非小细胞肺癌肿瘤血管生成研究现状

非小细胞肺癌（NSCLC）侵袭性生长，转移和预后依赖于血管生成，而血管生成受控于生长因子与细胞凋亡因子，蛋白水解酶和粘附分子间的复杂作用，研究发现，基质金属蛋白酶抑制因子，生长因子反义RNA，生长因子受体拮抗剂和天然抗血管生成肽类物质等具有良好的抗血管生成作用，为NSCLC治疗开辟了新的途径。     

非小细胞肺癌肿瘤血管生成研究现状

非小细胞肺癌(NSCLC)侵袭性生长、转移和预后依赖于血管生成.而血管生成受控于生长因子与细胞凋亡因子、蛋白水解酶和粘附分子间的复杂作用.研究发现,基质金属蛋白酶抑制因子、生长因子反义RNA、生长因子受体拮抗剂和天然抗血管生成肽类物质等具有良好的抗血管生成作用,为NSCLC治疗开辟了新的途径.     

非小细胞肺癌肿瘤血管生成研究进展

血管生成是机体正常生理过程所必需的,见于女性的生殖系统及胚胎发育,并受到严格控制[1];在病理情况下,见于机体创伤修复、类风湿关节炎、糖尿病视网膜病、肿瘤的生长和转移。研究证实,新生肿瘤血管是肿瘤获取代谢营养的形态学基础,也是肿瘤细胞迁移游走形成转移的必经之路[2]。非小细胞肺癌(non small celllungcancer,NSCLC)的生物学特性与其他实体肿瘤一样,血管形成对其生长转移有重要作用。我们就NSCLC肿瘤血管形成、检测方法以及肿瘤血管与肿瘤生物学行为的关系做一综述。一、肿瘤血管形成机制实体肿瘤NSCLC由两部分组成,即实体(…     

肿瘤血管生成抑制物的研究

肿瘤的生长及转移依赖于血管的生成(angiogenesis)，抑制肿瘤血管生成可以抑制肿瘤的生长，已经成为不同于常规肿瘤治疗的方法和热点。与直接杀伤肿瘤细胞的化学药物治疗相比，血管生成抑制剂有以下优点：(1)血管生成抑制剂直接作用于血管内皮细胞，而抗癌药物经组织扩散时受到组织坏死、纤维化、组织内高压的影响，常常在组织内达不到有效浓度；(2)血管内皮细胞属正常细胞，其基因型稳定，不易产生耐药性，而肿瘤细胞基因型不稳定，易产生耐药性；     

肿瘤血管生成与抗血管生成基因治疗

肿瘤血管生成是肿瘤生长浸润转移的关键步骤,其形成主要是促血管生成因子和抑制因子作用失衡的结果。以肿瘤血管生成为靶点的抗血管生成治疗作为肿瘤治疗新视野,已发展为重要的抗肿瘤策略。基因治疗则使抗血管生成治疗更具有靶向性,使这一治疗策略产生新的飞跃。本文就该领域研究情况作一综述。     

肿瘤血管生成抑制剂研究进展

肿瘤生长、侵袭、转移和复发是血管生成依赖性的,以肿瘤血管生成的各个环节为靶点,研制血管生成抑制剂,可有效地抑制肿瘤的转移和复发,成为肿瘤防治的新途径.本文就目前已进入临床试验的30多种血管生成抑制剂研究进展作一综述.     

血管生长因子与肿瘤血管生成

血管生成对恶性肿瘤的发生、发展和预后至关重要。就血管内皮生长因子、血小板源性内皮细胞生长因子、碱性成纤维细胞生长因子等血管生成调节因子的研究进展进行综述 ,介绍了抗血管生成治疗肿瘤的现状和发展动向。     

血管内皮生长因子在肿瘤血管生成的研究进展

人类肿瘤生长伴随血管生成早在一个多世纪前就被发现[1]。几十年对血管分子机制的研究,发现有很多种生长因子对肿瘤血管生成是有促进作用的,如血管内皮生长因子(VEGF)、成纤维生长因子(FGF)、血小板源性生长因子(PDGF)等,其中最重要的生长因子是VEGF[2],无论在生理     

Qingjie Fuzheng Granules regulates cancer cell proliferation,apoptosis and tumor angiogenesis in colorectal cancer xenograft mice via Sonic Hedgehog pathway

BackgroundSonic Hedgehog (SHh) signaling pathway plays a critical role in cell proliferation, apoptosis, and tumor angiogenesis in various types of malignancies including colorectal cancer (CRC). Qingjie Fuzheng Granules (QFG) is a traditional Chinese medicinal formula, which has been clinically used in various cancer treatments, including CRC. In this study, we explored the potential molecular mechanisms of QFG treatment effects on CRC via the SHh pathway.MethodsA CRC HCT-116 xenograft mouse model was utilized for all experiments. Mice were treated with intra-gastric administration of 1 g/kg of QFG or saline 6 days a week for 28 days (4 weeks). Body weight, length and shortest diameter of the tumor were measured every 3 days. At the end of the treatment, the tumor weight was measured. TUNEL staining assays were used to detect tumor apoptosis. Western blot and immunohistochemistry (IHC) assays were used to detect the expression of relative proteins.ResultsIn our results, QFG inhibited the increase of tumor volume and weight, and exhibited no impact on mouse body weight. Furthermore, QFG significantly decreased the expression of SHh, Smo and Gli proteins, indicating the action of SHh signaling. Consequently, the expression of pro-proliferative survivin, Ki-67, Cyclin-D1 and CDK4 were decreased and expression of anti-proliferative p21 was increased. The pro-apoptotic Bax/Bcl-2 ratio, cle-caspase-3 and TUNEL-positive cell percentage in tumor tissues were increased. Meanwhile, the pro-angiogenic VEGF-A and VEGFR-2 expression was down-regulated.ConclusionsQFG inhibited CRC cell proliferation and promoted CRC cell apoptosis and tumor angiogenesis in vivo through the suppression of SHh pathway, suggesting that QFG could be a potential therapeutic drug for CRC.     

白桦脂酸对人类大肠癌细胞裸鼠体内生长及血管生成的抑制作用(英文)

Objective:Angiogenesis plays a major role in the pathogenesis of many disorders.Vascular endothelial growth factor(VEGF) has been shown to be the key regulator of normal and pathological angiogenesis.Many studies showed that decreased expression of VEGF has been inhibited growth and migration of cancer cells.The aim of this study was to explore the effects of Betulinic acid on the VEGF expression and the growth of colorectal cell SW480 xenografts in nude mice.Methods:The xenografts derived from colorectal c...     

Genome variation in colorectal cancer patient with liver metastasis measured by whole-exome sequencing

BackgroundLiver metastasis of colorectal cancer (CRC) is an important cause of death from CRC, but its molecular mechanism is still unclear. In recent years, whole-exome sequencing has played an increasingly important role in the study of the occurrence and development of diseases, especially malignant tumors. Its high throughput and low cost advantages enable researchers to explore the pathogenic genes of diseases, and screen potential molecular markers and therapeutic targets from the level of genomics.MethodsThis study collected the primary tumor tissues, matched paracancerous, normal tissues, and liver metastases of 4 CRC patients admitted to the Department of General Surgery of the First Affiliated Hospital of Soochow University, and performed high-depth whole-exome sequencing, with the sequencing depth of each sample reaching 123× on average, then filtered the sequencing data, compared them, and analyzed the bioinformatics data.Resultswe found 8,565 single nucleotide variants (SNV) and 429 insertions/deletions (InDel) in the primary and hepatic lesion tissues, and the genes with the highest mutation frequency were titin (TTN), obscurin (OBSCN), and homeodomain-interacting protein kinase 2 (HIPK2). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the mutant genes was conducted, and it was found that the mutant genes were mainly concentrated in the cells, cell parts, and cellular process of GO. The results of KEGG pathway analysis showed that mutations were mainly distributed in circadian entrainment, insulin secretion, and glutamatergic synapse. Further, we identified 723 SNV and Indel genes with high frequency mutations including TTN, OBSCN, and hydrocephalus-inducing protein homolog (HYDIN) across all tissues of liver metastases. The GO analysis showed that the mutated genes in liver metastatic tissues were mainly concentrated in cell, cell part, and cellular process. The KEGG pathway analysis showed that high frequency mutation genes were focused on gastric acid secretion, bile secretion, and melanogenesis.ConclusionsThis study found some candidate genes related to the occurrence of CRC and liver metastasis through whole-exome sequencing of relevant tissues in CRC patients with liver metastasis, which is expected to provide new markers and therapeutic targets for such patients.     

miR-92a 在结直肠癌中的表达及其对肿瘤血管生成的作用*

目的：探讨miR-92a 在结直肠癌中的表达及其对肿瘤血管新生功能的影响和作用机制。方法：采用qRT-PCR方法检测广东医学院附属深圳南山医院2014年6 月至2015年12月经手术切除的25例结直肠癌组织和对应癌旁组织及4 种结直肠癌细胞（HCT 116、SW620、SW480、HT29）中miR-92a 的表达;免疫组织化学法检测结直肠癌和癌旁组织中CD31阳性表达的微血管密度（microvesseldensity,MVD）,Pearson相关性分析探讨miR-92a 表达与肿瘤血管新生MVD的相关性。通过转染miR-92a-mimic、inhibitor 上调或抑制结直肠癌细胞HCT 116、SW620 中miR-92a 的表达水平,采用小管形成实验检测miR-92a 不同表达对HUVEC小管形成的影响,免疫印迹法检测对其下游潜在靶点PTEN的蛋白表达的影响。结果：结直肠癌组织miR-92a 的表达水平显著高于对应癌旁组织（P < 0.01）;4 种人结肠癌细胞系miR-92a 的表达水平均显著高于正常肠上皮组织（P < 0.05）;结直肠癌组织CD31阳性微血管密度显著高于癌旁组织（P < 0.01）,miR-92a 表达水平与结直肠癌血管新生MVD呈显著正相关（r = 0.580,P = 0.01）;上调miR-92a 表达的HCT 116 细胞培养上清液可以显著促进HUVEC小管形成（P < 0.05）;上调miR-92a 表达可以显著抑制HCT116 细胞中PTEN蛋白表达水平（P < 0.01）。 结论：miR-92a 在结直肠癌细胞和组织中高表达,与肿瘤血管新生增加密切相关;miR-92a 可能通过抑制PTEN的表达发挥促进结直肠癌血管新生的生物学功能。     

Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients

In animal models, explosive growth of metastases after removal of the primary tumor has been attributed to abolishment of angiogenesis inhibition. We investigated the influence of (removal of) the primary tumor on vascularization of liver metastases in human colorectal cancer patients. We analyzed vascular density in synchronous liver metastases from patients with the primary tumor in situ, in synchronous metastases from patients with the primary tumor resected and in metachronous metastases. In a limited number of cases, biopsies from metastases from the same patient before and within 3 months after resection were analyzed. In addition, vascular density in metastases was compared to the vascular density in the corresponding primary tumor. Peritumoral and intratumoral vascular density were determined by staining for endothelial antigens CD31 and CD34, respectively. Both peritumoral and intratumoral vascular density were elevated in synchronous metastases from patients with the primary tumor removed compared to synchronous metastases from patients with the primary tumor in situ. Comparable results were observed in patients with metachronous metastases. An increase in vascular density after resection of the colorectal malignancy was also observed in biopsies taken from the same patient before and after tumor resection. Remarkably, vascular density in the liver metastases was always lower than that in the corresponding primary tumor. Our data show for the first time in humans that the presence of a primary tumor is correlated with decreased vascularization of its distant metastases. Resection of the primary tumor results in an increased vascularization of metastatic lesions.     

Zebrafish xenograft model for studying the function of lncRNA SNHG4 in the proliferation and migration of colorectal cancer

BackgroundThe zebrafish xenograft model has become a reliable in vivo model for human cancer research. Compared to a mouse model, the zebrafish xenograft has many advantages, including optical transparency, intuitive in vivo observation, and speed. Long noncoding RNAs (lncRNAs) have been identified as crucial regulatory factors in the progression of colorectal cancer (CRC). The biological function of lncRNA small nucleolar RNA host gene 4 (SNHG4) in CRC is still unclear.MethodsWe analyzed the expression of SNHG4 in CRC patient samples by the Gene Expression Profiling Interactive Analysis (GEPIA) software. The quantitative real time-polymerase chain reaction (qRT-PCR) was used to verify in CRC cell lines. The colony formation assay was used to study the cell proliferation, and we used the transwell assay to detect the migration ability. Then the zebrafish xenograft models were used to confirm these roles of SNHG4 in vivo. Moreover, we detected epithelial mesenchymal transition (EMT) related genes by qRT-PCR.ResultsWe found the expression of SNHG4 was upregulated in CRC patient samples by analyzing GEPIA software, which was also verified in CRC cell lines. We also found that silencing SNHG4 inhibited the proliferation and migration of CRC cells, and its roles were verified in zebrafish xenografts in vivo. Further, we found that the expression of E-cadherin was significantly upregulated and N-cadherin was downregulated when knocking-down SNHG4 in CRC cells.ConclusionsOur findings demonstrated that SNHG4 played oncogenic roles in CRC, which could be a potential target for treatment of CRC patients, and the results strongly revealed that zebrafish xenograft could be used for functional research of lncRNAs in human cancer.     

含Cetuximab方案治疗非肠癌消化道肿瘤近期疗效——单中心16例经验总结

Objective  

We measured CEA (carcinoembryonic antigen) levels in both serum and bile from patients with colorectal cancer (CRC) to evaluate the relationship between bile CEA levels and liver metastasis (LM).     

Association between nonalcoholic fatty liver disease and colorectal adenoma: a systemic review and meta-analysis

Background

Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome (MetS) and the most common chronic liver disease worldwide. The association between NAFLD and colorectal adenoma has been investigated in multiples studies but the results have been conflicting. We performed a systematic review and meta-analysis to evaluate this in asymptomatic patients who underwent screening colonoscopy.

Methods

We searched the literatures of all languages from PubMed, EMBASE and the Cochrane library from January 1, 1980 through July 15, 2014. Combined and subgroup analyses stratified by study designs, study locations, characteristics of adenoma (location, size, number, and advanced adenoma) were performed.

Results

Four cross-sectional and one cohort studies with a total of 6,263 subjects were included in the meta-analysis. NAFLD was significantly associated with colorectal adenoma [pooled odds ratio (OR) 1.74, 95% confidence interval (CI): 1.53-1.97]. The association was more significant in Asian population (pooled OR =1.77, 95% CI: 1.52-2.05, n=3 studies), compared to European/North American population (pooled OR =1.42, 95% CI: 0.75-2.67, n=2 studies). NAFLD was significantly associated with the number of colorectal adenoma (pooled OR =1.78, 95% CI: 1.10-2.86, n=2 studies), but not the location, size, or presence of advanced adenoma.

Conclusions

Our results suggest NAFLD is significantly associated with the presence of colorectal adenoma in asymptomatic patients undergoing screening colonoscopy. This finding provides additional risk stratifications for applying colorectal cancer (CRC) screening strategies. However, more studies of western population are needed to further investigate the ethnic disparity.     

结直肠癌肝转移差异表达基因与信号通路分析

目的：探讨结直肠癌（colorectal cancer, CRC）肝转移的关键基因和分子机制,为CRC肝转移的治疗提供潜在靶点和生物标志物。方法: 基于生物信息学方法从GEO 数据库下载CRC 肝转移基因表达数据集,筛选差异表达基因（differentially expressed gene, DEG）,利用DAVID 在线工具对DEG进行GO和KEGG富集分析,构建蛋白互作（protein-protein interaction, PPI）网络图,筛选出CRC关键基因并进行预后分析。结果: 从183 例CRC组织标本和39 例CRC肝转移组织标本中筛选出321 个DEG,其中上调基因153 个、下调基因168 个。GO和KEGG富集分析结果显示,DEG的功能主要涉及蛋白质激活级联反应、炎症反应、细胞外基质、血小板脱颗粒、补体与凝血级联反应等。PPI 网络图筛选出8 个CRC 关键基因为ALB、APOB、FGA、F2、APOA1、SERPINC1、FGG和AHSG。生存分析发现,SERPINC1、FGG表达高的患者预后不良（均P<0.05）。结论: DEG的生物学功能和信号通路与CRC肝转移的发生发展相关,8 个CRC关键基因可能是CRC肝转移治疗的潜在靶点,SERPINC1、FGG可能成为新的预后标志物。     

裸小鼠大肠癌肝脏微转移模型的建立及肿瘤细胞微转移的检测

目的　建立一种裸小鼠大肠癌肝脏微转移模型的方法。方法　运用盲肠造疝原位瘤块接种法建立裸小鼠的大肠癌模型 ,同时以Alu基因为标志 ,利用PCR法检测接种后不同时期的裸小鼠肝脏中发生微转移的肿瘤细胞。结果　盲肠原位接种瘤块后 2周 ,大部分裸小鼠均长出直径 1cm的盲肠实体瘤 ,接种成功率为 88%。接种后生长了四周以上的裸小鼠中有 5 7.1%在其肝组织中能够检测到Alu基因 ,而常规病理检查未发现异常 ,表明在这些裸小鼠的肝脏中存在着微转移的肿瘤细胞。结论　利用盲肠造疝瘤块原位接种法建立裸小鼠的大肠癌模型 ,其方法简单且成功率高 ,同时易于观察肿瘤的生长。大部分裸小鼠在接种后四周到六周就能够利用PCR法在肝脏中检测到微转移的肿瘤细胞。这一发现可为以后大肠癌微转移的基础研究提供一定的帮助。