VEGF分泌量及分泌来源对肿瘤血管生长影响的数值模拟

目的 数值模拟研究血管内皮生长因子（vascular endothelial growth factor, VEGF）分泌量及分泌来源对肿瘤血管生成的影响。方法 建立肿瘤内外血管生成的二维离散数学模型。围绕VEGF的分泌及其诱导新生血管形成肿瘤富血管区的过程,考虑细胞外基质的旁分泌作用以及对内皮细胞运动的趋触作用,以微血管密度作为定量指标,探讨VEGF的分泌量及不同的分泌来源对血管生成的影响。结果 肿瘤增殖细胞区、VEGF高浓度区、富血管区三者统一,微血管密度与VEGF的表达有关,随着增殖细胞区域的扩大,即VEGF的表达越来越多,微血管密度也越来越大,但在不同类型的肿瘤中,VEGF不同分泌来源的比重与微血管密度无明显相关性。结论 模型探讨了VEGF分泌量及分泌来源对肿瘤血管生成的影响,其中对VEGF的不同分泌来源的考虑可作为研究靶向VEGF治疗肿瘤的模型基础。     

血管内皮生长因子与肿瘤血管生成的研究进展

肿瘤的无限制侵袭性生长及转移依赖于血管的生成。肿瘤血管生成是一个复杂的多步骤过程,且有众多生长因子的参与,其中血管内皮生长因子(Vascular endothelial growth factor,VEGF)是最重要的促血管生长因子,与肿瘤的生长、转移及预后有关,也是抗肿瘤血管生成治疗的重要靶点之一。本文旨在对VEGF与肿瘤血管生成的研究进展作一综述。     

抗肿瘤血管生成主动免疫治疗研究进展

肿瘤血管生成在肿瘤生长、侵袭、转移中具有十分重要的作用。调控血管生成的因子很多，包括血管内皮细胞生长因子（VEGF）、成纤维细胞生长因子（FGF）、表皮细胞生长因子（EGF）等。近年来抗血管生成的肿瘤治疗已经取得较大进展，特别是抗肿瘤血管形成主动免疫治疗，已经成为抗肿瘤研究的热点。因而，以异种同源分子和非异种同源分子为疫苗的研究很有意义。     

骨髓来源免疫细胞对肿瘤血管生成的调节及临床应用研究进展

 近年来研究发现髓系细胞在肿瘤血管生成中发挥关键的调控作用。髓系细胞可以通过多种途径促进血管生成,包括分泌VEGF及不依赖于VEGF的方式,后者参与介导了抗血管生成治疗中肿瘤抵抗性的形成。此外,髓系细胞还限制了放化疗的治疗效果,促进复发。最后,本文初步探讨了其临床应用前景。     

血管内皮生长因子与肿瘤转移

血管内皮生长因子通过与其受体的相互作用调控血管生成 ,在血管新生的过程中起决定作用。血管新生对于原发癌和转移癌的生长都十分重要 ,在肿瘤组织中VEGF表达亢进 ,血管增生显著 ,VEGF还参与免疫系统的调节。VEGF阻止剂通过抑制血管增生 ,抑制肿瘤和微小转移灶的形成 ,达到治疗肿瘤的目的。     

VEGF在胃癌中的表达及临床意义

血管内皮生长因子(VEGF)具有高度特异性、在生理性及病理性血管生成中具有重要作用，而且还促使癌细胞脱落进人血管或向邻近纤维蛋白和结缔组织基质扩散，为肿瘤浸润转移创造条件。本文选取消化道常见肿瘤胃癌，应用SP免疫组化法，检测人胃癌组织中VEGF表达与胃癌临床病理指标的关系，为预测胃癌预后和肿瘤抗血管生成疗法，提供理论依据。     

干扰素治疗慢性粒细胞白血病前后骨髓血管生成的临床观察

有有研究表明，血管生成及其调控因子与血液系统恶性疾病的发生、演变和预后密切相关。血管内皮细胞生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）是血管新生的重要调控因子，观察慢性粒细胞白血病（CML）骨髓组织VEGF和bFGF表达以及微血管密度是研究血液肿瘤血管生成的常用方法。CML采用造血干细胞移植根治疾病或采用伊马替尼长期缓解病情，但由于经济原因，干扰素仍是大多数国内CML病人之首选。已知干扰素除有直接抗肿瘤细胞增殖作用外，还有明显的抗血管形成活性。我们对CML患者采用干扰素为主的治疗方法，观察治疗前后骨髓组织VEGF、bFGF和微血管数量变化，探讨干扰素抗血管生成的作用机制。     

血管生成素及其受体与肿瘤的血管生成

血管生成素 (Ang)家族是唯一含受体激动剂及抑制剂的促血管生成因子 ,编码四种结构相似的蛋白质 ,包括Ang 1,Ang 2 ,Ang 3和Ang 4 ,均能与内皮细胞上的酪氨酸激酶受体Tie 2结合 ,参与生理性及病理性的血管生成。Ang 1激活Tie 2 ,促进血管生成 ,维持血管稳定 ;Ang 2的作用呈VEGF依赖性 ,VEGF存在时 ,可促进血管出芽 ,VEGF缺乏时 ,则促进血管退化。Ang家族在不同的肿瘤中表达水平及分布形式不一。应用sTie 2或以Ang家族为靶标可抑制肿瘤性血管生成 ,对肿瘤的治疗有潜在的应用前景。     

微血管定量与大肠癌转移和预后的关系

肿瘤血管形成在实体瘤的发生、发展、转移及预后中起着重要作用,对指导治疗也有深远的影响。通过对大肠癌组织内微血管的定量计数,发现微血管计数与大肠癌病人的转移和生存率有明显相关性,是一个有价值的独立的预后因素。认为大肠癌组织内微血管的定量计数可反映肿瘤血管生成情况,在判断肿瘤预后,筛选高危复发或转移病人,指导治疗等方面有较大应用价值。本文综述了大肠癌组织内微血管定量的方法、微血管计数与大肠癌转移和预后的关系及意义。     

骨肉瘤血管生成与肿瘤治疗的实验研究

目的：研究人骨肉瘤OS－732细胞系促进血管生成作用及血管内皮生长因子（VEGF）抗体对其血管生成的抑制作用。方法：应用鸡胚绒毛尿囊膜模型。通过解剖显微镜、光镜及免疫组化方法观察人骨肉瘤OS－732细胞系血管生成活性，并探讨VEGF抗体的血管生成抑制作用。结果：OS－732细胞系具有较强的促血管生成能力，鸡胚绒毛尿囊膜移植瘤组织中VEGF、碱性成纤维细胞生长因子（bFGF）、转化生长因子β1（TGF-β1）均呈阳性表达，且VEGF呈持续高表达。给予VEGF抗体后VEGF抗体组血管数目、瘤细胞数低于PBS对照组。结论：VEGF、bFGF、TGF-β1可能共同参与骨肉瘤OS－732细胞系诱导的血管生成，其中VEGF可能起着主要作用。VEGF抗体能抑制本细胞系的血管生成，提示VEGF抗体对骨肉瘤治疗具有良好的应用前景。     

Vascular endothelial growth factor overproduced by tumour cells acts predominantly as a potent angiogenic factor contributing to malignant progression

To elucidate the role of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, in tumour angiogenesis and malignant progression, an expression vector harboring human VEGF cDNA was stably transfected into three human cancer cell lines with poor VEGF productivity. Though their in vitro growth rate and intrinsic productivity of another angiogenic factor, basic fibroblast growth factor (bFGF), were not changed by transfection, those clones with higher VEGF production were endowed with tumorigenic and angiogenic potentials as follows: firstly, nontumorigenic, lung carcinoma QG90 cells having lower bFGF productivity acquired tumorigenicity as well as significant in vivo angiogenesis-inducing ability, secondly, tumorigenic colorectal carcinoma RPMI4788 cells having higher potency for bFGF production could form more vascularized solid tumour with faster growth rate and thirdly, oestrogen-dependent breast carcinoma MCF-7 cells, which did not produce detectable bFGF, acquired tumorigenicity even in the absence of oestrogen and the solid tumour growth rate was remarkably enhanced, accompanied with increased vascularization, in the presence of oestrogen. These results suggest that tumour progression closely depends on angiogenesis, and VEGF significantly contributes to malignant progression of a variety of tumour cells through its potent angiogenic activity, independent on the bFGF productivity of tumour cells.     

Plasminogen activator system, vascular endothelial growth factor, and colorectal cancer progression.

AIMS: To plasminogen activator system (PAS) consists of the plasminogen activators (urokinase (uPA) and tissue-type (tPA) plasminogen activators), the uPA receptor (uPAR), and the plasminogen activator inhibitors (PAI-1 and PAI-2). Plasminogen activators activate plasminogen to plasmin, which can break down extracellular matrix (ECM) components. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and is involved in angiogenesis. VEGF has been shown to upregulate uPA and this may facilitate tumour angiogenesis further. METHODS: PAS components and VEGF were determined by enzyme linked immunosorbent assay (ELISA) in paired colorectal tumour and normal tissue (n = 50) and correlated with pathological staging. RESULTS: uPA, uPAR, PAI-1, and VEGF values were significantly higher in tumour tissue (for example, tumour uPA: median, 2.3 (range, 0.1-6.7) ng/mg protein v normal uPA: median, 0.2 (range, 0-2.6) ng/mg protein). tPA was significantly higher in normal mucosa and there was no difference in PAI-2. uPA, uPAR, PAI-1, and VEGF values significantly correlated with each other and with Dukes's staging (uPA in adenomas: median, 0.42 (range, 0.1-1.2) ng/mg protein; upA in Dukes's B tumours: median, 2.1 (range, 0.4-4.3) ng/mg protein; and uPA in Dukes's D tumours: median, 4.0 (range, 3.7-4.2) ng/mg protein) and lymphatic invasion. In addition PAI-1 also correlated with tumour size and differentiation. CONCLUSION: The involvement of the PAS and VEGF in colorectal cancer appears to be complex. uPA, uPAR, PAI-1, and VEGF were upregulated in tumour tissue and this correlated with Dukes's staging and lymphatic invasion.     

Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer

Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-alpha (TNF-alpha), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0. 006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour.     

新型pH敏感性材料及其给药系统在现代药剂学中的应用进展

 目的 探讨血管内皮生长因子（VEGF）在结直肠癌组织中的表达及其作为肿瘤新生血管标志的临床价值。 方法 采用免疫人VEGF单克隆抗体及鼠抗人因子Ⅷ相关抗原（F-8 RAg）单克隆抗体，通过免疫组化技术对48例结直肠癌手术切除的癌组织及癌旁正常组织（对照组织）中VEGF和F-8 RAg的表达进行检测。 结果 结直肠癌组织VEGF表达阳性率为62.5%（30/48），对照组为16.7%（8/48），χ²＝64.352，P<0.01。结直肠癌组织F-8 RAg标记的MVD为100.9 ± 16.0，对照组为46.8 ± 11.9，t =18.351，P<0.01。VEGF的表达与大肠癌的淋巴结转移（P<0.01）、远处转移（P<0.05）及临床分期有关（P=0.01）；而F-8 RAg标记的MVD与大肠癌的淋巴结转移、远处转移及临床分期无明显相关（P>0.05）。VEGF在结肠癌组织的表达与F-8 RAg的表达无相关性（P>0.05）。 结论 VEGF在结直肠癌组织新生血管有良好表达，可以作为结直肠癌新生血管有价值的标志     

Neuropilin-1 expression in cancer and development

Neuropilin (NRP)-1 is a co-receptor for vascular endothelial growth factor (VEGF). Preclinical data suggest that blockade of NRP1 suppresses tumour growth by inhibiting angiogenesis, in addition to directly inhibiting tumour cell proliferation in certain models. A humanized monoclonal antibody to NRP1 is currently being evaluated as a potential anti-cancer therapy in clinical trials. However, the expression of NRP1 in cancer and physiological angiogenesis has yet to be systematically described. Here we characterize the in situ expression of NRP1 in human cancer and during mammalian development. A monoclonal antibody to human NRP1 was generated and validated for immunohistochemistry by western blotting, use of formalin-fixed cell pellets transfected with NRP1, immunofluorescence, and comparison with in situ hybridization. NRP1 expression was assessed in whole sections of 65 primary breast carcinomas, 95 primary colorectal adenocarcinomas, and 90 primary lung carcinomas. An additional 59 human metastases, 16 xenografts, and three genetically engineered mouse tumour models were also evaluated. Immunoreactivity for NRP1 was seen in vessels from normal tissues adjacent to cancer and in 98-100% of carcinomas. Tumour cell expression of NRP1 was also observed in 36% of primary lung carcinomas and 6% of primary breast carcinomas, but no colorectal adenocarcinomas. NRP1 was evaluated in mouse embryos, where expression was limited to the nervous system, endocardium, vascular smooth muscle, and, focally, endothelium on subsets of vessels. Moreover, in a model of VEGF-dependent angiogenesis in the postnatal mouse trachea, blockade of NRP1 signalling resulted in defective angiogenesis and recapitulated the effects of anti-VEGF treatment. These observations confirm NRP1 as a valid anti-angiogenic target in malignancy, and as a potential direct anti-tumour target in a subset of cancers. The data also confirm a role for NRP1 in physiological, VEGF-mediated angiogenesis.     

Tumour proliferation, angiogenesis, and ploidy status in human colon cancer

AIMS: Tumour angiogenesis is essential for carcinogenesis and facilitates the process of tumour development and metastasis. Vascular endothelial growth factor (VEGF) is a well characterised angiogenetic factor and is known to play a crucial role in new vessel development. To gain further insight into the effects of microvessel density and VEGF expression in colon cancer, their relation with tumour proliferation, ploidy status, and p53 expression was investigated in colon cancer. METHODS: Tissue samples of 50 archived colon cancers were analysed by immunohistochemistry for VEGF, p53, and the endothelial cell marker, von Willebrand factor (VWF), using specific antibodies. The same samples were re-cut for flow cytometric studies to obtain S phase fraction (SPF) and ploidy status. RESULTS: A positive significant correlation was found between SPF and angiogenesis. The median microvessel count in high SPF tumours was significantly higher than in low SPF ones. No association was found between VEGF expression and SPF. A positive correlation was found between ploidy status and p53 expression and microvessel count. Furthermore, a positive correlation was established between DNA ploidy, VEGF expression, and microvessel count. CONCLUSION: This study provides evidence that in colon cancer, tumour growth may be stimulated by vascular supply, and the lack of a correlation between tumour cell proliferation and VEGF expression indicates that these two parameters may be regulated by separate mechanisms. Furthermore, the positive correlation between microvessel density, VEGF expression, and ploidy status provides more evidence that genetic alterations are involved in tumour angiogenesis.     

Anti-angiogenic alternatives to VEGF blockade

Angiogenesis is a major requirement for tumour formation and development. Anti-angiogenic treatments aim to starve the tumour of nutrients and oxygen and also guard against metastasis. The main anti-angiogenic agents to date have focused on blocking the pro-angiogenic vascular endothelial growth factors (VEGFs). While this approach has seen some success and has provided a proof of principle that such anti-angiogenic agents can be used as treatment, the overall outcome of VEGF blockade has been somewhat disappointing. There is a current need for new strategies in inhibiting tumour angiogenesis; this article will review current and historical examples in blocking various membrane receptors and components of the extracellular matrix important in angiogenesis. Targeting these newly discovered pro-angiogenic proteins could provide novel strategies for cancer therapy.     

Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis

To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis.     

COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables

BACKGROUND: There is evidence that the anti-neoplastic effect of non-steroidal anti-inflammatory drugs is attributable to cyclooxygenase-2 (COX-2) inhibition, but the exact mechanisms whereby COX-2 can promote tumour cell growth remain unclear. One hypothesis is the stimulation of tumour angiogenesis by the products of COX-2 activity. To data, there have been few clinicopathological studies on COX-2 expression in human ampullary carcinoma and no data have been reported about its relation with tumour angiogenesis. Objective: To investigate by immunohistochemistry the expression of COX-2 and the angiogenesis process in a series of primary untreated ampullary carcinomas. METHODS: Tissue samples from 40 archival ampullary carcinomas were analysed for COX-2, vascular endothelial growth factor (VEGF), and an endothelial cell marker von Willebrand factor (vWF) by immunohistochemistry, using specific antibodies. RESULTS: COX-2 expression was detected in 39 tissue samples (97.5%), of which two (5%) were graded as weak, 26 (65%) as moderate, and 11 (27.5%) as strong. Only one lesion (2.5%) was negative for COX-2 expression. VEGF expression was detected in 36 tissue samples (90%). A significant positive correlation was found between COX-2 and VEGF expression. No statistic correlation was found between COX-2 expression and microvessel density. CONCLUSIONS: COX-2 is highly expressed in ampullary carcinomas. This suggests an involvement of the COX-2 pathway in ampullary tumour associated angiogenesis, providing a rationale for targeting COX-2 in the treatment of ampullary cancer.