Dickkopf-1在消化系肿瘤中的研究现状与进展

Dickkopf-1(DKK1)是Wnt信号通路的一种拮抗剂,他在肿瘤的发生、发展中起着重要的作用.多项研究表明,DKK1在不同肿瘤中组织学和血清学的表达水平不同,说明其对于不同肿瘤发生、发展的作用机制也不完全相同.近年来有较多DKK1与消化系肿瘤的相关研究报道,我们通过学习相关文献,发现DKK1在消化系不同肿瘤中的表现也不一致.     

雌激素受体的特征及与胃肠道肿瘤的关系

早在60年代初有学者发现同样的肿瘤其性别不同,预后也不同,且乳腺癌等性激素靶器官肿瘤常在其发生前后同时并发胃肠道肿瘤,因此认为机体内雌激素环境影响了某些消化道肿瘤的自然发展历程.近年来发现在结、直肠癌、类癌、胰腺癌和胃癌中的确存在雌激素受体(Estrogen receptor,ER).部份病例采用内分泌治疗取得了一定的疗效.但这些肿瘤中的ER是否具有指导诊断和治疗的价值,这是肿瘤病因学和内分泌治疗中有兴趣的问题.本文就雌激素受体的特征及与胃肠道肿瘤的关系综述如下.     

肝细胞癌微血管形态与其临床病理学特性关系的研究

目的 探讨肝细胞癌肿瘤微血管形态特征与其临床病理学特性的关系.方法 收集我院手术切除前未做过栓塞治疗的肝细胞癌标本55例,对此组肝细胞癌病理标本做了肿瘤微血管形态分型、分化级别划分、肿瘤大小测量、有无包膜及卫星结节鉴定,并对各观察指标做相关统计分析.结果 肝癌细胞分化级别、大小与肿瘤微血管分型级别呈正相关趋势.无包膜的肝癌微血管分型级别高于有包膜的肝癌.肝癌微血管分型在肿瘤有无卫星结节间无差别.结论 肝癌在生长的不同阶段,其肿瘤微血管形态特征不同,并有一定的规律.低分化、大肝挝癌、无包膜者微血管分型级别较高.     

CD133和CD90在肝细胞癌中的表达及其意义

存在于肿瘤组织中的少数具有干细胞性质的细胞群体被称为肿瘤干细胞(CSCs),可促进肿瘤的发生和发展,也是肿瘤耐药性、复发及转移的根源.有报道CD133和CD90可能为肿瘤干细胞表面标志物,但CD133和CD90在肝癌中的表达及其意义报道尚少.本研究采用免疫组织化学方法检测不同肝组织中CD133及CD90蛋白的表达水平,探讨其在肝癌中的表达情况及其与肝癌生物学特性及预后的关系.     

CD133和CD90在肝细胞癌中的表达及其意义

存在于肿瘤组织中的少数具有干细胞性质的细胞群体被称为肿瘤干细胞(CSCs),可促进肿瘤的发生和发展,也是肿瘤耐药性、复发及转移的根源.有报道CD133和CD90可能为肿瘤干细胞表面标志物,但CD133和CD90在肝癌中的表达及其意义报道尚少.本研究采用免疫组织化学方法检测不同肝组织中CD133及CD90蛋白的表达水平,探讨其在肝癌中的表达情况及其与肝癌生物学特性及预后的关系.     

DLL4/NOTCH通路与肿瘤血管生成关系研究进展

Notch信号通路是进化保守的影响胚胎和出生后发育分化进程和细胞命运的细胞间信号通路[1].许多研究证明其对血管的发生发展有重要的调控功能,其在脉管系统不同发育阶段均有表达.研究发现Notch信号通路配体Dll4在人类许多肿瘤血管中呈现高表达.因此对Dll4深入研究可为肿瘤新生血管分子靶向治疗提供新的策略和靶标.现就Notch 信号通路组成,传导,调控与肿瘤血管生成关系做一综述.     

15省市1991-2005年住院糖尿病患者与肿瘤相关死亡原因的调查分析

目的 探讨糖尿病患者死亡原因与肿瘤之间的关系.方法 通过分析我国15省市1991-2005年住院患者中伴有糖尿病的死亡病例,调查根据ICD-10确定的主要死因为肿瘤的患者情况. 结果 共2895例合并糖尿病的死亡患者中有520例主要死亡原因为肿瘤,占总死亡病例的18.0%.主要死亡原因为肿瘤的患者中前5位肿瘤部位分别为肺、肝、血液系统、胃和胰腺.不同年龄阶段死因肿瘤部位不同.在1991-2005年期间,各部位肿瘤比例无明显变化. 结论 肿瘤是糖尿病患者的主要死亡原因之一.     

环氧合酶抑制剂在肝癌预防和治疗中的研究进展

研究显示在许多肿瘤中, 环氧合酶(COX)2及其产物过度表达. 非甾体类抗炎药可以抑制环氧合酶的活性, 从不同途径达到抑制肿瘤细胞的生长、诱导凋亡, 抑制血管形成、降低肿瘤的侵袭力和转移性. 肝癌是世界常见的恶性肿瘤之一, 预后较差, 形成机制尚未清楚, 其预防和治疗水平有限. 因此找到一种新的抗癌药物并研究其抗肝癌的作用机制,在肝癌的预防和治疗中有重要意义. 本文对COX抑制剂与肝癌形成和肝癌的预防和治疗中进展作一综述.     

生长抑素受体亚型SSTR2、SSTR5 mRNA在消化系肿瘤中的表达

目的 探讨消化系统恶性肿瘤组织中生长抑素受体亚型SSTR2、SSTR5 mRNA表达状况及其与肿瘤的相关性.方法 收集消化系肿瘤标本共66例,均经手术及病理证实.男性44例,女性22例,PCR扩增SSTR2、SSTR5 mRNA,并进行琼脂糖凝胶电泳,测其OD值并进行分析.结果 不同肿瘤SSTR2 mRNA 的表达频率不同,肝癌组织明显高于胃癌、结肠癌和胰腺癌(P＜0.05), 胃癌、结肠癌和胰腺癌之间表达无明显差异.肝癌癌组织与癌旁组织之间表达水平无明显差异,但与正常组织表达水平有显著差异(P＜0.05);胃癌、结肠癌和胰腺癌癌组织与癌旁组织、正常组织之间表达无显著性差异(P＞0.05).SSTR5 mRNA的表达频率和表达水平在消化系肿瘤中差异不显著(P＞0.05).结论 (1)胃癌、结肠癌、肝癌及胰腺癌组织中有SSTR2、5亚型表达,以SSTR2亚型为主.(2)SSTR2亚型在胃癌、结肠癌、肝癌及胰腺癌的表达频率及表达水平不同.在肝癌中呈高表达,在胃癌、结肠癌及胰腺癌中表达水平较低.(3)SSTR2、5亚型的表达频率、表达水平与癌组织分化程度、有无淋巴结转移密切相关,结肠癌与肿瘤分期有密切关系.(4)SSTR2亚型鉴定对胃癌、结肠癌、肝癌及胰腺癌是否适合生长抑素治疗具有一定指导意义.     

基于生物信息学分析PDE2A基因在消化系统肿瘤预后及免疫浸润的临床意义

背景 消化系统肿瘤是最常见的恶性肿瘤之一,然而其预后仍不好.探索潜在生物标志物是肿瘤研究的重要方向.我们拟利用生物信息学方法探索消化系统的潜在标志物.目的 探究在消化系统肿瘤中PDE2A表达与免疫浸润相关性,探索PDE2A在消化系统肿瘤中的预后价值.方法 通过HPA、TIMER和UALCAN数据库分析PDE2A在不同消化系统肿瘤中的mRNA及蛋白表达,利用GEPIA数据库探索PDE2A在不同消化系统肿瘤患者预后的影响.通过TIMER数据库探索PDE2A表达与不同消化系统肿瘤免疫浸润相关性.利用cB ioP ortal数据库分析PDE2A在不同消化系统肿瘤的遗传突变信息.通过STRING数据库探索PDE2A的潜在蛋白相互作用网络.结果 PDE2A基因mRNA和蛋白在肝癌、胃癌、胰腺癌、结肠癌和食管癌组织中表达低于正常癌旁组织.PDE2A高表达的肝癌和胰腺癌患者较PDE2A低表达的患者预后良好. PDE2A表达与肝癌、胃癌、胰腺癌、结肠癌和食管癌不同免疫细胞如CD4+T淋巴细胞、CD8+T淋巴细胞、B细胞、巨噬细胞和中性粒细胞呈正相关或负相关. PDE2A基因在胃癌、胰腺癌、结肠癌及食管癌中存在错义突变等遗传改变.结论 PDE2A表达与消化系统肿瘤免疫浸润有关. PDE2A高表达的肝癌和胰腺癌患者预后良好. PDE2A基因可能为潜在的消化系统肿瘤免疫治疗靶点和预后标志物.     

Impaired tumor growth,metastasis, angiogenesis and wound healing in annexin A1-null mice

Despite 2 decades of research, no clear function for annexin A1 (AnxA1) has been established. Using AnxA1-KO mice, we show that tumor growth and metastasis are significantly decreased, whereas rodent survival and tumor necrosis are greatly increased when tumors grow in AnxA1-KO mice. Systems analysis of gene expression in these tumors specifically implicates 2 related vascular functions, angiogenesis and wound healing, in this impairment. Both tumor vascular development and wound healing are greatly retarded in KO tissues. Aortic ring assays reveal induced AnxA1 expression on sprouting endothelial cells of normal mice whereas KO aortas exhibit impaired endothelial cell sprouting that is rescued by adenoviral expression of AnxA1. Key differences in specific gene regulation may define new molecular pathways mediating angiogenesis, including a reset profile of pro- versus anti-angiogenic factors, apparently distinct for physiological versus pathological angiogenesis. These studies establish novel pro-angiogenic functions for AnxA1 in vascular endothelial cell sprouting, wound healing, and tumor growth and metastasis, thereby uncovering a new functional target for repairing damaged tissue and treating diseases such as cancer. They also provide critical new evidence that the tumor stroma and its microenvironment can greatly affect tumor progression and metastasis.     

Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide

Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.     

低密度脂蛋白胆固醇对人单核细胞膜联蛋白A1表达水平的影响

目的探讨LDL-C对人外周血单核细胞中膜联蛋白(annexin)A1表达水平的影响,为LDL-C致动脉粥样硬化机制提供新的视点。方法在体外分离培养人外周血单核细胞,随机分为对照组、不同浓度组(0.7、1.3、2.6、3.9 mmol/L LDL-C处理)和不同时间组(2、8、1 6、24 h用3.9 mmol/L LDL C处理),应用流式细胞仪检测annexinA1表达水平。结果与对照组比较,各浓度组annexin A1表达水平下降,且随浓度增加其抑制作用增强(P<0.01)。8 h后各时间组annexin A1表达水平明显下降,且随时间延长其抑制作用增强(P<0.05)。结论LDL-C可以通过降低人单核细胞annexin A1表达而影响单核细胞与内皮细胞黏附,进而启动动脉粥样硬化的发生发展,但具体机制有待进一步阐明。     

Overexpression of annexin 1 in pancreatic cancer and its clinical significance

AIM: To investigate the expression of annexin I in pancreatic cancer and its relationship with the clinicopathologic factors, and to evaluate its potential clinical significance. METHODS: Annexin I expression was analyzed by Western blot and immunohistochemical staining in pancreatic adenocarcinoma and multi-tissue microarrays (MTAs). RESULTS: Western blot analysis showed that annexin I was overexpressed in 84.6% (11/13) pancreatic ductal adenocarcinomas. Immunohistochemistry analysis of pancreatic cancer in MTAs showed that annexin I protein was 71.4%(30/42) positive which was markedly increased compared with that in the tumor matched normal pancreas tissues 18.4%(7/38) (P<0.01). In the meantime, the high expression of annexin 1 was correlated with the poor differentiation of pancreatic adenocarcinoma. CONCLUSION: Annexin 1 overexpression is a frequent biological marker and correlates with the differentiation of pancreatic cancer during tumorigenesis.     

Homozygous somatic Wt1 point mutations in sporadic unilateral Wilms tumor.

Wilms tumor may be caused by loss of function of genes at different loci. A Wilms tumor suppressor gene, WT1, at chromosome 11 band p13, has recently been cloned and characterized. WT1 has been implicated in the development of Wilms tumor by virtue of mutations in patients with genitourinary anomalies and susceptibility to Wilms tumor. Homozygous intragenic mutations have been reported in Wilms tumors, but usually not in sporadic unilateral Wilms tumors, which constitute the majority of Wilms tumor cases. Using the single-strand conformational polymorphism assay, we have identified three sporadic unilateral Wilms tumors with homozygous point mutations: one with a de novo germ-line nonsense point mutation within WT1 exon 8, and two carrying a somatic mutation within WT1 exon 10. In all three cases loss of the wild-type allele was demonstrated by tumor loss of heterozygosity. This report provides an example of two somatic mutations in the same tumor expected to inactivate WT1 function.     

Organizing Committee:

Platelets bind annexin V when stimulated with combinations of platelet agonists such as collagen and thrombin. Previous studies have demonstrated significant heterogeneity of platelets binding annexin V. The relative role of the thrombin protease-activated receptors (PARs), PAR1 and PAR4, together with different methods of platelet preparation on annexin V binding to platelets is unclear. We therefore investigated the role of PAR1- and PAR4-activating peptides in combination with collagen-related peptide on annexin V binding. In diluted whole blood, PAR1- and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding. However, in washed platelets, PAR-activating peptides were less potent than thrombin at inducing annexin V binding. This difference was more pronounced when experiments were performed at 37°C compared to room temperature. In studies of diluted whole blood, platelet rich plasma and washed platelets, platelets incubated at room temperature bound more annexin V than platelets incubated at 37°C. We also saw a significant effect of time on annexin V binding, in that more annexin V bound to platelets with longer incubation times. In conclusion, PAR1 and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding in combination with collagen-related peptide in diluted whole blood and platelet rich plasma, but not in washed platelets. In addition, incubation temperature and time has a strong influence on annexin V binding to platelets. Thus variations in these conditions may explain the differences observed between previous studies.     

An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer

The identification of circulating tumor antigens or their related autoantibodies provides a means for early cancer diagnosis as well as leads for therapy. The purpose of this study was to identify proteins that commonly induce a humoral response in lung cancer by using a proteomic approach and to investigate biological processes that may be associated with the development of autoantibodies. Aliquots of solubilized proteins from a lung adenocarcinoma cell line (A549) and from lung tumors were subjected to two-dimensional PAGE, followed by Western blot analysis in which individual sera were tested for primary antibodies. Sera from 54 newly diagnosed patients with lung cancer and 60 patients with other cancers and from 61 noncancer controls were analyzed. Sera from 60% of patients with lung adenocarcinoma and 33% of patients with squamous cell lung carcinoma but none of the noncancer controls exhibited IgG-based reactivity against proteins identified as glycosylated annexins I and/or II. Immunohistochemical analysis showed that annexin I was expressed diffusely in neoplastic cells in lung tumor tissues, whereas annexin II was predominant at the cell surface. Interestingly, IL-6 levels were significantly higher in sera of antibody-positive lung cancer patients compared with antibody-negative patients and controls. We conclude that an immune response manifested by annexins I and II autoantibodies occurs commonly in lung cancer and is associated with high circulating levels of an inflammatory cytokine. The proteomic approach we have implemented has utility for the development of serum-based assays for cancer diagnosis as we report in this paper on the discovery of antiannexins I and/or II in sera from patients with lung cancer.     

Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors

Although in situ hybridization has been used to examine the distribution of messenger RNA for somatostatin receptor subtypes (sst) in human tumors, the cellular localization of sst1 and sst2A receptors has not been reported. In this study, we describe the cellular localization of human sst1 and sst2A receptor proteins in both cryostat- and paraffin-embedded sections of 25 human tumor tissues using two recently developed polyclonal antibodies. Six somatostatin (SS) receptor (SSR) positive tumors (two gastrinomas, three carcinoids, one pheochromocytoma) and one SSR negative tumor (renal cell carcinoma), selected by positive and negative SSR autoradiography, respectively, were studied by both immunohistochemistry and Western blot analysis. The six SSR positive tumors expressed sst2A, while 4 of 5 expressed sst1 as well. The SSR negative tumor did not express either sst1 or sst2A. Western blot analysis of wheat germ agglutinin purified membrane proteins confirmed the presence of the sst1 and sst2A glycosylated receptors. The paraffin-embedded sections gave best information with respect to the subcellular localization. Sst1 immunoreactivity was observed both on the membrane and in the cytoplasm, while sst2A showed predominantly membrane-associated immunoreactivity. This subcellular distribution of sst1 or sst2A receptors was confirmed in paraffin-embedded sections of 8 additional intestinal carcinoids, 5 gastrinomas and 5 pheochromocytomas. Sst1 receptors were detected in 7 out of 8 carcinoids, in all gastrinomas, and in 4 out of 5 pheochromocytomas, while 6 out of 8 carcinoids, all gastrinomas, and 3 out of 5 pheochromocytomas expressed sst2A receptors. In conclusion, sst1 and sst2A receptors show a differential subcellular localization in human SSR positive tumors. The use of SSR subtype selective antibodies to detect the subcellular distribution of SSR subtypes in individual tumor cells is an important step forward to understand more about the pathophysiological role of the different SSR subtypes in human tumors.     

Angiostatin binds to tyrosine kinase substrate annexin II through the lysine-binding domain in endothelial cells

Angiostatin(AS), an internal fragment of plasminogen, is one of the most potent specific inhibitors of angiogenesis. Angiostatin treatment has resulted in the complete regression of human tumors implanted subcutaneously into nude mice and has great therapeutic value (O'Reilly et al., Nat. Med. 2, 689-692, 1996). Despite promising therapeutic value in the treatment of cancer, the mechanism of its action is still unknown. We found that angiostatin binds to a 35-kDa protein in bovine aortic endothelial (BAE) cells (Sharma et al., Proc. Am. Assoc. Cancer Res. 42, 568, A3050, 2002). In an attempt to begin to understand angiostatin's mechanism of action, we have purified and characterized this 35-kDa protein from BAE cells. Internal peptide sequence analysis of purified protein demonstrated (SLYYIQQDTK, SYSPYDMLESIK, and ALLYLXGGDD) 100% sequence identity with tyrosine kinase substrate annexin II. Solid phase binding analysis suggests that angiostatin specifically bound to purified annexin II immobilized on 96-well plastic plates. Hundred-fold molar excess of unlabeled AS and anti-annexin II antibody inhibited bindings 85 and 55%, respectively, suggesting specific interaction. Annexin II is a predominant receptor for angiostatin, since neutralizing the angiostatin by soluble receptor (annexin II) effectively blocks angiostatin's anti-EC activity. Similarly, saturating the annexin II receptor by plasminogen in endothelial cells also blocks angiostatin's activity. Both angiostatin and plasminogen bind to purified annexin II in BAE cells saturably with apparent K(d) values of 101 and 164 nM, respectively, for purified annexin II and K(d) values of 83 and 125 nM, respectively, for BAE cells. Anti-annexin II monoclonal antibody inhibited angiostatin and plasminogen binding to endothelial cells by 68 and 62%, respectively, supporting our in vitro studies that annexin II is a receptor for angiostatin. Angiostatin-binding protein/annexin II specifically expressed in endothelial cells but not in fibroblasts suggests its EC-specific function. Epsilon-aminocaproic acid, a lys analogue, effectively blocks angiostatin and annexin II interaction, indicating that the lysine-binding domain of AS is required for binding to annexin II. These results suggest that the antiangiogenic action of angiostatin may be mediated via interaction with annexin II. Identification of annexin II as a receptor for angiostatin provides further evidence that clotting and fibrinolytic pathways are directly involved in the angiogenic process.