非小细胞肺癌组织血管生成相关因子表达及临床病理分析

目的探讨血管内皮生长因子(VEGF)及其受体(Flt-1)、转化生长因子β1(TGF-β1)在非小细胞肺癌(non-smallcelllungcancer,NSCLC)组织血管形成中的意义及与肿瘤临床、生物学行为的关系。方法免疫组化染色观察VEGF、血管内皮生长因子受体-1(Flt-1)、TGF-β1在NSCLC组织中的表达,以CD34免疫组化染色来显示NSCLC组织中微血管生成情况和进行微血管密度判断。结果NSCLC组织中癌细胞不同程度地表达VEGF、血管内皮生长因子受体因子、TGF-β1,而对照组肺组织基本不表达(P<0·05);VEGF、Flt-1、TGF-β1阳性表达的NSCLC组织内微血管计数明显高于VEGF、Flt-1、TGF-β1表达阴性的NSCLC组织(P<0·05);NSCLC组织中VEGF、Flt-1、TGF-β1的阳性表达率和表达强度均与肿瘤淋巴结转移密切相关;随年龄增长,VEGF及其受体Flt-1的阳性表达率有所降低(P<0·05)。结论VEGF、Flt-1、TGF-β1的表达与NSCLC组织内肿瘤血管生成和淋巴结转移有密切关系,VEGF、Flt-1的表达与患者的年龄有一定关系。     

非小细胞肺癌组织中VEGF与P53蛋白表达及意义

目的:探讨VEGF和P53在非小细胞肺癌(NSCLC)中的表达及其生物学行为的关系。方法:采用免疫组织化学方法,对病理确诊的62例非小细胞肺癌组织进行VEGF和P53表达的检测。结果:62例非小细胞肺癌VEGF阳性表达率58.1%(36/62),其表达与NSCLC的组织分化程度、生存期有相关性(P<0.05),与组织学类型、有无淋巴结转移、临床病理分期无关。P53阳性表达率46.8%(29,62),表达与肿瘤组织类型、TNM分期、有无淋巴结转移无关(P<0.05)。结论:VEGF和P53可作为评价非小细胞肺癌预后的重要指标。用免疫组化检测出P53蛋白可间接反映P53基因的突变。本组资料检测的结果显示,P53基因阳性表达率46.8% (29/62),表明近一半肺癌病例已失去P53蛋白的抑癌功能,且P53基因的突变可能与非小细胞肺癌的发生有关。P53和VEGF都是潜在的新型肿瘤表型标志物,它们的检测可作为肿瘤病理分级诊断的主要参考依据。同时检测P53和VEGF的表达状态,可通过肿瘤血管形成的生物学行为信息,进一步研究肿瘤血管形成的分子水平调控机制,这有助于抗肿瘤药物的开发研究。     

血管生成拟态和E-cad在食管鳞状细胞癌中的表达及临床意义

目的 探讨血管生成拟态( vasculogenic mimicry,VM)与E-钙粘蛋白(E-cadherin,E-cad))在食管鳞癌(esophageal squamous cell carcinoma)组织中的表达及意义.方法 收集食管鳞状细胞癌术后标本100例和30例癌旁正常食管黏膜,应用免疫组化法和组织化学法检测食管鳞状细胞癌和正常食管黏膜组织中VM和E-cad的表达情况.结果 在食管鳞状细胞癌组织和正常食管黏膜组织中,VM和E-cad的阳性表达率分别为47.0％、48.0％和0％、70.0％,差异有统计学意义(P＜0.05);VM及E-cad的表达与食管鳞癌的组织学分级、临床分期及淋巴结转移(P＜0.05);VM与E-cad在食管鳞癌中的表达呈负相关(r=-0.865,P=0.000).多因素分析:PTNM分期、淋巴结转移、VM和E-cad的表达是影响食管鳞癌根治术后患者预后的独立因素(P＜0.05);VM阳性组与阴性组的5年生存率分别为4.3％和64.2％,,差异有统计学意义(P=0.000);E-cad阳性组与阴性组5年生存率分别为60.4％和15.4％,差异有统计学意义(P=0.000).结论 具有VM结构的食管鳞状细胞癌的分化程度低,恶性度高,预后差,VM和E-cad表达的程度与食管鳞状细胞癌的进展和预后密切相关.     

Ⅰ期非小细胞肺癌组织血管内皮生长因子C、细胞角蛋白19表达与患者预后的相关性

目的:分析Ⅰ期非小细胞肺癌(NSCLC)组织血管内皮生长因子C(VEGF-C)、细胞角蛋白19(CK19)水平的变化,并探讨其与患者预后的相关性。方法:采用免疫组化检测肺癌组织中VEGF-C、CK19蛋白的表达,分析其与肺癌患者临床病理特点的相关性。随访至少3年,采用Kaplan-Meier法分析不同VEGF-C、CK19蛋白表达患者术后复发及疾病进展时间的差异。结果:VEGF-C和CK19在不同分化程度、胸膜侵犯患者肺癌组织中的表达比较差异均有统计学意义(P0.05)。VEGF-C表达与CK19表达呈显著正相关(r=0.483,P0.05)。术后3年,VEGF-C和CK19阳性患者复发率均显著高于VEGF-C和CK19阴性患者(x~2=14.16, 17.25,P0.05)。Kaplan-Meier法显示VEGF-C阳性、阴性者中位TTP分别为29.2个月(95%CI:27.5～30.9)、36.2个月(95%CI:35.0～37.5);CK19阳性、阴性者中位TTP分别为28.4个月(95%CI:26.6～30.2)、37.8个月(95%CI:36.4～39.1)。VEGF-C、CK19阴性者与阳性者的中位TTP比较差异有统计学意义(x~2=15.77、18.45,P0.05)。结论:I期NSCLC患者肺癌组织VEGF-C、CK19呈高表达,与术后局部复发密切相关,并可作为患者预后评估的参考指标。     

血管内皮标记物及血管内皮生长因子在胸水细胞中的表达和意义

探讨CD31、CD34、CD105及VEGF在胸水中的表达.应用免疫细胞化学染色,免疫荧光染色,Western-blot技术检测200例非小细胞肺癌患者胸水、30例增生胸水和20例炎性胸水中CD31、CD34、CD105及VEGF的表达.CD31、CD34、CD105及VEGF在非小细胞肺癌胸水中的表达量明显高于增生和炎性胸水表达(P＜0.05).非小细胞肺癌胸水患者CD31、CD34、CD105及VEGF高表达,并且在存在着肿瘤细胞血管样管型结构中表达量明显高于未发现肿瘤细胞血管样管型的胸腔积液.检测CD31、CD34、CD105及VEGF在胸腔积液中的表达情况可能对判断患者的预后有一定价值.     

外周血CTC、VEGF的水平与晚期非小细胞肺癌临床特征及化疗疗效关系的研究

摘要 目的：探讨外周血循环肿瘤细胞（CTC）、血管内皮生长因子（VEGF）的水平与晚期非小细胞肺癌临床特征及化疗疗效的关系。方法：选取我院2017年1月到2020年1月收治的80例晚期非小细胞肺癌患者作为研究对象,所有患者均采取一线方案化疗,分析外周血CTC、VEGF的水平与患者的年龄、性别等的关系,并对晚期非小细胞肺癌化疗疗效进行单因素与多因素COX分析。结果：CTC、VEGF与不同性别、年龄患者和TNM分期无明显关系（P＞0.05）,与淋巴结转移、肿瘤分化程度、肿瘤大小有关（P＜0.05）;80例患者中,客观缓解率（ORR）为51.25 %（41/80）,疾病控制率（DCR）为71.25 %（57/80）;淋巴结转移、肿瘤分化程度、CTC和血清VEGF水平为晚期非小细胞肺癌患者ORR、DCR的影响因素（P＜0.05）;COX分析分析表明：肿瘤中、低分化、CTC阴性、VEGF降低为晚期非小细胞肺癌化疗ORR和DCR提升的独立影响因素（P＜0.05）。结论：外周血CTC、VEGF检测对于晚期非小细胞肺癌化疗近远期疗效评估具有重要价值,属于预后独立影响因素。因此,CTC、VEGF可作为晚期非小细胞肺癌的预后及疗效判断的指标。     

非小细胞肺癌靶向药物研究的新进展

NSCLC是最常见的恶性肿瘤之一,化学治疗对NSCLC的疗效已经达到平台期,但本世纪初靶向治疗研究的突破性进展为人们带来了新的希望。根据靶点的不同将靶向药物分为:以EGFR为靶点、以VEGF为靶点及多靶点药物等,本文将介绍吉非替尼、厄洛替尼、西妥昔单抗等代表药物在NSCLC靶向一线、二线及维持治疗中的新进展。     

非小细胞肺癌靶向药物研究的新进展

NSCLC是最常见的恶性肿瘤之一,化学治疗对NSCLC的疗效已经达到平台期,但本世纪初靶向治疗研究的突破性进展为人们带来了新的希望。根据靶点的不同将靶向药物分为：以EGFR为靶点、以VEGF为靶点及多靶点药物等,本文将介绍吉非替尼、厄洛替尼、西妥昔单抗等代表药物在NSCLC靶向一线、二线及维持治疗中的新进展。     

血管生成拟态和肿瘤的关系

血管生成拟态指由恶性肿瘤细胞而非血管内皮细胞连接形成的、能为肿瘤提供血供的管网状结构．存在于恶性黑素瘤、卵巢癌、前列腺癌、炎性乳腺癌和某些软组织肉瘤。其发生和肿瘤细胞呈现出多潜能的胚胎样表型有关。进一步研究血管生成拟态的分子机制,探索有效的拮抗其过程的方案,有可能提供一种能有效治疗肿瘤、并且对正常生理过程的影响较小的策略     

黄芪多糖对非小细胞肺癌患者外周血CA125、VEGF及MMP-9表达的影响

目的:探讨黄芪多糖对非小细胞肺癌外周血糖类抗原125(CA125)、血管内皮生长因子(VEGF)及基质金属蛋白酶-9(MMP-9)表达的影响。方法:选取我院收治的非小细胞肺癌患者100例,随机分为两组,每组各50例,对照组予常规放疗,实验组在对照组的基础上,加以注射用黄芪多糖250 mg,溶于500 ml生理盐水中,日1次,与放疗同步,7日为1个疗程,治疗2个疗程。治疗后,观察和比较两组患者的临床疗效,血常规、血CA125、VEGF及MMP-9的表达情况。结果:1治疗后,实验组的总有效率为86.0%,对照组的总有效率为64%,显著低于实验组,差异有统计学意义(P0.05)。2治疗后,对照组Hb、WBC、NEUT较治疗前均显著降低,而RBC变化不明显,实验组Hb、WBC、NEUT均显著高于对照组,差异均有统计学意义(P0.05)。3治疗后1、5、14天,两组患者的外周血CA125、VEGF及MMP-9表达均较治疗前有所降低,且实验组治疗后5、14天外周血CA125、VEGF及MMP-9表达均显著低于对照组,差异有统计学意义(P0.05)。结论:黄芪多糖能够有效降低非小细胞肺癌患者外周血CA125、VEGF及MMP-9表达,提高其临床疗效,改善放疗所致骨髓抑制。     

Signalling pathways in vasculogenic mimicry

Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.     

Pro-angiogenic activity and vasculogenic mimicry in the tumor microenvironment by leptin in cancer

The acquired ability to induce the formation of a functional vasculature is a hallmark of cancer. Blood vessels in tumors are formed through various mechanisms, among the most important in cancer biology, angiogenesis, and vasculogenic mimicry have been described. Leptin is one of the main adipokines secreted by adipocytes in normal breast tissue and the tumor microenvironment. Here, we provide information on the relationship between leptin and the development of angiogenesis and vasculogenic mimicry in different types of cancer. Here, we report that leptin activates different pathways such as JAK-STAT3, MAPK/ERK, PKC, JNK, p38, and PI3K-Akt to induce the expression of various angiogenic factors and vasculogenic mimicry. In vivo models, leptin induces blood vessel formation through the PI3K-Akt-mTOR pathway. Interestingly, the relationship between leptin and vasculogenic mimicry was more significant in breast cancer. The information obtained suggests that leptin could be playing an essential role in tumor survival and metastasis through the induction of vascular mechanisms such as angiogenesis and vasculogenic mimicry; thus, leptin-induced pathways could be suggested as a promising therapeutic target.     

Canstatin基因转染对人肝癌HepG-2细胞体外血管生成拟态的影响

目的:探讨转染Canstatin基因对人肝癌HepG-2细胞体外形成血管生成拟态的影响。方法:将Canstatin基因通过脂质体法转染人肝癌HepG-2细胞,行G418筛选获得转基因细胞克隆。用SDS-PAGE电泳检测Canstatin蛋白在转基因细胞培养上清液中的表达;建立HepG-2细胞人工基底膜基质凝胶体外三维细胞培养模型,观察HepG-2细胞能否形成血管生成拟态,并比较转基因和未转基因细胞的管道形成能力。结果:Canstatin在转染人HepG-2细胞中表达并分泌至上清液中,人肝癌HepG-2细胞在体外三维培养条件下能够形成血管生成拟态。Canstatin基因转染HepG-2细胞组的管状结构数量高于空载体组和HepG-2细胞组,转染细胞管道形成能力明显受抑制。结论:人肝癌HepG-2细胞株可形成血管生成拟态,Canstatin能抑制人肝癌细胞株HepG-2体外血管生成拟态形成。     

Advanced research on vasculogenic mimicry in cancer

Vasculogenic mimicry (VM) is a brand‐new tumour vascular paradigm independent of angiogenesis that describes the specific capacity of aggressive cancer cells to form vessel‐like networks that provide adequate blood supply for tumour growth. A variety of molecule mechanisms and signal pathways participate in VM induction. Additionally, cancer stem cell and epithelial‐mesenchymal transitions are also shown to be implicated in VM formation. As a unique perfusion way, VM is associated with tumour invasion, metastasis and poor cancer patient prognosis. Due to VM's important effects on tumour progression, more VM‐related strategies are being utilized for anticancer treatment. Here, with regard to the above aspects, we make a review of advanced research on VM in cancer.     

MMP‐2 and MMP‐13 affect vasculogenic mimicry formation in large cell lung cancer

Matrix metalloproteinases (MMPs) have critical functions in tumour vasculogenic mimicry (VM). This study explored the mechanisms underlying MMP‐13 and MMP‐2 regulation of tumour VM formation in large cell lung cancer (LCLC). In our study, laminin5 (Ln‐5) fragments cleaved by MMP‐2 promoted tubular structure formation by the LCLC cell lines H460 and H661 in three‐dimensional (3D) cultures. Transient up‐regulation of MMP‐13 or treatment with recombinant MMP‐13 protein abrogated tubular structure formation of H460 cells in 3D culture. Treated cells with Ln‐5 fragments cleaved by MMP‐2 stimulated EGFR and F‐actin expression. Ln‐5 fragments cleaved by MMP‐13 decreased EGFR/F‐actin expression and disrupted VM formation. MMP‐13 expression was negatively correlated with VM, Ln‐5 and EGFR in LCLC tissues and xenograft. In vivo experiments revealed that VM was decreased when the number of endothelium‐dependent vessels (EDVs) increased during xenograft tumour growth, whereas MMP‐13 expression was progressively increased. In conclusion, MMP‐2 promoted and MMP‐13 disrupted VM formation in LCLC by cleaving Ln‐5 to influence EGFR signal activation. MMP‐13 may regulate VM and EDV formation.     

RhoC/ROCK2 promotes vasculogenic mimicry formation primarily through ERK/MMPs in hepatocellular carcinoma

Vasculogenic mimicry (VM) results in the formation of an alternative circulatory system that can improve the blood supply to multiple malignant tumors, including hepatocellular carcinoma (HCC). However, the potential mechanisms of RhoC/ROCK in VM have not yet been investigated in HCC. Here, RhoC expression was upregulated in HCC tissues, especially the VM-positive (VM+) group, compared to noncancerous tissues (P < 0.01), and patients with high expression of RhoC had shorter survival times (P < 0.001). The knockdown of RhoC via short hairpin RNA (shRNA) in SK-Hep-1 cells significantly decreased VM formation and cell motility. In contrast, cell motility and VM formation were remarkably enhanced when RhoC was overexpressed in HepG2 cells. To further assess the potential role of ROCK1 and ROCK2 on VM, we stably knocked down ROCK1 or ROCK2 in MHCC97H cells. Compared to ROCK1 shRNA, ROCK2 shRNA could largely affect VM formation, cell motility and the key VM factors, as well as the epithelial-mesenchymal transition (EMT) markers in vitro and in vivo. Moreover, p-ERK, p-MEK, p-FAK, p-paxillin, MT1-MMP and MMP2 levels were clearly altered following the overexpression of RhoC, but ROCK2 shRNA had little effect on the expression of p-FAK, which indicated that RhoC regulates FAK/paxillin signaling, but not through ROCK2. In conclusion, our results show that RhoC/ROCK2 may have a major effect on VM in HCC via ERK/MMPs signaling and might be a potential therapeutic target for the treatment of HCC.     

Contribution of cancer stem cells to tumor vasculogenic mimicry

Vasculogenic mimicry (VM), a newly-defined pattern of tumor blood supply, provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis. The biological features of the tumor cells that form VM remain unknown. Cancer stem cells (CSCs) are believed to be tumor-initiating cells, capable of self-renewal and multipotent differentiation, which resemble normal stem cells in phenotype and function. Recently CSCs have been shown to contribute to VM formation as well as angiogenesis. These findings challenge the previous understanding of the cellular basis of VM formation. In this review, we present evidence for participation of CSCs in VM formation. We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche. Based on the importance of VM in tumor progression, it constitutes a novel therapeutic target for cancer.     

HER2/neu expression correlates with vasculogenic mimicry in invasive breast carcinoma

Vasculogenic mimicry (VM) refers to the condition in which tumour cells mimic endothelial cells to form extracellular matrix‐rich tubular channels. VM is more extensive in more aggressive tumours. The human epidermal growth factor receptor 2 (HER2) gene is amplified in 20–30% of human breast cancers and has been implicated in mediating aggressive tumour growth and metastasis. However, thus far, there have been no data on the role of HER2 in VM formation. Immunohistochemical and histochemical double‐staining methods were performed to display VM in breast cancer specimens. Transfection in MCF7 cells was performed and clones were selected by G418. The three‐dimensional Matrigel culture was used to evaluate VM formation in the breast cancer cell line. According to statistical analysis, VM was related to the presence of a positive nodal status and advanced clinical stage. The positive rate of VM increased with increased HER2 expression. In addition, cases with HER2 3+ expression showed significantly greater VM channel count than those in other cases. The exogenous HER2 overexpression in MCF‐7 cells induced vessel‐like VM structures on the Matrigel and increased the VM mediator vascular endothelial (VE) cadherin. Our data provide evidence for a clinically relevant association between HER2 and VM in human invasive breast cancer. HER2 overexpression possibly induces VM through the up‐regulation of VE cadherin. Understanding the key molecular events may provide therapeutic intervention strategies for HER2+ breast cancer.