整合素与肿瘤的转移与血管生成

整合素是一类介导细胞与细胞外基质及细胞与细胞间黏附的细胞黏附分子受体,肿瘤细胞与胞外基质的相互作用对肿瘤的生成及转移有着重要的影响,整合素在肿瘤的生成、侵袭、转移以及肿瘤血管的生成过程中起着重要的作用。本文对整合素的结构、功能,以及它在肿瘤的血管生成过程中的作用,它与细胞外基质间的相互关系做了介绍。     

整合素α6亚单位和肿瘤的发生、发展与转移

整合素为跨膜糖蛋白,属于细胞表面的粘附分子。胞外域介导细胞与细胞及细胞与细胞外基质间的识别与结合,胞质域与细胞骨架和信号转导系统相连。α6亚单位与β1或β4亚单位非共价结合形成异二聚体,是细胞外基质蛋白质——层粘连蛋白的单特异性受体,与肿瘤的发生、发展和转移有着非常密切的关系。多种肿瘤的发生伴有整合素α6表达水平的变化,包括表达水平的升高、降低或极性分布的变化。表现为一些不表达α6β1的细胞,如肝细胞癌变后通过新合成的α6β1介导了肿瘤细胞与基底膜间相互作用而促进了肿瘤细胞的转移;表达α6β1的细胞α6β1失去沿基底膜的极性分布,导致细胞与基底膜的结合减弱,癌细胞易于脱落而发生转移;还可以通过促进细胞基质金属蛋白酶的分泌而促进肿瘤的转移,并导致肿瘤细胞的低分化表型。整合素α6可以促进肿瘤新生脉管的生成,一方面增加瘤组织的血供和营养,促进肿瘤的生长;另一方面促进脱落的肿瘤细胞进入血循环发生转移。     

整合素及其信号传导通路

整合素是位于细胞表面的重要黏附分子,通过其双向信号传导通路,介导细胞与细胞外基质及细胞与细胞间的黏附.整合素由胞外域、跨膜域和胞内域3部分组成.胞内域与细胞内信号分子结合,启动胞内一胞外信号传导激活整合素,提高与相应配体亲合力.而胞外域与相应配体结合后,通过胞外-胞内信号传导,调节细胞生存、增殖、黏附、分化功能.近年研究显示,整合素结构功能及信号传导通路异常与多种疾病有关.     

整合素在细胞黏附中的生物学功能

整合素是一种跨膜蛋白,属于黏附分子家族.其主要功能是参与细胞和细胞、细胞和细胞外基质(ECM)的黏附和信号转导.整合素是含有α和β两条肽链的异源二聚体,来源不同的α、β亚基所形成的整合素具有不同的ECM结合能力.阐述了整合素的结构、生物学功能以及生理、病理学意义,并概述了其研究进展.     

α_vβ_3整合素与恶性肿瘤侵袭转移关系的研究进展

整合素家族是细胞粘附分子的重要种类之一,主要作用是介导细胞与细胞之间、细胞与细胞外基质之间的粘附效应。医学研究证实整合素家族与肿瘤的侵袭及远处转移等生物学行为密切相关。整合素αvβ3是整合素家族中的一种重要分子,肿瘤血管内皮细胞中αvβ3的表达水平对肿瘤侵袭转移及血管生成有着重要作用,调节αvβ3的表达水平可明显影响肿瘤的侵袭转移及肿瘤组织中新生血管的形成。深入研究整合素αvβ3的分子调节机制可以为肿瘤治疗提供新的治疗靶点。     

整合素及其在胚泡植入中的作用

整合素是一类由α、β亚基构成的异二聚体粘附分子,能够与胶原蛋白、纤连蛋白和玻连蛋白等细胞外基质组分相互作用,调节细胞粘附和通讯.作为双向传递分子,整合素通过“胞内→胞外”和“胞外→胞内”两种方式介导细胞信号传递.成功的植入是侵入性的胚泡和接受性的子宫内膜相互作用的结果,整合素能够调节胚泡滋养层与子宫内膜之间的细胞-细胞及细胞-细胞外基质相互作用,是“植入窗口”期子宫内膜接受性的标记分子.     

细胞外基质在肝癌侵袭和转移中的变化

探讨肝细胞癌 (hepatocellular carcinoma,HCC)细胞外基质 (extracellular m atrix,ECM)层粘蛋白 (laminin,L N)、胶原蛋白 (collagen ,Col )的分布表达及其临床意义。利用免疫组化结合计算机图像分析技术观察 5 4例 HCC组织中 L N、 Col 的分布特点和表达水平。结果表明 L N和 Col 的分布方式相似。低分化、侵袭性和伴肝内转移的 HCC其 ECM分布呈中断的索周型和血管型 ,而高分化、非侵袭性及无肝内转移的 HCC的 ECM分布主要是连续的索周型 (P<0 .0 1)。低分化 HCC的 L N、Col 表达水平均低于高分化 HCC(P<0 .0 5和 P<0 .0 1)。侵袭性和伴肝内转移的 HCC其 L N、Col 表达水平分别低于非侵袭性和不伴肝内转移的 HCC (P<0 .0 1)。提示 HCC组织 ECM的分布和表达与肿瘤的侵袭转移密切相关 ,ECM作为结构屏障可能在防止肿瘤侵袭和转移方面起重要作用     

整合素αvβ6与肿瘤关系的研究进展

肿瘤的发生发展受到多种因素影响,因肿瘤而死亡的原因仍然是我国居民死亡的主要原因之一,对于肿瘤的防治一直是我国乃至世界医学界关注的重点。整合素(integrin, ITG)是能够介导细胞与细胞之间、细胞与基质之间相互黏附的一类细胞膜上的跨膜糖蛋白。研究证明,整合素是由αv与β6两个亚基组成的一种最具特征性、在肿瘤中表达异常的异二聚体。近年来大量的研究证明整合素αvβ6在正常和良性肿瘤上皮组织中与在多种恶性肿瘤上皮组织中表达具有明显差异,在肿瘤进展中具有重要意义。本文主要就整合素αvβ6与肿瘤的关系进行概述。     

细胞外基质和细胞粘附分子表达与细支气管肺泡癌淋巴结转移的关系

用免疫组化方法检测50例细支气管肺泡癌（BAC）（其中18例伴有淋巴结转移）及其三个亚型粘液型、非粘液型、硬化型中基底膜细胞外基质（ECM）层粘连蛋白（LN）、Ⅳ型胶原（CollⅣ）、纤粘连蛋白（FN）分布和细胞粘附分子A－CAM（又称N－钙粘素）表达情况。结果发现粘液型、非粘液型、硬化型BAC的淋巴结转移率分别为57％（8／14）、32％（7／22）和21％（3／14）。在BAC及BAC各亚型中,三种ECM在基底膜水平的分布状态与淋巴结转移无关（P均＞0.05）、A－CAM在伴或不伴淋巴结转移的BAC原发瘤中的表达率分别为56％（10／18）和53％（17／32）（P＞0.05）。提示BAC三个亚型中粘液型淋巴结转移率有高于其它两亚型的倾向。基底膜ECM（LN、CollⅣ、FN）分布完整与否及细胞粘附分子A－CAM表达高低与BAC淋巴结转移无关。     

整合素αVβ3与病毒感染

整合素αvβ3是一类表达于细胞表面的跨膜糖蛋白粘附分子,由α和β两种Ⅰ型膜蛋白亚单位以非共价键形式连接形成异源二聚体分子。整合素αvβ3可表达于多种细胞,细胞外信号通过不同分子可与其发生相互作用,经整合素αvβ3将细胞外信号传递至细胞内,引起钙离子、Pyk2和磷脂酰肌醇-3(PI-3)激酶等细胞内信号发生变化。整合素αvβ3在血管生成、胚胎发育、肿瘤转移、免疫应答等多种生理和病理过和中发挥着重要的作用。近几年,整合素αvβ3与病毒感染的相关研究进展迅速,本文就整合素αvβ3与病毒感染作一综述。1整合素αvβ3概述1·1整合素αv…     

The role of alpha3beta1 integrin in determining the supramolecular organization of laminin-5 in the extracellular matrix of keratinocytes

Analyses of mice with targeted deletions in the genes for alpha3 and beta1 integrin suggest that the alpha3beta1 integrin heterodimer likely determines the organization of the extracellular matrix within the basement membrane of skin. Here we tested this hypothesis using keratinocytes derived from alpha3 integrin-null mice. We have compared the organizational state of laminin-5, a ligand of alpha3beta1 integrin, in the matrix of wild-type keratinocytes with that of laminin-5 in the matrix of alpha3 integrin-null cells. Laminin-5 distributes diffusely in arc structures in the matrix of wild-type mouse keratinocytes, whereas laminin-5 is organized into linear, spike-like arrays by the alpha3 integrin-null cells. The fact that alpha3 integrin-null cells are deficient in their ability to assemble a proper laminin-5 matrix is also shown by their failure to remodel laminin-5 when plated onto surfaces coated with purified laminin-5 protein. In sharp contrast, wild-type keratinocytes organize exogenously added laminin-5 into discrete ring-like organizations. These findings led us next to assess whether differences in laminin-5 organization in the matrix of the wild-type and alpha3 integrin-null cells impact cell behavior. Our results indicate that alpha3 integrin-null cells are more motile than their wild-type counterparts and leave extensive trails of laminin-5 over the surface on which they move. Moreover, HEK 293 cells migrate significantly more on the laminin-5-rich matrix derived from the alpha3 integrin-null cells than on the wild-type keratinocyte laminin-5 matrix. In addition, alpha3 integrin-null cells show low strength of adhesion to surfaces coated with purified laminin-5 compared to wild-type cells although both the wild type and the alpha3 integrin-null keratinocytes adhere equally strongly to laminin-5 that has been organized into arrays by other epithelial cells. These data suggest: (1) that alpha3beta1 integrin plays an important role in determining the incorporation of laminin-5 into its proper higher-order structure within the extracellular matrix of keratinocytes and (2) that the organizational state of laminin-5 has an influence on laminin-5 matrix function.     

Stat3与肿瘤的侵袭转移

Stat3是信号传导与转录激活因子家族(STATs)的成员之一,是一种重要的核转录因子,被细胞外细胞因子、生长因子等多肽类配体激活,作用于细胞核内特异的DNA片段,调控靶基因的转录,促进肿瘤细胞的增殖、血管形成、侵袭转移及免疫逃逸。诸多肿瘤细胞系及人的癌变组织中存在Stat3持续激活,因而Stat3有可能成为肿瘤分子治疗的新靶点。     

PDGF-BB enhances expression of,and reduces adhesion to,laminin-5 in vascular smooth muscle cells

The laminin family of extracellular matrix (ECM) proteins plays crucial roles in regulating cellular growth, migration, and differentiation. We report here that laminin-5 is expressed in the tunica media of the rat aorta and pulmonary arteries. Using indirect immunofluorescence microscopy, Western blots, and RT-PCR analysis, we found that primary cultures of rat arterial smooth muscle cells express laminin-5 and deposit it into their insoluble ECM. These cells also attach strongly to laminin-5 via beta1 integrin receptors in 30 min adhesion assays. Laminin-5 expression in these cells is upregulated by growth factors in vitro and platelet-derived growth factor (PDGF-BB) stimulation reduces adhesion to laminin-5. As laminin-5 promotes enhanced migration of other cell types, the production of and adhesion to laminin-5 by vascular smooth muscle cells may play a role in the pathological growth and migration of these cells associated with restenosis following vascular injury.     

膜联蛋白A1与恶性肿瘤侵袭转移

膜联蛋白A1(Annexin A1,ANXA1,lipocortin I)是膜联蛋白超家族中的一员,它参与细胞信号转导、分化及凋亡等多种重要的生命过程.近年来的研究表明其表达水平在不同肿瘤组织中有差异,在同一肿瘤的不同类型中有显著变化,可能与肿瘤的侵袭转移相关,如乳腺癌、胃肠癌、肝癌、头颈部肿瘤、前列腺癌等.本文结合ANXA1的基本结构及生物学特性对以上研究的进展作一综述.     

Expression of Gangliosides GD3 and 3'-isoLM1 in Autopsy Brains from Patients with Malignant Tumors

Abstract: Three autopsy brains from patients who succumbed to malignant gliomas have been analyzed in various regions with regard to their ganglioside content. The study focused on the gangliosides GD3 and 3'-isoLM1, which in a previous study of biopsies were found to be associated with these tumors. In particular, 3'-isoLM1, was suggested to be a marker for malignant gliomas. The highest concentrations (200–1,000 nmol of sialic acid/g wet weight) of GD3 was found in specimens of macroscopically pure tumor, where the proportion of GD3 was, at the most, 78% (range, 11–78%) of the total ganglioside sialic acid compared with <10% in normal brain tissue. The proportion of the total ganglioside sialic acid made up by GD3 was also elevated in the periphery of the tumor and in the same region in the opposite hemisphere, where no tumor cells were detected. In four of eight brain metastases of various carcinomas, GD3 was >10% of the total ganglioside sialic acid (range, 3–37%). The ganglioside 3'-isoLM1, as determined by TLC-enzyme-linked immunosorbent assay using a specific monoclonal antibody (SL-50), was not present at detectable levels in any of the macroscopically homogenous tumor areas. It was, however, found in the periphery of the tumor, in the corpus callosum, and at highest concentrations in the region of the opposite hemisphere corresponding to the tumor. The concentration varied between 0.1 and 6.0 nmol/g wet weight of tissue. The 3'-isoLM1 ganglioside was not detected in normal gray or white matter or in the normal corpus callosum, but in one of three breast cancer metastasis, one of two low differentiated cancer metastases, and one stomach cancer. The concentration was 1–4 nmol/g wet weight. These results indicate a unique distribution of the gangliosides GD3 and 3'-isoLM1 and suggest that they play distinct roles in interaction between tumor cells and brain.     

恶性卵巢肿瘤淋巴转移与相关基因表达

恶性卵巢肿瘤严重威胁着妇女健康和生命,其重要原因之一是易发生淋巴转移,给临床诊断和治疗带来困难。近年来国内外对恶性卵巢肿瘤淋巴转移的机制及其与相关基因表达进行了一系列的研究,现就这方面的进展作一综述。     

RhoGDI2 在结直肠癌组织中的表达及其与临床侵袭转移的关系

目的:研究鸟嘌呤核苷酸解离抑制因子2(Rho GDI2)在结直肠癌(CRC)组织中的表达及其与临床侵袭转移的关系。方法:收集本院于2015年1月至2015年12月收治的80例CRC患者手术切除的原发灶组织和正常癌旁组织。采用免疫组化法检测各组织标本中Rho GDI2的表达情况,并分析其表达量与临床病理特征的相关性。结果:(1)Rho GDI2主要表达于CRC癌细胞胞浆中,在肿瘤原发灶和正常癌旁组织中的阳性表达率分别为26.25%和0.00%,差异具有统计学意义(P0.05);(2)肿瘤原发灶中Rho GDI2的阳性表达率与患者的性别、年龄、肿瘤位置、大小、数量、组织学分级、原发灶分期、血管浸润、神经浸润间均不存在相关关系(P0.05),而与淋巴结转移及远端转移有关(P0.05)。结论:Rho GDI2在CRC肿瘤原发灶中呈阳性表达,且其高表达可促进CRC的侵袭转移,可作为CRC治疗的作用靶点。     

Enhanced expression of Hab18g/CD147 and activation of integrin pathway in HCC cells under 3-D co-culture conditions

CD147 is reported to be correlated with the malignancy of some cancers, and its overexpression affects the progression of tumor. In the present study, we investigated the function of HAb18G/CD147, a member of CD147 family, on hepatocellular carcinoma (HCC) adhesion, invasion and metastasis in 3-dimensional (3-D) cell co-culture model. The results showed that the extracellular microenvironment could determine the cellular phenotypes and then affected the cellular functions. The expressions of HAb18G/CD147 in HCC cells and fibroblasts were both obviously elevated in 3-D co-culture model. The overexpression of HAb18G/CD147 increased MMPs' (MMP-2 and MMP-9) production (P < 0.01), and was obviously accompanied with enhanced expressions of paxillin, FAK and p-FAK in 3-D cell co-culture model. All the results suggest that HAb18G/CD147 plays an important role in HCC adhesion, invasion and metastasis mainly via modulating synthesis of MMPs and activating integrin signal pathways in fibroblasts and tumor cells themselves under the 3-D co-culture conditions.