肿瘤血管生成和抗血管生成治疗的研究进展

肿瘤组织中的新生血管是保证肿瘤持续生长所必需的,也是肿瘤转移的重要途径之一.针对促进肿瘤血管生成和血管生成抑制物制定新策略,采用合适手段与方法,抑制肿瘤内血管新生,消除或减少肿瘤内原有血管,可达到治愈肿瘤的目的.     

抗血管生成疗法治疗肿瘤的研究进展

目前肿瘤的抗血管生成治疗已成为肿瘤研究的热点及肿瘤治疗的新策略。本文就肿瘤抗血管治疗的基本理论、常用抗血管生成抑制剂的种类、以及目前的应用进展作一综述。     

抗血管生成疗法治疗肿瘤的研究进展

目前肿瘤的抗血管生成治疗已成为肿瘤研究的热点及肿瘤治疗的新策略。本文就肿瘤抗血管治疗的基本理论、常用抗血管生成抑制剂的种类、以及目前的应用进展作一综述。     

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。     

抗血管生成抑制剂疗法研究进展

1　抗血管生成抑制剂的研究　　肿瘤血管形成的主要过程目前认为是:诱发因素→肿瘤细胞被活化分泌可能性血管生成刺激因子,如VEGF(血管内皮生长因子)、FGF(成纤维细胞生长因子)→激活内皮细胞和金属蛋白酶→基底膜被破坏,内皮细胞收缩,趋化,迁移,增殖,形成血管芽→血管芽吻合成血管。因为肿瘤血管及其生长过程的某些特殊性使得其更有利于肿瘤生长和转移,而抗血管生成的所有方法都是靶定内皮细胞而不是肿瘤细胞,这样使得抗血管疗法具有不产生耐药性,而广泛性、毒副作用小等优点。目前抗血管生成抑制剂疗法主要有三种:1.1　“血管生成抑制…     

抗血管生成因子的抗肿瘤作用及其机制

越来越多的证据表明,实体肿瘤的生长和转移具有血管生成（angiogenesis)依赖性。随着人们对肿瘤诱导血管生成过程的深入了解,寻找能阻断或干扰血管生成过程的因子的研究已成为抗肿瘤研究的热 点之一。近年来,特异性针对血管生成过程或“抗血管生成”治疗肿瘤的研究取得了可喜的进展,已报道了多种天然或合成的有效的抗血管生成因子。本文就几种能影响内皮细胞增殖和功能的较有可能成为抗癌因子的重要抗血管生成因子研究进展作一综述,这些因子是：ECs增殖抑制剂（抗VEGF抗体和抗VEGFR抗体）、VEGF受体酷氨酸激酶抑制剂（SU5416、ZD4190、PD0173074）和影响EC功能的药物（TNP0－470、Combretastatin A-4、Angiostatin和Endostatin)。     

血管内皮生长因子与血管生成的研究进展

现已证实血管内皮细胞生长因子 (VEGF)是唯一对血管形成具有特异性作用的生长因子 ,其它生长因子 (如成纤维细胞生长因子、血小板衍生生长因子等 )能作用于包括血管内皮细胞在内的多种细胞 ,是不具特异性的。目前 ,通过基因工程研究发现血管内皮细胞特异性生长因子包括VEGF的 5个亚型(VEGF -A、B、C、D、E) ,血管生成素的四个亚型和一个ephrin家族成员[1 ] 。绝大多数对血管有影响的生长因子及其受体在动物实验中通过基因分析和 或转基因表达揭示了其生理作用及病理性血管生成机制。要使功能性血管形成 ,必须要这些因子协调作用 ,其…     

整合素与肿瘤血管生成及抗血管生成作用

肿瘤血管生成不仅与肿瘤的生长和转移密切相关 ,而且在肿瘤病理分级、治疗和预后判断上具有重要的评估价值。研究表明 ,细胞粘附分子介导的细胞粘附行为异常在肿瘤的浸润和转移中有重要作用。近年 ,随着免疫和分子生物学的发展 ,肿瘤血管生成及抗血管生成逐渐成为肿瘤研究的重点和热点之一 ,细胞粘附分子与血管生成的关系也日益受到关注〔1〕。现就其中整合素家族在肿瘤血管生成及抗血管生成中的作用作一简要综述。1　整合素分子的基本结构整合素家族 (ｉｎｔｅｇｒｉｎｆａｍｉｌｙ)为细胞粘附分子家族的重要成员之一 ,是一组广泛分布于细…     

周细胞在抗肿瘤血管生成中的研究进展

众所周知,肿瘤的生长和转移依赖于新生血管,没有新生血管,肿瘤将停止生长。肿瘤新生血管由内皮细胞、周细胞／平滑肌细胞、基底膜组成。目前抗肿瘤血管生成的研究主要在内皮细胞和内皮祖细胞,对周细胞的研究很少。而周细胞在肿瘤血管的发展、稳定、成熟及重塑过程中发挥着关键作用,成为抗血管生成治疗的热点和新靶点。本文就近年来关于周细胞在抗肿瘤血管生成中的研究作一综述。     

Vascular endothelial growth factor in tumor tissue and blood serum from patients with breast cancer

Enzyme immunoassay showed that the content of free vascular endothelial growth factor increases in tumor cytosols and blood serum from patients with breast cancer. A positive correlation was found between the contents of vascular endothelial growth factor in tumor cytosols and blood serum. After removal of the tumor the content of vascular endothelial growth factor decreased only in 49% patients. It should be emphasized that changes in these parameters did not depend on their initial values.     

VEGF-C及其受体Flt4在乳腺癌转移中的作用

目的　探讨VEGF C/VEGFR 3(Flt4)在乳腺癌转移中的作用和意义。方法　采用免疫组化S P法检测 10 1例乳腺癌组织中VEGF C、Flt4的表达。结果　 10 1例乳腺癌组织VEGF C阳性率为 93 1%(94/10 1) ,Flt4阳性率为 86 1%(87/10 1) ,且VEGF C与Flt4表达呈正相关。VEGF C阳性指数在转移组 (6 1 89± 17 79)高于未转移组 (44 2 8± 17 87) (P <0 0 5 )。随着癌细胞VEGF C表达强度增强 ,Flt4阳性脉管数也随之增加 ,各组间差异均有显著性 (P <0 0 1)。乳腺癌中Flt4阳性脉管数在淋巴结转移组 (15 5 5± 3 6 3)高于未转移组 (10 71± 2 90 ) (P <0 0 5 )。结论　乳腺癌细胞高水平表达VEGF C、Flt4,两者表达呈正相关。Flt4阳性脉管数与淋巴结转移密切相关。     

Vascular endothelial growth factor A and C gene expression in endometriosis

Angiogenesis is essential for the pathogenesis of endometriosis. Gene expression levels of vascular endothelial growth factor (VEGF) A and C in 10 eutopic endometrial, 23 normal peritoneal, and 62 endometriotic tissues surgically obtained from 47 women with endometriosis (group 2) were compared with those in 12 control eutopic endometrial and 9 normal peritoneal tissues from 15 women without endometriosis (group 1). VEGF-A mRNA expression levels in eutopic endometrium of group 2 were higher than those of group 1 throughout the menstrual cycle (P <0.01) and increased in the secretory phase. VEGF-A gene expression in peritoneal endometriotic lesion was statistically higher than that in normal peritoneum (P <0.01) and similar to that in eutopic endometrium of group 2. In contrast, gene expression levels of VEGF-C were relatively lower than those of VEGF-A in each lesion, and no cyclic variation was found. VEGF-A and C mRNA expression levels were significantly higher in ovarian endometriomas >6 cm in size than in those <6 cm in size. Immunohistochemical expression of VEGF-A and C was detected in the cytoplasm of glandular epithelial and stromal cells of ovarian endometrioma. These results suggest that endometriosis may arise from eutopic endometrium with higher levels of angiogenic activity possibly induced by VEGF-A in women with endometriosis. Moreover, VEGF-C as well as VEGF-A may be involved in the pathogenesis of ovarian endometrioma.     

CTGF在胃癌中的表达及其促进血管生成的机制

目的研究CTGF在人胃癌标本中表达情况及其促进血管生成的机制。方法应用Real Time PCR和免疫组织化学染色检测胃癌标本中CTGF mRNA,VEGF mRNA及其在组织中蛋白表达情况;应用pcDNA3.1质粒上调AGS细胞中CTGF的表达,并用Real Time PCR和Western blot检测VEGF mRNA水平和蛋白水平表达变化;AGS稳定株细胞接种于裸鼠,成瘤后肿瘤组织切片,免疫组化染色。结果与正常组织相比,胃癌组织中CTGF mRNA,VEGF mRNA表达水平均显著增加,免疫组化亦显示CT-GF、VEGF在胃癌的标本中显色比正常对照组织强。统计显示两者mRNA水平及免疫组化表达有相关性（P〈0.05）。转染pcD-NA3.1 CTGF质粒后,AGS细胞中CTGF蛋白的表达上调,Real Time PCR及Western blot检测显示过表达CTGF后,VEGF表达上调。与对照细胞相比,过表达CTGF的AGS的肿瘤形成和生成速度明显加快（P〈0.05）。免疫组化染色显示VEGF的染色明显强于对照组。结论在胃癌中CTGF,VEGF表达明显增加,CTGF可能通过上调VEGF表达促进肿瘤血管生成。     

Role of vascular endothelial growth factor during breast cancer

We review the results of experimental and clinical observations on neoangiogenesis in patients with breast cancer. Vascular endothelial growth factor is an important positive regulator of this process. Experiments showed the possibility of using various direct and indirect antiangiogenic means in the therapy of breast cancer, but clinical efficiency of these methods was not proved. Expression of vascular endothelial growth factor can serve as a prognostic criterion in breast cancer. Antiangiogenic preparations should not be used as monotherapy, but as the treatment complementary to standard therapy.     

Inactivation of the PTEN gene protein product is associated with the invasiveness and metastasis, but not angiogenesis, of breast cancer

PTEN is a novel tumor-suppressor gene located on chromosomal band 10q23. Loss of PTEN function has been implicated in the progression of several types of cancer, but the correlation between loss of PTEN expression and advanced carcinomas is not well established. The capacity for angiogenesis of a tumor is known to play a very important role in growth and metastasis, and there have been reports that PTEN relates to angiogenesis. In the present study, formalin-fixed and paraffin embedded tissues from 101 patients with breast carcinomas, including 88 cases of invasive ductal carcinomas and 13 cases of ductal carcinoma in situ (DCIS), were evaluated by immunohistochemical methods for the expression of PTEN and vascular endothelial growth factor (VEGF), as well as microvessel density (MVD). The results were compared with the clinicopathologic parameters. There was no loss of PTEN expression in any of the cases of DCIS, but 28 (32%) of the 88 invasive cases did not express PTEN. Loss of PTEN expression was associated with lymph node metastasis ( P  = 0.03), but did not correlate with tumor size, tumor grade, MVD or recurrence. VEGF expression significantly correlated with lymph node metastasis in invasive ductal carcinoma ( P  = 0.01). There was no correlation between the expression of PTEN and that of VEGF ( P  = 0.63). The present study suggests that loss of PTEN expression is common and correlates with tumor progression and lymph node metastasis in breast carcinoma. The relationship between loss of PTEN and progression of breast cancer may not be explained by modulation of angiogenesis.     

Altered ratios of pro‐ and anti‐angiogenic VEGF‐A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma

Infantile haemangioma (IH), the most common neoplasm in infants, is a slowly resolving vascular tumour. Vascular endothelial growth factor A (VEGF‐A), which consists of both the pro‐ and anti‐angiogenic variants, contributes to the pathogenesis of IH. However, the roles of different VEGF‐A variants in IH progression and its spontaneous involution is unknown. Using patient‐derived cells and surgical specimens, we showed that the relative level of VEGF‐A₁₆₅b was increased in the involuting phase of IH and the relative change in VEGF‐A isoforms may be dependent on endothelial differentiation of IH stem cells. VEGFR signalling regulated IH cell functions and VEGF‐A₁₆₅b inhibited cell proliferation and the angiogenic potential of IH endothelial cells in vitro and in vivo. The inhibition of angiogenesis by VEGF‐A₁₆₅b was associated with the extent of VEGF receptor 2 (VEGFR2) activation and degradation and Delta‐like ligand 4 (DLL4) expression. These results indicate that VEGF‐A variants can be regulated by cell differentiation and are involved in IH progression. We also demonstrated that DLL4 expression was not exclusive to the endothelium in IH but was also present in pericytes, where the expression of VEGFR2 is absent, suggesting that pericyte‐derived DLL4 may prevent sprouting during involution, independently of VEGFR2. Angiogenesis in IH therefore appears to be controlled by DLL4 within the endothelium in a VEGF‐A isoform‐dependent manner, and in perivascular cells in a VEGF‐independent manner. The contribution of VEGF‐A isoforms to disease progression also indicates that IH may be associated with altered splicing. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Differences of vascular endothelial growth factor (VEGF) expression between liver and abdominal metastases from colon cancer. Implications for the treatment with VEGF inhibitors

The vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis, and it is the target of innovative anti-cancer therapies. In colorectal carcinomas, differences in the VEGF expression have been found between the primary tumor and its metastases. We postulated that differences in the VEGF expression may also exist between liver and abdominal metastases from colon cancer. Consecutive colon cancer patients with liver or abdominal metastases were considered eligible for the study. Biopsies had to be performed before chemotherapy and the VEGF analysis were conducted through immunohistochemistry. The staining results were correlated to the metastatic pattern. The study population consisted of 41 patients with a metastatic site in the liver in 19 patients and the abdomen in 22 patients. A positive VEGF staining was found in 19 of the 41 metastatic samples (46%). Cases with positive VEGF expression were found more frequently in abdominal (15 out of 22 patients; 68%) than in liver metastases (4 out of 19 patients; 21%). Also, the degree of VEGF immunoreactivity was significantly higher in abdominal than in liver metastases. Evidence is supported that the VEGF expression may be different between colon cancer metastatic sites. The efficacy of anti-VEGF treatments may depend on the VEGF expression status, and this finding deserves further investigation. This revised version was published online in July 2006 with corrections to the Cover Date.     

Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas

AIMS: Tumour vascularity and vascular endothelial growth factor (VEGF) expression were studied in 41 primary brain tumours of astrocytic and oligodendroglial origin, in order to define the potential role of VEGF in the vascularization and growth of these tumours. METHODS AND RESULTS: Two commercial monoclonal antibodies to the VEGF protein (from R&D Systems and NeoMarkers), raised against different isoforms, were utilized. Each monoclonal antibody consistently detected the expression of VEGF in different cell types. The R&D Systems antibody only produced surface staining of endothelial cells in tumour capillaries, whereas staining with the Neomarkers antibody was largely confined to tumour cell cytoplasm. High levels of staining were seen with the R&D Systems and NeoMarkers antibodies in 13 and 14 of 15 glioblastomas, respectively, four and three of five oligodendrogliomas, four and seven of 10 anaplastic astrocytomas, one and three of six low-grade astrocytomas and none and none of five pilocytic astrocytomas. There was a close correlation between VEGF expression, tumour vascularity and grade. CONCLUSIONS: These findings support a role for VEGF in the angiogenesis of glioblastoma, anaplastic astrocytoma and oligodendroglioma. The distinct immunoreactivities of the two commercial monoclonal antibodies indicate either there is expression of different splice variants of VEGF or that the epitopes are differentially revealed during synthesis, secretion and receptor-binding of the growth factor. This highlights the importance of using more than one antibody in the evaluation of tissue VEGF expression.     

甲状腺癌组织中VEGF和VEGF-C的表达及意义

目的　探讨血管内皮生长因子(VEGF)、VEGF- C在甲状腺癌中的表达及其意义。方法　应用免疫组化S P法检测44例甲状腺癌中VEGF、VEGF C的表达情况,并以17例癌旁正常甲状腺组织作对照。结果　VEGF、VEGF- C在甲状腺癌中呈高水平表达(88. 6%、81. 8% )。VEGF表达随癌组织分化程度的减低而增高, 9例死亡病例均为阳性表达;VEGF- C表达随癌组织分化程度的减低而减低,乳头状癌阳性表达(88 .9% )高于其它类型,VEGF- C阳性率在有淋巴结转移组(92. 0% )明显高于无淋巴结转移组(68. 4% ) (P<0. 05)。9例死亡病例中7例为阳性表达,且7例同时VEGF呈阳性表达。结论　VEGF、VEGF- C表达与甲状腺癌病理分型及预后可能有一定关系,VEGF- C与甲状腺癌淋巴结转移密切相关。