎大鼠不同时间点滑膜血管内皮生长因子表达和微血管计数的变化,探讨血管内皮生长因子和微血管在类风湿关节炎发病机制中的作用及其相关性。 方法：采用Ⅱ型胶原与完全福氏佐剂诱导SD大鼠实验性关节炎模型,采用免疫组织化学方法观察实验性关节炎大鼠不同时间点滑膜组织血管内皮生长因子的表达水平和新生血管计数,并同时观察发病时间与关节炎指数积分、血管内皮生长因子及滑膜新生血管数之间的关系。用直线相关分析法分析血管内皮生长因子表达与滑膜新生血管数之间的关系,用等级相关分析法分析关节炎指数积分与血管内皮生长因子表达及滑膜新生血管数之间的关系。 结果与结论：随着实验性关节炎发病时间的延长,滑膜新生血管逐渐增多,滑膜增厚,关节炎指数积分逐渐增加,血管内皮生长因子表达水平和微血管数也随之升高;其关节炎指数积分与血管内皮生长因子表达水平呈正相关关系(r=0.535、P < 0.05), 血管内皮生长因子表达水平与微血管计数呈显著正相关关系(r=0.860,P < 0.01) 。血管内皮生长因子参与了实验性关节炎大鼠滑膜血管翳的形成过程,血管内皮生长因子与微血管密度在类风湿关节炎的发病中具有重要意义。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

血管内皮生长因子及其受体在子宫内膜癌中的表达

目的探讨血管内皮生长因子(VEGF)及其受体fms样酪氨酸受体-1 (flt-1)和含插入区的激酶受体(KDR)在子宫内膜癌血管生成中的作用及其与内膜癌分化程度的关系.方法采用免疫组织化学及原位杂交方法对23例子宫内膜癌及6例正常绝经期子宫内膜中VEGF、flt-1、KDR蛋白质及其mRNA进行检测,并对少数病例行Western印迹分析,以检测VEGF亚型在内膜癌组织的分布,用内皮细胞标志Ⅷ因子标记内膜癌组织中的微血管密度.结果 VEGF、flt-1、KDR蛋白质及其mRNA主要分布在子宫内膜癌组织血管内皮细胞及癌细胞胞质内.VEGF蛋白质在中分化(G2)、低分化(G3)内膜癌血管内皮细胞及癌细胞上的表达高于高分化内膜癌(G1)及正常绝经期子宫内膜(P<0.05), VEGF mRNA在不同分化程度内膜癌组织的表达差异无显著性意义(P>0.05),但均大于正常绝经期子宫内膜(P<0.05);flt-1蛋白质及flt-1mRNA在G3内膜癌血管内皮细胞的表达高于G1、G2及正常绝经期子宫内膜(P<0.05),在癌细胞的表达差异无显著性意义(P>0.05) ,但均高于正常绝经期子宫内膜(P<0.05);KDR蛋白质在子宫内膜癌组织血管内皮细胞及癌细胞上的表达较强,但不随分化程度发生变化,其mRNA在中分化(G2)、低分化(G3)内膜癌血管内皮细胞及癌细胞上的表达高于正常绝经期子宫内膜(P<0.05).G3子宫内膜癌组织的血管密度(48个±12个)高于G1(27个±14个)、G2(26个±16个)及正常绝经期子宫内膜(26个±11个,P<0.05).结论 VEGF、flt-1、KDR及mRNA在子宫内膜癌中的表达形式提示其与癌组织血管生成及血管通透性相关,VEGF及其受体是与子宫内膜癌旺盛生长相关的因子之一.     

Microvessel density and expression of vascular endothelial growth factor and its receptors in diffuse large B-cell lymphoma subtypes

Angiogenesis is known to play a major role in neoplasia, including hematolymphoid neoplasia. We assessed the relationships among angiogenesis and expression of vascular endothelial growth factor and its receptors in the context of clinically and biologically relevant subtypes of diffuse large B-cell lymphoma using immunohistochemical evaluation of tissue microarrays. We found that diffuse large B-cell lymphoma specimens showing higher local vascular endothelial growth factor expression showed correspondingly higher microvessel density, implying that lymphoma cells induce local tumor angiogenesis. In addition, local vascular endothelial growth factor expression was higher in those specimens showing higher expression of the receptors of the growth factor, suggesting an autocrine growth-promoting feedback loop. The germinal center-like and nongerminal center-like subtypes of diffuse large B-cell lymphoma were biologically and prognostically distinct. Interestingly, only in the more clinically aggressive nongerminal center-like subtype were microvessel densities significantly higher in specimens showing higher vascular endothelial growth factor expression; the same was true for the finding of higher vascular endothelial growth factor receptor-1 expression in conjunction with higher vascular endothelial growth factor expression. These differences may have important implications for the responsiveness of the two diffuse large B-cell lymphoma subtypes to anti-vascular endothelial growth factor and anti-angiogenic therapies.     

Mucinous colon carcinomas with microsatellite instability have a lower microvessel density and lower vascular endothelial growth factor expression

We determined the association between cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and microsatellite instability (MSI) or the histological type in colon adenocarcinomas. Sixty-six cases were studied, 28 MSI+ and 38 MSI-. MSI phenotype was determined using polymerase chain reaction. MVD was assessed after CD31 staining in ten x400 fields (0.96 mm(2)) in the most vascularized areas. VEGF and COX-2 expression were studied by means of immunohistochemistry. MVD positively correlated with the levels of VEGF expression (P=10(-4)) and also with the levels of COX-2 expression (P=0.007). MVD and VEGF expression were lower in MSI+ carcinomas (P=0.002 and P=0.03 respectively). When mucinous tumors were excluded from the statistical analysis, the association between low MVD, low VEGF and MSI status disappeared (P=0.5, P=1, respectively). MSI+ mucinous carcinomas had a lower MVD and VEGF expression than other MSI+ carcinomas (P=0.008 and P=0.004, respectively) and MSI- mucinous carcinomas (P=0.01 and P=0.001, respectively). COX-2 expression was lower in medullary carcinomas (P=0.001). In conclusion, mucinous MSI+ colon carcinomas represent a special group of colon adenocarcinomas relating to angiogenesis, with a lower MVD and VEGF expression than both MSI- mucinous carcinomas and MSI+ non-mucinous carcinomas. A low COX-2 expression could be related to the medullary phenotype. However, this has to be confirmed in a larger series. Finally, the low MVD of MSI+ mucinous colon adenocarcinomas could participate in their overall better prognosis.     

COX-2、VEGF以及MVD在子宫内膜异位症中的表达及意义

目的通过探讨环氧合酶-2（COX-2）、血管内皮生长因子（VEGF）以及微血管密度（MVD）在子宫内膜异位症（EMs）在位内膜、异位内膜及正常子宫内膜组织中的表达,探讨子宫内膜异位症的发病机制。方法采用免疫组化SP法检测EMs患者32例在位内膜、28例异位内膜及40例对照组正常子宫内膜中COX-2、VEGF的蛋白表达,计数微血管密度（MVD）值,并进行相关性分析。结果 （1）COX-2、VEGF在EMs在位内膜、异位内膜阳性表达率明显高于正常对照组,差异具有统计学意义（P〈0.05）,EMs异位内膜组COX-2、VEGF阳性表达率高于在位内膜组,差异有统计学意义（P〈0.05）。（2）MVD的计数在正常对照组,在位内膜组,异位内膜组依次递增,在位内膜组、异位内膜组与正常对照组比较有统计学差异（P〈0.05）,而在位内膜组与异位内膜组比较有统计学差异（P〈0.05）。（3）EMs在位内膜、异位内膜组患者和正常对照组COX-2蛋白表达与VEGF蛋白及MVD值的变化呈正相关。结论 COX-2与VEGF在EMs中的高表达,与子宫内膜异位的血管生成有关。     

Localization of vascular endothelial growth factor in nontumorous human pituitaries

Vascular endothelial growth factor (VEGF) is a key mediator of endothelial cell proliferation, angiogenesis, and vascular permeability. Our aim was to investigate whether VEGF is expressed in various cell types of the human pituitary. Eight nontumorous pituitaries were investigated by histology, immunocytochemistry, double immunostaining, and immunoelectron microscopy. Immunocytochemistry, including double immunostaining, showed VEGF immunoreactive cells to be distributed throughout the adenohypophysis. Immunopositivity was evident in all adenohypophysial cell types, but was colocalized mainly with somatotroph and stellate cell antigen (i.e., growth hormone and S-100 protein). Weak to moderate VEGF immunoreactivity was also noted in posterior lobe pituicytes as well as in most endothelial and perivascular smooth muscle cells.In situ hybridization confirmed these findings in demonstrating a strong signal in corticotrophs, somatotrophs, and stellate cells. Immunoelectron microscopy showed VEGF to be present mainly within secretory granules where it colocalized with the full spectrum of adenohypophysial hormones. The subcellular distribution of VEGF suggests that hypothalamic factors play a role in its release from adenohypophysial cells. Further studies are required to examine the possible role of VEGF in affecting both the pituitary’s vasculature and endocrine activity.     

Clinical prognostic values of vascular endothelial growth factor, microvessel density,and p53 expression in esophageal carcinomas

Vascular endothelial growth factor (VEGF) is known to play a key role in tumor angiogenesis. The tumor-suppressor gene p53 has been thought to regulate VEGF. We investigated the effect of VEGF on esophageal carcinoma and the correlation between VEGF and p53. Tissue samples were taken from 81 patients with esophageal carcinoma after surgery. VEGF and p53 expressions were examined by immunohistochemical staining. Microvessels in the tumor stained for CD34 antigen were also counted. VEGF and p53 expressions were observed in 51.3% (41/80) and 51.9% (41/79), respectively. The microvessel density was 70.9+/-6.7 (mean+/-SE) in VEGF-positive group and 68.7+/-5.1 in VEGF-negative group. However, no correlation was noted between VEGF and p53 expression. Whereas the tumor size, nodal status, depth of invasions, and tumor stage were associated with poor overall survival, VEGF expression or p53 expression was not. These results indicate that VEGF and p53 are highly expressed in esophageal carcinomas. Since the VEGF expression is not correlated with the p53 expression, microvessel density or clinicopathological findings, further studies with other angiogenic molecules are needed to determine the role in esophageal carcinomas.     

Cyclooxygenase-2 in human malignant fibrous histiocytoma: correlations with intratumoral microvessel density, expression of vascular endothelial growth factor and thymidine phosphorylase

Cyclooxygenase-2 (COX-2) has been found to be up-regulated in several types of human malignant tumors and proposed to have a role in the angiogenic process. This study examined the expression of COX-2 in two human malignant fibrous histiocytoma (MFH) cell lines by Western blotting, which showed a specific single band at 72 kDa. Immunohistochemistry was conducted in 35 MFHs and 30 benign fibrohistiocytic tumors (BFHTs), comparing the expression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), as well as intratumoral microvessel density (IMVD). COX-2 expression was noted in 22 (62.9%) MFHs, but in no BFHT. IMVD values were significantly higher in the MFHs (90.6+/-8.0) than BFHTs (27.9+/-3.1), and also in the COX-2 positive (104.5+/-11.3) than negative (67.2+/-5.8) MFHs. VEGF and TP expression was also associated with a significantly higher level of COX-2, as well as greater IMVD. The highest IMVD values were noted in the 17 MFHs (120.8+/-11.5) expressing all three factors. Clinical analysis demonstrated poorer survival in the 18 COX-2 positive MFHs than in the 10 negative ones, although the small number of cases did not reveal a significant difference. The results overall indicated that COX-2 expression is associated with intratumoral angiogenesis, which might provide favorable conditions for tumor progression in human MFHs.     

Expression of vascular endothelial growth factor and its receptors in the developing rat lung

We examined the regulation of the expression of vascular endothelial growth factor (VEGF) and its specific receptors, fetal liver kinase receptor (Flk-1), and fms-like tyrosine kinase receptor (Flt-1) during formation of the capillary network in the developing rat lung. An immunohistochemical study of lung tissue from 19- and 21-d-old fetuses and 1-, 3-, 5-, 7-, and 14-d-old animals revealed that the level of expression of both VEGF and Flk-1 is significantly higher before birth (p < 0.0001) than after. Increased expression of Flt-1 on the first day after birth (p < 0.0001) suggests that this receptor might play an important role in capillary growth in the perinatal period. Immunostaining also revealed the colocalization of VEGF, Flt-1, and Flk-1 in endothelial cells of the lung capillaries at the ultrastructural level. The present studies revealed that VEGF and its two receptors are upregulated during the development of capillaries in the fetal and newborn rat lung.     

Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor

BACKGROUND: We have previously shown that the progesterone antagonist mifepristone is a contraceptive when given in a dose of 2 or 5 mg per day. The majority of women experience amenorrhoea rather than the irregular break through bleeding usually occurring with other estrogen-free contraceptive pills, such as progestogen-only pill (POP). We investigated the effects of low-dose mifepristone on endometrial parameters which may be associated with changes in endometrial function, such as microvasculature, vascular endothelial growth factor (VEGF) and glucocorticoid receptor (GR) content. METHODS AND RESULTS: Endometrial biopsies were collected from 16 women before (late proliferative phase) and 60 and 120 days after taking 2 or 5 mg mifepristone daily for 120 days. Seven of the eight women who received 2 mg mifepristone and all eight women who received 5 mg were amenorrhoeic during the study. Mean estradiol (E(2)) concentrations remained in the mid-proliferative range, and the majority (9/16) of women showed proliferative endometrial histology at 60 and 120 days following treatment. There was a significant increase in the density of the endometrial stroma (P < 0.05) and microvessels (P < 0.01) following 120 days of treatment. Immunocytochemistry showed that GR, hitherto localized specifically in endometrial stroma, was up-regulated in the nuclei of glands (P < 0.05) and surface (luminal) epithelium (P < 0.01) by 60 days and maintained at 120 days. There was a significant reduction in stromal VEGF protein expression by day 120 of treatment (P < or = 0.01). CONCLUSION: The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.