alpha-v-beta 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alpha-v-beta-3是整合素家族中的一种重要分子,肿瘤血管内 皮细胞中alpha-v-beta-3的表达水平对肿瘤侵袭转移及血管生成有着重要作用,调节琢v茁3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alpha-vbeta-3的分子调节机制可以为肿瘤治疗提供新的治疗靶点。     

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。     

Ezrin蛋白信号转导通路及其对肿瘤侵袭转移的最新进展

肿瘤转移是一个多阶段、多途径、涉及多基因及其信号通路变化的一系列复杂过程。了解肿瘤转移相关基因的信号传导通路以及对肿瘤转移的作用机制,为寻找抑制肿瘤转移的关键靶点具有重要的意义。Ezrin高表达与肿瘤转移密切相关,它可通过改变肿瘤细胞极性及细胞运动、调节肿瘤细胞间黏附及细胞与细胞外基质黏附、参与肿瘤细胞内信号转导而影响恶性肿瘤转移。Ezrin过度表达可以破坏正常细胞内信号传递网络的平衡,其中主要涉及的为细胞信号转导相关分子(Rho)及受体酪氨酸蛋白激酶等信号传导途径。Ezrin借助于细胞内错综复杂的信号转导网络调控细胞的形态构成、黏附、吞噬、运动、血管形成等一系列的生物学过程,最终实现肿瘤细胞的侵袭和转移。本文就Ezrin蛋白的信号转导通路及其对肿瘤转移作用的研究进展做一综述。     

Ezrin与肿瘤的侵袭和转移

Ezrin是细胞骨架与细胞膜连接的特定蛋白之一,它有助于细胞内摄作用、细胞胞吐作用及跨膜信号发放的途径.研究表明,Ezrin在不同肿瘤组织中表达异常,推测它可能参与肿瘤的侵袭转移,其通过改变肿瘤细胞极性及细胞运动、调节肿瘤细胞间黏附及细胞与细胞外基质黏附、参与肿瘤细胞内信号转导而影响恶性肿瘤转移.本文主要介绍了Ezrin生物学特性、与CD44相互关系以及目前在肿瘤研究中的现状.     

综述: 整合素相关微环境调控肿瘤转移

整合素是肿瘤微环境的重要组成部分,是广泛存在于细胞膜表面的黏附分子,可以识别并结合细胞外基质中相应的配体,参与许多重要的生理过程,包括肿瘤转移．整合素可以促进肿瘤转移的各个阶段,肿瘤微环境也会反过来影响整合素的表达,从而促进癌症的发生发展．     

整合素相关微环境调控肿瘤转移

整合素是肿瘤微环境的重要组成部分,是广泛存在于细胞膜表面的黏附分子,可以识别并结合细胞外基质中相应的配体,参与许多重要的生理过程,包括肿瘤转移.整合素可以促进肿瘤转移的各个阶段,肿瘤微环境也会反过来影响整合素的表达,从而促进癌症的发生发展.     

黏着斑激酶与肿瘤微环境

黏着斑激酶（focal adhesion kinase, FAK）是一种胞质非受体酪氨酸激酶。FAK和肿瘤密切相关,在多种癌细胞中高表达,促进癌细胞的发生、生长、存活、增殖、粘附、转移和侵袭以及血管生成等过程。肿瘤微环境包括肿瘤细胞、周围血管、免疫细胞、纤维母细胞、内皮细胞、信号分子和细胞外基质,它对癌症的发展和恶化具有重要作用。肿瘤细胞可以通过分泌细胞外信号影响微环境,使其有利于肿瘤生存和发展|肿瘤微环境中的基质细胞能通过产生趋化因子、基质降解酶和生长因子促进肿瘤侵袭和转移。本文综述肿瘤微环境在癌症发生发展过程中的作用及FAK在肿瘤微环境中的调控作用,为肿瘤疾病的治疗提供新思路。     

细胞微环境对免疫细胞黏附与迁移的调控

免疫细胞的黏附与迁移是机体免疫与宿主防御的关键环节,在机体免疫监视以及稳态维持中发挥重要作用,甚至参与到癌细胞转移的过程中。免疫细胞在血管内皮表面的滚动、活化、稳定黏附和定向迁移依赖整合素功能,并受到细胞微环境,包括生物微环境、化学微环境以及物理微环境的多因子协同作用和调控。细胞微环境的紊乱往往导致免疫细胞黏附与迁移的异常,引发炎症性疾病,甚至肿瘤。将对细胞微环境通过整合素调控免疫细胞黏附与迁移进行概述,重点介绍生物微环境、化学微环境和物理微环境对免疫细胞黏附与迁移的调控机制。     

肿瘤浸润转移分子机制的研究进展

肿瘤浸润转移是多因素参与、多步骤完成的生物化学变化过程。人们已经逐渐认识到浸润转移不仅与肿瘤细胞有关,更是肿瘤细胞和肿瘤组织微环境复杂的相互作用的结果,其过程涉及多个分子作用机制和信号转导途径,包括细胞和细胞的黏附分子、细胞外基质降解、生长因子、趋化因子和淋巴血管生成因子等。本文综述了肿瘤浸润转移的分子机制。     

CCN1与肝脏疾病的研究进展

CCN1即富半胱氨酸61(cysteine rich 61,Cyr61),是CCN家族成员之一,可与多种因子相互作用,是一种重要的细胞外基质调节因子。其与肝素及多种细胞整合素结合,在细胞黏附、迁移与增殖,以及血管生成、炎症反应和组织重构等生理、病理过程中发挥重要的调节作用。本文主要对CCN1与肝脏疾病的研究进展予以综述。分别对CCN1的结构和功能进行介绍,并进一步探讨了CCN1在肝损伤、肝纤维化、肝细胞癌的作用及可能机制,为研究和治疗肝病提供新思路。     

基底膜和肿瘤转移

基底膜是一种特化的细胞外基质,是肿瘤转移过程中必须穿越的物理屏障。基底膜的组成成分通过和细胞表面受体整合素相互作用,在调节肿瘤转移的过程中发挥了重要作用。另一方面,肿瘤细胞通过分泌基质降解酶类破坏基底膜的组织结构,同时调节细胞外基质受体整合素的表达,为穿过：基底膜和在靶器官粘附、增殖创造有利条件。了解细胞和基底膜的相互作用可以为抗转移药物的研发提供新的策略。     

Integrins and tumor invasion

Cell-extracellular matrix interactions are important in the process of tumor cell invasion and metastasis. In particular, the interactions of tumor cells with basement membranes of tissue epithelial, as well as vascular endothelial, cells are likely to represent key steps in the metastatic process. The interactions between cells and the connective tissue matrix are mediated by a large family of cell surface receptors, the integrins, which represent multiple receptors for extracellular matrix and basement membrane components. Here, I review recent progress in elucidating the roles of integrins in tumor cell invasion. Altered expression of this large family of receptors on invasive tumor cells, as compared with non-invasive cells, may represent a fundamental step in the progressive expression of the invasive phenotype.     

Multiple roles of integrins in cell motility

Motility is essential for many important biological events, including embryonic development, inflammatory responses, wound healing, and tumor metastasis. During these events cells are in dynamic contact with the extracellular matrix through integrins. Integrins are the primary receptors for extracellular matrix proteins and consequently are required for cell motility. Cells have evolved multiple mechanisms to modulate integrin adhesive functions, which impact cell migration. In addition to providing a mechanism that allows cells to contact the extracellular matrix, integrins also promote intracellular signals that stimulate and regulate cell movement. Here we discuss the role of integrins during the multiple steps of cell migration.     

Role of integrins in cancer: survey of expression patterns

Tumor cells are characterized by uncontrolled growth, invasion to surrounding tissues, and metastatic spread to distant sites. Mortality from cancer is often due to metastasis since surgical removal of tumors can enhance and prolong survival. The integrins constitute a family of transmembrane receptor proteins composed of heterodimeric complexes of noncovalently linked alpha and beta chains. Integrins function in cell-to-cell and cell-to-extracellular matrix (ECM) adhesive interactions and transduce signals from the ECM to the cell interior and vice versa. Hence, the integrins mediate the ECM influence on cell growth and differentiation. Since these properties implicate integrin involvement in cell migration, invasion, intra- and extra-vasation, and platelet interaction, a role for integrins in tumor growth and metastasis is obvious. These findings are underpinned by observations that the integrins are linked to the actin cytoskeleton involving talin, vinculin, and alpha-actinin as intermediaries. Such cytoskeletal changes can be manifested by rounded cell morphology, which is often coincident with tumor transformation via decreased or increased integrin expression patterns. For the various types of cancers, different changes in integrin expression are further associated with tumor growth and metastasis. Tumor progression leading to metastasis appears to involve equipping cancer cells with the appropriate adhesive (integrin) phenotype for interaction with the ECM. Therapies directed at influencing integrin cell expression and function are presently being explored for inhibition of tumor growth, metastasis, and angiogenesis. Such therapeutic strategies include anti-integrin monoclonal antibodies, peptidic inhibitors (cyclic and linear), calcium-binding protein antagonists, proline analogs, apoptosis promotors, and antisense oligonucleotides. Moreover, platelet aggregation induced by tumor cells, which facilitates metastatic spread, can be inhibited by the disintegrins, a family of viper venom-like peptides. Therefore, adhesion molecules from the integrin family and components of angiogenesis might be useful as tumor progression markers for prognostic and for diagnostic purposes. Development of integrin cell expression profiles for individual tumors may have further potential in identifying a cell surface signature for a specific tumor type and/or stage. Thus, recent advances in elucidating the structure, function, ECM binding, and signaling pathways of the integrins have led to new and exciting modalities for cancer therapeutics and diagnoses.     

Crosstalk between Epidermal Growth Factor Receptors (EGFR) and integrins in resistance to EGFR tyrosine kinase inhibitors (TKIs) in solid tumors

Cell adhesion to the extracellular matrix (ECM) is important in a variety of physiological and pathologic processes, including development, tumor invasion, and metastasis. Integrin-mediated attachment to ECM proteins has emerged to cue events primitively important for the transformed phenotype of human cancer cells. Cross-talk between integrins and growth factor receptors takes an increasingly prominent role in defining adhesion, motility, and cell growth. This functional interaction has expanded beyond to link integrins with resistance to Tyrosine kinase inhibitors (TKIs) of Epidermal Growth Factor Receptors (EGFRs). In this regard, integrin-mediated adhesion has two separate functions one as a clear collaborator with growth factor receptor signaling and the second as a basic mechanism contributing in Epithelial to Mesenchymal Transition (EMT) which affects response to chemotherapy. This review provides an overview of these mechanisms and describes treatment options for selectively targeting and disrupting integrin interaction to EGFR for cancer therapy.     

RSK2 Protein Suppresses Integrin Activation and Fibronectin Matrix Assembly and Promotes Cell Migration

Modulation of integrin activation is important in many cellular functions including adhesion, migration, and assembly of the extracellular matrix. RSK2 functions downstream of Ras/Raf and promotes tumor cell motility and metastasis. We therefore investigated whether RSK2 affects integrin function. We report that RSK2 mediates Ras/Raf inactivation of integrins. As a result, we find that RSK2 impairs cell adhesion and integrin-mediated matrix assembly and promotes cell motility. Active RSK2 appears to affect integrins by reducing actin stress fibers and disrupting focal adhesions. Moreover, RSK2 co-localizes with the integrin activator talin and is present at integrin cytoplasmic tails. It is thereby in a position to modulate integrin activation and integrin-mediated migration. Activation of RSK2 promotes filamin phosphorylation and binding to integrins. We also find that RSK2 is activated in response to integrin ligation to fibronectin. Thus, RSK2 could participate in a feedback loop controlling integrin function. These results reveal RSK2 as a key regulator of integrin activity and provide a novel mechanism by which it may promote cell migration and cancer metastasis.     

β1 integrin: An emerging player in the modulation of tumorigenesis and response to therapy

Historically, a hallmark of tumorigenesis was the ability to grow in an anchorage-independent manner. Hence, tumors were thought to proliferate and survive independently of integrin attachment to the substratum. However, recent data suggest that integrins regulate not only tumor cell proliferation, survival and migration, but may also influence their response to anti-cancer agents. Interestingly, these influences are largely masked by growth of tumor cells in the standard, yet artificial, environment of 2D cell culture, but are readily apparent under 3D in vitro culture conditions and in tumor growth in vivo. We, and others, have recently demonstrated that the β1 integrin subunit controls the growth and invasion of prostate tumor cells in 3D culture conditions. Recently, the importance of integrins has also been demonstrated using tissue specific conditional knockout strategies in transgenic mouse tumor models, where they control primary tumor growth and dictate the site of metastatic spread. Furthermore, integrin-extracellular matrix interactions may modulate the response of tumors to standard chemotherapy agents or radiation. Taken together, these results highlight the important role of integrins in regulating tumor growth and metastasis; however, point out that the evaluation of their contribution to these processes requires appropriate contextual modeling.     

The talin-tail interaction places integrin activation on FERM ground

Integrins are essential receptors for the development and functioning of multicellular animals because they mediate cell migration and cell adhesion, and regulate cell proliferation and apoptosis. Cellular regulation of the affinity of integrins for ligands - so-called 'integrin activation' - is a central property of these receptors. Integrin activation controls cell adhesion, migration and extracellular matrix assembly, thereby contributing to processes such as angiogenesis, tumor cell metastasis, inflammation, the immune response and hemostasis. Recent studies indicate that a crucial, final step in integrin activation is the binding of talin, a cytoskeletal protein, to the cytoplasmic domain of the integrin beta subunit. These results provide a focus for unraveling the many biochemical pathways implicated in integrin activation and suggest a general structural model for the connections between integrins and diverse cellular signal transduction pathways.     

cDNA cloning of a novel cell adhesion protein expressed in human squamous carcinoma cells

A novel protein (SQM1 protein) present in human squamous epithelial cells has been found to be involved in cell adhesion in squamous epithelial cells, endothelial cells and extracellular matrix proteins. The corresponding cDNA that encodes a 135-residue polypeptide has been isolated. Sequence analysis indicates that the encoded polypeptide is distinct yet related to the beta subunit of integrins. A new sequence motif consisting of a heptadic repeat of positively-charged residues present in the polypeptide has been identified and is proposed to be important in protein-protein interaction. These results suggest that SQM1 protein, a new cell adhesion molecule expressed in squamous epithelial cells, may play an important role in tumor metastasis.