内皮抑素抑制肿瘤生长和转移的机制

恶性肿瘤的生长和转移离不开新生血管.抗肿瘤血管生成是近年来出现的倍受关注的一种种肿瘤治疗新方法,并得到了较为广泛和深入的研究.内皮抑素是胶原蛋白ⅩⅧ的C末端水解片段,是重要的内源性血管抑制因子,在抗肿瘤血管生成方面表现出显著效果,其为治疗恶性肿瘤提供了新的途径.本文就内皮抑素的生物学特性及其在抑制肿瘤生长和转移作用机制中的研究进展作一介绍.     

血管内皮生长因子-C表达与非小细胞肺癌淋巴管生成和淋巴结转移的相关性

目的观察血管内皮生长因子(VEGF)-C在非小细胞肺癌(NSCLC)组织中央部位、侵犯边缘和癌周肺组织的表达情况,分析VEGFC与淋巴结转移、淋巴管侵犯和淋巴管生成的相关性。方法选择人NSCLC新鲜组织样本96例,采用免疫组织化学法和实时定量RT-PCR(QRTPCR)法检测NSCLC组织中央部位、侵犯边缘和癌周肺组织的VEGF-C蛋白及mRNA表达情况,用D2-40标记淋巴管检测NSCLC组织中的淋巴管密度。结果 QRT-PCR显示,VEGF-C mRNA在肿瘤边缘部位的表达明显高于在肿瘤中央部位的表达,而且VEGF-C mRNA的表达亦高于其在周围肺组织的表达。免疫组织化学结果显示了同样的表达不均一性。肿瘤边缘VEGF-C高表达组淋巴结转移的发生率明显高于低表达组,而且VEGF-C高表达组淋巴管侵犯的发生率亦明显增高。肿瘤边缘高淋巴管密度组的VEGF-C mRNA的表达也明显高于低密度组。结论肿瘤侵犯边缘的VEGFC高表达与淋巴结转移和淋巴管侵犯密切相关,参与了NSCLC淋巴管生成和淋巴结转移过程。     

血管内皮生长因子-D表达与非小细胞肺癌淋巴管生成和淋巴结转移的相关性

目的观察血管内皮生长因子(VEGF-D)在非小细胞肺癌(NSCLC)组织中央部位、侵犯边缘和癌周肺组织的表达情况及肺癌组织微淋巴管密度(LMVD)与淋巴结转移、淋巴管侵犯和淋巴管生成的相关性。方法选择人NSCLC新鲜组织样本96例,应用免疫组织化学法和实时适量(QRT)-PCR法检测NSCLC组织中央部位、侵犯边缘和癌周肺组织的VEGF-D蛋白及mRNA表达情况,应用单克隆抗体(D2-40)标记淋巴管,检测NSCLC组织中的LWVD。结果 QRT-PCR显示,VEGF-D mRNA在肿瘤边缘部位的表达明显高于在肿瘤中央部位的表达,而且VEGF-D mRNA的表达亦高于其在周围肺组织的表达。免疫组织结果显示了同样的表达不均一性。肿瘤边缘VEGF-D高表达组淋巴结转移的发生率明显高于低表达组,而且VEGF-D高表达组其淋巴管侵犯的发生率亦明显增高。肿瘤边缘高LWVD组的VEGF-D mRNA的表达也明显高于低密度组。结论肿瘤侵犯边缘的VEGF-D的高表达与淋巴结转移和淋巴管侵犯密切相关,参与了NSCLC的淋巴管生成和淋巴结转移过程。     

内皮抑素在肺腺癌中的表达及其与淋巴管生成和淋巴结转移的关系

目的研究肺腺癌中内皮抑素(ES)表达及其与淋巴管生成和淋巴结转移关系。方法免疫组化法检测54例肺腺癌组织中ES表达及肺腺癌组织微淋巴管密度(MLVD),分析ES表达与肺腺癌临床病理特征及MLVD关系。结果 ES在肺腺癌组织中表达强阳性率、阳性率分别为48%、24%,显著高于癌周正常肺组织;ES表达水平与肺癌原发肿瘤大小、P-TNM分期、细胞分化程度、有无远处转移均有密切关系(P0.05),而与患者性别、年龄等均无关(P0.05),与M IVD关系密切(P0.05)。结论 ES在肺腺癌中表达,与肺腺癌淋巴管生成和淋巴结转移关系密切。     

血管内皮生长因子和内皮抑素在肝癌抗肿瘤相关血管治疗中的作用

肿瘤的发生机制一直未阐明，其治疗效果也不尽人意。自20世纪70年代末，Hanahan等提出肿瘤血管调控平衡学说后，血管生成与肿瘤发生发展的相关性逐渐受到重视。抗肿瘤相关血管治疗已成为攻克肿瘤的重要途径之一。肿瘤的生长依赖于肿瘤血管的生成，只有当大量的肿瘤相关血管长入肿瘤实质内部，才能促使肿瘤持续生长和转移；反之，肿瘤生长将受到明显抑制，肿瘤细胞会出现凋亡及坏死。肿瘤相关血管的产生与否取决于血管生成促进因子和血管生成抑制因子的共同调节。     

血管抑素和内皮抑素与冠心病的关系

近年来不断发现的新的内源性血管抑制因子，提示在人体内存在与凝血／纤溶系统类似的血管生成／抑制系统。本文就血管抑制因子中的血管抑素和内皮抑素的来源，生物学特性，与已知血管新生因子的关系。作用机制，及与冠脉粥样硬化，冠脉侧枝循环，冠脉成形术手再狭窄等方面作一综述。     

内皮抑素和血管抑素表达与大肠肿瘤侵袭转移的关系

目的探讨内皮抑素和血管抑素在大肠肿瘤组织中的表达,与大肠癌不同阶段的关系及临床意义。方法应用免疫组织法检测20例正常大肠组织、20例大肠腺瘤和60例大肠癌及其组织中内皮抑素和血管抑素的表达情况。应用χ2检验对内皮抑素和血管抑素两者在大肠肿瘤不同阶段的表达关系进行统计分析,两者表达间的相关性探讨采用spearman相关分析。结果内皮抑素和血管抑素阳性表达与大肠肿瘤不同阶段的关系spearman相关系数分别为-0.438、-0.362,两者的表达与大肠癌的Dukes分期、淋巴结转移显著相关(P<0.05),均与腺瘤的类型无相关性。结论内皮抑素和血管抑素可以抑制大肠癌的侵袭转移。内皮抑素和血管抑素在大肠癌组织中呈低表达,且两者的阳性表达率随着临床分期的进展而降低,提示其与大肠癌的发生、发展、浸润及转移有明显关系。两者在大肠癌组织中的表达呈明显的一致性,对两者进行联合检测,有助于大肠癌的早期诊断、治疗及预后的评估。     

血管内皮生长因子和内皮抑素在肺纤维化中的作用

血管内皮牛长因子是一种生长因子,在正常肺组织和多种肺部疾病中均有表达.通过血管内皮牛长因子受体发挥生理作用,具有促进内皮细胞分裂增殖、促血管生成、增加血管通透性及抗凋亡等作用.内皮抑素是一种内源性血管生成抑制剂,可以抑制血管内皮细胞增殖、迁移并诱导其调亡,从而达到抑制血管生成作用.在肺纤维化中二者均有异常表达,但具体作...     

结直肠癌淋巴管生成与淋巴结转移相关检测的临床研究进展

结直肠癌是人类常见的可经淋巴道转移的恶性肿瘤,其淋巴管生成与转移过程中牵涉了多种生物标志物表达水平的改变,检测这些相关生物标志物可为结直肠癌的诊断、治疗和预后情况提供重大参考价值．本文主要综述近年来与结直肠癌淋巴管生成与淋巴结转移相关检测的临床研究进展．     

血管抑素和内皮抑素抑制肿瘤血管新生的动物实验研究

目的　建立小鼠背部开窗模型 ,在直视下观察肿瘤生长情况及血管抑素 (AS)和内皮抑素 (ES)对肿瘤的影响。方法　免疫组化测定血管内皮细胞生长因子 (VEGF)、细胞表面磷酸化糖蛋白 (CD34 )的表达 ,了解肿瘤血管生长的情况。结果　本实验肿瘤细胞移植 1 3d后 ,对照组所有小鼠移植肿瘤均生长状态良好 ,肿瘤的生长已使小鼠的行动发生困难 ;而给药组肿瘤小 ,行动不受限制 ,也未见到药物副作用的表现。给药组肿瘤的生长被明显抑制 ,其肿瘤体积小 ,重量明显减轻 .。高剂量给药组与对照组间有显著性差异 (P<0 .0 1 ) ;而且抑制肿瘤生长的作用亦明显高于低剂量对照组 (P<0 .0 1 ) ;高剂量给药组肿瘤中心发生坏死也比较明显。结论　成功建立开窗可视模型 AS、ES抑制肿瘤血管新生起重要作用。     

COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer

Lymphangiogenesis has been shown to promote lymph node metastasis in cancers, making it an important target in cancer therapy. Vascular endothelial growth factor (VEGF)-C is upregulated in various tumors/cancers and is one of the most potent growth factors for inducing lymphangiogenesis and promoting lymph node metastasis (LNM). Likewise, cyclooxygenase (COX)-2 plays major roles in carcinogenesis, tumor growth and metastasis via multiple mechanisms including inactivation of host antitumor immunity and promotion of tumor cell migration, tumor cell invasiveness and tumor-associated angiogenesis and lymphangiogenesis. We previously demonstrated an association between COX-2 and VEGF-C in an in vitro model of lung cancer. However, little is known about the regulation of VEGF-C by COX-2 in cervical cancer. In this study, we measured the COX-2 and VEGF-C expressions by immunohistochemistry in 23 LNM-positive and 20 LNM-negative cervical cancer specimens. We then examined the correlations among the expressions and the lymphatic microvessel density (LMVD) and ultrastructural changes to the lymphatic vessel walls by enzyme histochemical staining and electron microscopy. In addition, we used the HeLa cervical cancer cell line to explore the in vitro regulation of VEGF-C by COX-2 and its metabolite, PGE₂, using siRNA-mediated gene silencing and EP receptor blockade. The LNM-positive specimens exhibited significantly higher VEGF-C expression, COX-2 expression and LMVD than the LNM-negative specimens. Furthermore, there were strong correlations between the levels of COX-2 expression and the levels of VEGF-C expression and secretion and a significant positive association between the LMVD and LNM. siRNA-mediated knockdown of COX-2 expression inhibited VEGF-C mRNA expression while EP1 and EP4 receptor antagonists reduced the VEGF-C protein level and tyrosine phosphorylation of Src kinase. Moreover, inhibition of Src kinase with the tyrosine kinase inhibitor PP1 attenuated VEGF-C expression. Collectively, our data provide evidence for a clinical association between COX-2 and VEGF-C expressions in cervical cancer. EP1 and EP4 receptors may be involved in the COX-2-mediated regulation of VEGF-C protein and mRNA expressions. Src may be a downstream mediator of EP1 and EP4 receptors. COX-2 inhibition may diminish LNM by suppressing VEGF-C-mediated lymphangiogenesis.     

Cavitating lymph node metastasis demonstrated by endobronchial ultrasound

Cavitation of primary non-small cell lung carcinoma (NSCLC) occurs in a small number of patients. We report a case of cavitation of lymph node metastases in NSCLC. CT chest showed central low attenuation of the subcarinal lymph node, suggestive of necrosis, and endobronchial ultrasound (EBUS) imaging demonstrated two cystic spaces within the lymph node. Transbronchial needle aspiration of the cystic space confirmed the presence of metastatic NSCLC. Cystic necrosis was only demonstrable by EBUS. The incidence of such findings is unknown, however with the increasing use of EBUS for evaluation of the mediastinum such images may be more commonly encountered in the future.     

Sclerosing haemangioma with lymph node metastasis

Sclerosing haemangioma (SH) of the lung is an intrapulmonary tumour composed of polygonal and cuboidal cells arranged in a heterogeneous pattern. SH is generally regarded as benign or very low-grade; only rarely have cases of lymph node metastasis been reported. We report a case of SH with metastasis to the regional lymph nodes in an 18-year-old male, whose left lung tumour was identified incidentally on routine CXR. The left upper lobe was removed and the regional lymph nodes dissected. The tumour consisted of proliferative cuboidal and polygonal cells arranged in a papillary pattern within the sclerotic stroma. Subcapsular metastasis was observed in a lymph node. SH with lymph node metastasis was diagnosed. The patient was disease-free at follow up after 2 years. Lobectomy with nodal dissection is suggested for the treatment of pulmonary SH, especially in the case of large tumours with enlargement of regional lymph nodes. Investigation of more cases and long-term follow up are necessary to assess the clinical significance of lymph node metastasis.     

Sentinel lymph node concept in gastric cancer with solitary lymph node metastasis

AIM: To study the localization of the solitary metastases in relation to the primary gastric cancers and the feasibility of sentinel lymph node (SLN) concept in gastric cancer. METHODS: Eighty-six patients with gastric cancer, who had only one lymph node involved, were regarded retrospectively as patients with a possible sentinel node metastasis, and the distribution of these nodes were assessed. Thirteen cases with jumping metastases were further studied and followed up. RESULTS: The single nodal metastasis was found in the nearest perigastric nodal area in 65.1% (56/86) of the cases and in 19.8% (17/86) of the cases in a fairly remote perigastric area. Out of 19 middle-third gastric cancers,3 tumors at the lesser or greater curvatures had transverse metastases. There were also 15.1% (13/86) of patients with a jumping metastasis to N2-N3 nodes without N1 involved. Among them, the depth of invasion was mucosal (M) in 1 patient, submucosal (SM) in 2, proper-muscular (MP) in 4, subserosal (SS) in 5, and serosa-exposed (SE) in 1. Five of these patients died of gastric cancer recurrence at the time of this report within 3 years aftersurgery. CONCLUSION: These results suggest that nodal metastases occur in a random and multidirectional process in gastric cancer and that not every first metastatic node is located in the perigastric region near the primary tumor. The rate of “jumping metastasis” in gastric cancer is much higher than expected, which suggests that the blind examination of the nodal area close to the primary tumor can not be a reliable method to detect the SLN and that a extended lymph node dissection (ELND) should be performed if the preoperative examination indicates submucosal invasion.     

Functional impact of lymphangiogenesis on fluid transport after lymph node excision

When a lymph node is excised, lymphangiogenesis occurs to maintain flow in the affected area. However, a complex network of small vessels replaces the node and these newly formed vessels might increase resistance to lymph transport. To test this in sheep, the popliteal lymph node from one hind limb was removed surgically. The contralateral node was left intact. After 4 to 6 weeks (a period that allowed regenerated vessels to restore flow), a prenodal lymphatic vessel in each limb was cannulated with a polyethylene catheter to permit saline infusion into the node or lymphatic regeneration site. Infusion pressures were monitored from t-pieces inserted between the infusion pump and the point of entry of the catheters in the prenodal ducts. We observed that the flow rate versus perfusion pressure relationships were significantly different in the 2 experimental preparations (node intact limbs, n = 13; node excised limbs, n = 10). In the limbs undergoing lymphangiogenesis, much higher infusion pressures were required to generate a given flow rate. Additionally, the regenerated lymphatic network provided a significantly increased resistance to flow. The data suggested that lymphangiogenesis restored fluid continuity to some extent in the area occupied originally by the popliteal lymph node. However, the transport properties exhibited by the newly formed lymphatics were insufficient to restore flow parameters to their original state.     

Prediction of lymph node metastasis by size of early gastric carcinoma

BACKGROUND/AIMS: Tumor size requires more investigation as a factor in determining extent of regional lymph node dissection in early gastric carcinoma. We retrospectively investigated 573 patients with such tumors to identify predictors of lymph node metastasis. METHODOLOGY: Postoperative survival was examined for groups of patients defined by tumor size under 2 cm, between 2 and 4cm, and over than 4cm. Factors predicting tumor recurrence and regional lymph node metastasis also were determined. RESULTS: Postoperative survival of patients with tumors larger than 4 cm was significantly worsethan that of patients with tumors smaller than 2 cm. Multivariate analysis identified lymph node metastasis as a significant risk factor for recurrence of early gastric carcinoma, while identifying primary tumor size and lymphatic vessel involvement as significant risk factors for lymph node metastasis. CONCLUSIONS: Lymph node metastasis, which increased risk of postoperative recurrence in early gastric carcinoma, was related to tumor size.     

胃癌淋巴结转移规律及其清扫范围探讨

目的　探讨胃癌淋巴结转移规律及其清扫范围。方法　对188例接受手术治疗的胃癌患者,于术中用美蓝-胃癌单克隆抗体(MAb)3H11标记淋巴结,并对染色淋巴结进行清扫,术后统计切除标本的淋巴结转移情况及病理特征。结果 188例胃癌患者的淋巴结转移率为62.8％(118／188)。胃上1／3(U区)、中1／3(M区)、下1／3(L区)及全胃癌患者的淋巴结转移率分别为61.9％、60.0％、57.5％及95.0％。早、中、晚期胃癌患者淋巴结转移率依次呈递增趋势,P<0.05。浸润型(Ⅲ、Ⅳ型)转移率(76.1％)明显高于局限型(Ⅰ、Ⅱ型)(44.3％),P<0.05。肿瘤直径≤4cm、-7cm和≥8cm者的淋巴结转移率依次增加,差异有显著性,P均<0.01。结论 胃癌淋巴结转移率较高。尤其晚期、浸润型及直径>4cm的胃癌,其淋巴结转移率更高,术中应按胃癌的临床病理分期、部位、大小及Borrman分型,选择淋巴结清扫范围。如果根据术中美蓝-MAb3H11标记结果确定淋巴清扫范围将更准确可靠。     

Esophageal cancer with distant lymph node metastasis: prognostic significance of metastatic lymph node ratio

The cervical and celiac lymph node metastases are defined as distant metastasis (Mlym) from thoracic esophageal carcinoma by TNM (primary tumor, regional lymph nodes, and distant metastasis) classification. The prognostic factors, however, of such distant node metastases are not fully understood. Of 85 patients with node-positive thoracic esophageal carcinoma who were treated with the same modalities of treatment, 31 (37%) had Mlym. Prognostic factors for long-term survival were analyzed by univariate and multivariate analyzes. Three patients are alive and free of cancer, and two patients survived over 5 years. Fifteen patients died of recurrent esophageal cancer and 11 patients succumbed to causes unrelated to esophageal cancer. Two patients with a single Mlym died without recurrence of esophageal cancer at 1.4 years and after more than 5 years, respectively. The 1-, 2-, 3-, and 5-year overall survival rates of all 31 patients were 64.5%, 24.8%, 17.0%, and 12.8%, respectively. The factors influencing survival rate were depth of invasion (pT1,2 vs. pT3,4) and metastatic lymph node ratio (< or =0.104 vs. > or =0.105). The survival rates were not influenced by number of lymph node metastasis, number of Mlym, or by metastatic lymph node ratio of Mlym. Among those two significant variables verified by univariate analysis, independent prognostic factor for survival determined by multivariate analysis was the metastatic lymph node ratio (risk ratio = 3.4, p = 0.0345). The results of this study indicate that a significant number of patients can be cured of esophageal carcinoma by extensive resection along with extended lymph node dissection even when the disease metastasizes to distant nodes.