整合素家族与肿瘤骨转移相关性研究进展

整合素家族作为黏附分子,主要介导细胞与细胞外基质间的黏附,调节许多类型肿瘤细胞的迁移、存活、增殖和血管生成等。近期许多研究证实,整合素家族还和恶性肿瘤的骨转移有着密切的关系。本文就整合素家族结构与功能、整合素家族信号通路与肿瘤转移关系、整合素与肿瘤骨转移的形成等方面进行综述。     

整合素家族与肿瘤骨转移相关性研究进展

整合素家族作为黏附分子,主要介导细胞与细胞外基质间的黏附,调节许多类型肿瘤细胞的迁移、存活、增殖和血管生成等。近期许多研究证实,整合素家族还和恶性肿瘤的骨转移有着密切的关系。本文就整合素家族结构与功能、整合素家族信号通路与肿瘤转移关系、整合素与肿瘤骨转移的形成等方面进行综述。     

整合素与肿瘤转移

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.肿瘤细胞的生长、分化、浸润及转移等行为与细胞黏附密切相关.全文就整合素与肿瘤转移关系作一综述.     

整合素αvβ6在卵巢癌中的作用

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，αvβ6是整合素家族的一员，参与肿瘤的发生、发展与转移。这种作用可能是通过影响肿瘤细胞与细胞外基质黏附、细胞外基质水解、诱导肿瘤血管生成、调节肿瘤细胞凋亡等作用而实现的。深入研究αvβ6在卵巢癌中的表达与功能，有助于进一步认识卵巢癌侵袭转移的分子机制，有可能为恶性肿瘤的诊断和预后判断提供新的指标．为开发肿瘤治疗新思路提供了理论依据。     

ADAM蛋白家族与肿瘤

去整合素和金属蛋白酶(ADAM)家族是一类含有去整合素和金属蛋白酶结构域的蛋白分子,在人类多种恶性肿瘤组织中异常表达,并可通过影响肿瘤细胞之间及细胞与细胞外基质的黏附、蛋白水解、调节肿瘤细胞信号传导、诱导肿瘤血管的生成等作用参与肿瘤的进展.     

整合素家族与甲状腺癌

整合素作为细胞表面受体、细胞间的黏附分子,对细胞与细胞间、细胞与细胞外基质间的黏附起介导作用。近几十年来,恶性肿瘤甲状腺癌的发病率急速攀升,很大原因是由于恶性肿瘤细胞极易增殖、侵袭和转移,而这种特性与细胞表面黏附分子整合素有密切的关系。有研究发现,整合素α3β1、α6β1、αvβ3等通过与细胞间黏附分子1(ICAM-1)、血管细胞黏附分子1(VCAM-1)、血小板反应蛋白(thrombospondin, TSP)和细胞外基质胶原(collagen, CO)、层黏连蛋白(laminin, LN)、纤连蛋白(fibronectin, FN)等配体结合,激活FAK-Ras-Raf或磷脂酰肌醇3激酶(PI3K)-Akt-mTOR等信号转导通路,调控甲状腺癌细胞的生长、繁殖、侵袭和转移。通过针对整合素信号通路上多个靶点进行分子靶向干预,可能研发出甲状腺癌的针对性治疗方案。本文主要对整合素在甲状腺癌的增殖、侵袭、转移、诊断和治疗等方面所起的作用作一综述。     

细胞黏附分子在肿瘤浸润转移中的作用

肿瘤转移是多步骤的癌细胞与宿主细胞相互作用的连续过程,即癌细胞与细胞外基质相互作用的结果,包括肿瘤细胞的脱落、迁移和黏附等.细胞黏附分子(cell adhesion molecules,CAM)在癌细胞的浸润转移中起重要作用:肿瘤细胞自原发灶游离与细胞间黏附降低有关;肿瘤细胞与细胞外基质黏附改变利于肿瘤的转移;管腔内瘤栓形成是游离癌细胞黏附的结果;瘤细胞在游出管腔过程中与管腔内皮及基底膜黏附改变是转移的重要因素.本文对各种黏附分子在肿瘤浸润、转移中的研究进展进行综述.     

整合素与肿瘤侵袭及转移的关系

肿瘤细胞与细胞外基质间的相互作用影响肿瘤的发生、增殖、存活和转移到其他组织的能力。许多是由分布广泛的整合素介导的。整合素是细胞黏附、细胞迁移、细胞周期和程序化死亡 (凋亡 )所必须的 ,它和其他信号途径一起调节肿瘤的发生、侵袭及转移。就整合素的结构、功能及其与肿瘤临床资料的关系予以综述     

骨桥蛋白参与肿瘤转移相关信号途径的研究进展

骨桥蛋白是一种分泌型磷酸化糖蛋白,是细胞基质蛋白小整合素结合配体N端连结糖蛋白(small integrin-binding ligand,N-linked glycoprotein,SIBLING)家族中的一员,广泛表达于多种组织细胞中.骨桥蛋白与细胞外基质发生相互作用,作为信号分子涉及到多种生物学功能,包括细胞黏附、迁移、免疫反应、炎症反应、骨的钙化以及抗凋亡等.随着研究的深入,发现骨桥蛋白在肿瘤侵袭和转移的多个环节中起着重要作用并涉及多条相关信号途径.本文主要讨论骨桥蛋白在肿瘤转移中相关信号通路的新近研究进展及其在肿瘤转移过程中的作用.     

整合素和胰腺癌侵袭转移

肿瘤侵袭转移是一个多因素共同作用的多阶段连续过程，其中肿瘤细胞与细胞外基质(extracellular matrix，ECM)的黏附是发生侵袭转移的首要步骤。近年来研究表明，整合素(integrins)黏附分子作为ECM的受体，通过介导细胞与细胞、细胞与ECM间的识别和结合，在肿瘤侵袭转移过程中起着极其重要的作用。     

Melanoma cell migration on vitronectin: Regulation by components of the plasminogen activation system

Tumor cell migration and invasion require complex interactions between tumor cells and the surrounding extracellular matrix. These interactions are modified by cell adhesion receptors, as well as by proteolytic enzymes and their receptors. Here, we study the influence of the protease urokinasetype plasminogen activator (uPA) and its receptor (uPAR) on melanoma cell adhesion to, and migration on, the extracellular matrix protein vitronectin (VN). Cell adhesion to VN, but not to type I collagen, is significantly enhanced in the presence of either uPA or its amino-terminal fragment (ATF). Soluble uPAR can inhibit this effect, indicating that uPA/uPAR on melanoma cells can function as a VN receptor. In the absence of bivalent cations, uPA/uPAR can promote cell attachment on VN, but not cell spreading, suggesting that the glycosylphosphatidylinositol (GPI)-anchored uPAR alone is unable to organize the cytoskeleton. Chemotactic melanoma cell migration on a uniform VN matrix is inhibited by uPA and ATF, implying that cell motility decreases when uPA/uPAR acts as a VN receptor. In contrast, plasminogen activator inhibitor I (PAI-I) can stimulate melanoma cell migration on VN, presumably by inhibiting uPA/uPAR-mediated cell adhesion to VN and thereby releasing the inhibition of cell migration induced by uPA. Together, our data implicate components of the plasminogen activation system in the direct regulation of cell adhesion and migration, thereby modulating the behavior of malignant tumor cells. Int. J. Cancer, 71:116–122, 1997. © 1997 Wiley-Liss, Inc.     

Stimulation of beta1 integrin down-regulates ICAM-1 expression and ICAM-1-dependent adhesion of lung cancer cells through focal adhesion kinase

Adhesion molecules are involved in intracellular signaling in various physiological and pathological processes including metastasis and growth of tumor cells. Tumor cells interact with various host cells as well as with extracellular matrices through certain adhesion molecules such as integrins. We here propose that stimulation of beta1 integrin reduces intercellular adhesion molecule (ICAM)-1-mediated interaction of lung cancer cells with CTLs. This concept is based on the following findings: (a) engagement of beta1 integrins on certain lung cancer cells by a specific antibody or by ligand matrices such as fibronectin and collagen markedly reduced ICAM-1 expression on the cell surface and induced sICAM-1; (b) down-regulation of ICAM-1 by stimulation of beta1 integrins was abrogated by tyrosine kinase inhibitors or by transfection of dominant negative truncations of focal adhesion kinase (FAK); (c) engagement of beta1 integrins also reduced ICAM-1-dependent adhesion of lung cancer cells to T cells, a process completely inhibited by tyrosine kinase inhibitors and by transfection of dominant negative forms of FAK; and (d) stimulation of beta1 integrins prevented killing of lung cancer cells by autologous CTLs. In malignant tumors, cancer cells, including lung cancer cells, are surrounded by extracellular matrix proteins such as fibronectin and collagen. This suggests that the engagement of beta1 integrins by matrix proteins potentially occurs in cancer cells in vivo and that continuous stimulation via beta1 integrins reduces ICAM-1-expression, ICAM-1-mediated adhesion of cancer cells to CTLs and their killing by CTLs. Our results suggest that such processes can lead to the escape of lung cancer cells in vivo from immunological surveillance.     

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.     

Altered in vitro spreading and cytoskeletal organization in human glioma cells by downregulation of urokinase receptor

The interaction of urokinase-type plasminogen activator (uPA) with its cell-surface receptor (uPAR) is implicated in diverse biological processes such as cell migration, tissue remodeling, and tumor cell invasion. Recent studies indicated that uPAR can act as an extracellular matrix receptor during cell adhesion. Recently, we showed that transfection of the humanglioma cell line SNB19 with antisense uPAR resulted in downregulation of uPAR at both the mRNA and protein levels. In this study, we used SNB19 to determine how the presence or absence of uPAR promotes cellspreading and associated changes in cell morphology. Microscopic analysis of cell spreading revealed that antisense uPAR–transfected cells were larger, remained round, and did not spread efficiently over extracellular matrix substrate type IV collagen and fibronectin, unlike parental SNB19 cells, which were smaller and spindle shaped. Biochemical studies showed that antisense uPAR–transfected cells, in addition to not spreading, exhibited increased expression of α3β1 integrin but not α5β1 integrin. However, we could not find a change in the expression of extracellular matrix components or altered growth rate in these cells. Furthermore, despite the increased α3β1 integrin expression, antisenseuPAR–transfected cells failed to form an organized actin cytoskeleton when plated on type IV collagen or fibronectin, unlike parental SNB19 cells, which displayed an organized cytoskeleton. These findings show that the absence of uPAR in human glioma cells leads to morphological changes associated with decreased spreading and a disorganized cytoskeleton resulting in altered cell morphology, suggesting that coordinated expression of uPAR and integrin may be involved in spreading of antisense uPAR–transfected glioma cells. Mol. Carcinog. 20:355–365, 1997. © 1997 Wiley-Liss, Inc.     

The role of the plasminogen activation system in angiogenesis and metastasis

The urokinase plasminogen activator system (uPA) has been demonstrated to be required for the movement of cells through a matrix. These observations have been extended to the migration of endothelial cells during the process of angiogenesis, and recent data suggest that the uPA system is central to this process. uPA is a serine protease that is capable of initiating an extracellular cascade of proteolysis that involves the activation of plasminogen and matrix metalloproteases. These proteolytic cascades remodel extracellular matrix (ECM) and basement membrane (BM), allowing for the movement of cells across and through these barriers. In addition, these proteolytic cascades process and release various growth and differentiation factors that are sequestered on the cell surface or within the ECM, which contribute to the evolution of a migratory or invasive cell phenotype. uPA is also able to modulate signaling and cell adhesion through its specific cell surface receptor, uPAR. Recent data suggest that the nonproteolytic activities of the uPA system are coupled to adhesion, migration and signaling through various integrins. This article reviews the evidence for the role of this system in tumor angiogenesis and metastasis, which suggests that the uPA system initiates multiple cascades that contribute to these processes.     

The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy

Cancer dissemination and metastasis is synonymous with invasive cell migration; a process in which the extracellular matrix (ECM) plays the dual role of the substratum on which the cells move as well as the physical obstacle that the cells have to surpass. To degrade the physical obstacle, which the ECM poses in the direction of migration, cells use proteolytic enzymes capable of degrading the ECM components. A major protease system responsible for ECM degradation is the plasminogen activation system, which generates the potent serine protease plasmin. The subject of this review, the urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays an impressive range of distinct, but overlapping functions in the process of cancer invasion and metastasis: Firstly, uPA/uPAR promotes extracellular proteolysis by regulating plasminogen activation. Secondly, uPA/uPAR regulates cell/ECM interactions as an adhesion receptor for vitronectin (Vn) and through its capacity to modulate integrin function. Thirdly, uPA/uPAR regulates cell migration as a signal transduction molecule and by its intrinsic chemotactic activity. This review is focused on recent insight into the cancer related biology of the uPA/uPAR system as well as its implications for clinical cancer diagnosis, prognosis and therapy.     

Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton

Previous studies have shown that several proteolytic enzymes are associated with membrane protrusions at the leading edge of migrating tumor cells. In this study we demonstrate that seprase and the urokinase plasminogen activator receptor (uPAR), co-localize in the plasma membrane of LOX malignant melanoma cells. Cells were labeled with fluorochrome-conjugated monoclonal antibodies (mAb) directed against seprase and uPAR. Proximity between these two molecules was detected with resonance energy transfer (RET) imaging, single-cell emission spectrophotometry, and single-cell excitation spectrophotometry. Significant RET signals were detected on LOX cells when adherent to uncoated and extracellular matrix (ECM)-coated surfaces. This indicates that seprase and uPAR are within approximately 7 nm in the plasma membrane of LOX cells. When LOX cells adhered to a 3D extracellular-like matrix, seprase-uPAR complexes were found to be associated with invadopodia. Further microscopy experiments demonstrated gelatinolytic activity, a functional attribute of seprase, in association with seprase-uPAR membrane domains. Formation of seprase-uPAR membrane complexes is dependent upon both the cytoskeleton and integrins. Specifically, the involvement of beta(1)-integrins was demonstrated by the inhibition of RET by an inhibitory anti-beta(1)-integrin mAb. Based on these findings, we speculate that formation of heterogeneous lytic domains in the invading membranes of LOX cells increases the efficiency of directed pericellular proteolysis.     

The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

The receptor for the urokinase plasminogen activator (uPAR) is up-regulated in malignant tumors. Historically the function of uPAR in cancer cell invasion is strictly related to its property to promote uPA-dependent proteolysis of extracellular matrix and to open a path to malignant cells. These features are typical of mesenchymal motility. Here we show that the full-length form of uPAR is required when prostate and melanoma cancer cells convert their migration style from the “path generating” mesenchymal to the “path finding” amoeboid one, thus conferring a plasticity to tumor cell invasiveness across three-dimensional matrices. Indeed, in response to a protease inhibitors-rich milieu, prostate and melanoma cells activated an amoeboid invasion program connoted by retraction of cell protrusions, RhoA-mediated rounding of the cell body, formation of a cortical ring of actin and a reduction of Rac-1 activation. While the mesenchymal movement was reduced upon silencing of uPAR expression, the amoeboid one was almost completely abolished, in parallel with a deregulation of small Rho-GTPases activity. In melanoma and prostate cancer cells we have shown uPAR colocalization with β1/β3 integrins and actin cytoskeleton, as well integrins-actin co-localization under both mesenchymal and amoeboid conditions. Such co-localizations were lost upon treatment of cells with a peptide that inhibits uPAR-integrin interactions. Similarly to uPAR silencing, the peptide reduced mesenchymal invasion and almost abolished the amoeboid one. These results indicate that full-length uPAR bridges the mesenchymal and amoeboid style of movement by an inward-oriented activity based on its property to promote integrin-actin interactions and the following cytoskeleton assembly.     

Altered cell-matrix contact: a prerequisite for breast cancer metastasis?

The integrins are receptors that regulate interaction between epithelial cells and the extracellular matrix. Previous studies have shown that a reduction in the expression of the alpha2beta1, alpha3beta1, alpha6beta1, alpha(v)beta1 and alpha(v)beta5 integrins in primary breast cancer is associated with positive nodal status. In order to assess the functional significance of altered integrin expression, primary breast cancer cells were derived from individual patients with known tumour characteristics using immunomagnetic separation. Purified human fibronectin, vitronectin, laminin and type IV collagen were used to represent the principal extracellular matrix proteins in an in vitro adhesion assay. Primary breast cancer cells from lymph node-positive patients were significantly less adhesive to each of the matrix proteins studied (P<0.001, Mann-Whitney U-test). Matrix adhesion of primary breast cancer cells from node-negative patients was inhibited by appropriate integrin monoclonal antibodies (P<0.001, paired Wilcoxon test). Adhesion to fibronectin, vitronectin and laminin, but not type IV collagen, was influenced by the inhibitor arginine-glycine-aspartate, suggesting that breast cancer cell recognition of collagen IV is mediated through alternative epitopes. Weak matrix adhesion correlated with loss of integrin expression in tissue sections from corresponding patients assessed using immunohistochemistry. This study demonstrates a link between altered integrin expression and function in primary breast cancers predisposed to metastasize.