结缔组织生成和肿瘤

肿瘤的发生并不只是由肿瘤细胞本身恶化引起的,肿瘤基质也发挥了非常重要的作用,肿瘤发生是肿瘤细胞和围绕它的肿瘤基质相互作用的产物。肿瘤细胞可以通过各种途径激活与其相邻的间质,促进成纤维细胞的增生、细胞外基质的沉积、免疫细胞浸润和血管生成,这种现象被称为结缔组织生成。结缔组织生成形成了一个支持肿瘤发展的微环境,通过多种途径促进了肿瘤的发生、发展和转移。针对结缔组织生成进行肿瘤治疗可以为肿瘤的临床治疗提供新的思路。     

结缔组织生成和肿瘤

肿瘤的发生并不只是由肿瘤细胞本身恶化引起的,肿瘤基质也发挥了非常重要的作用,肿瘤发生是肿瘤细胞和围绕它的肿瘤基质相互作用的产物。肿瘤细胞可以通过各种途径激活与其相邻的间质,促进成纤维细胞的增生、细胞外基质的沉积、免疫细胞浸润和血管生成,这种现象被称为结缔组织生成。结缔组织生成形成了一个支持肿瘤发展的微环境,通过多种途径促进了肿瘤的发生、发展和转移。针对结缔组织生成进行肿瘤治疗可以为肿瘤的临床治疗提供新的思路。     

肿瘤相关成纤维细胞促进肿瘤侵袭转移的作用机制

肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中最主要的成分之一,在肿瘤的发生发展中发挥着必不可少的作用。骨髓和脂肪的局部组织固有成纤维细胞及间充质干细胞是CAFs来源的主要前体细胞。大量研究表明,CAFs并不作为单独细胞在肿瘤周围存在,而是和肿瘤细胞相互作用,促进肿瘤的生长与存活并维持其恶性倾向。肿瘤细胞可以影响CAFs前体的招募,并诱导正常成纤维细胞活化为CAFs;同时,CAFs可以分泌多种细胞因子、生长因子和细胞外基质蛋白质,促进肿瘤细胞的增殖、耐药及侵袭转移,从而影响肿瘤的预后。CAFs还参与血管淋巴管的生成、细胞外基质重塑、免疫抑制以及肿瘤细胞上皮间质转化等有利于肿瘤发生发展的外源性途径,为肿瘤细胞提供了一个良好的微环境。大量研究显示,研发靶向CAFs的药物可以中断其与肿瘤细胞之间的联系,从而抑制肿瘤的生长和转移。因此,深入了解CAFs促肿瘤的作用机制将有利于肿瘤治疗新靶点的发现。本文将对CAFs促进肿瘤侵袭转移的作用机制加以综述。     

肿瘤细胞与肿瘤微环境间的相互作用

在肿瘤组织中,除了肿瘤细胞外还有其他成分包括间质细胞和细胞外基质(ECM),这些共同构成肿瘤微环境。这些间质细胞包括:成纤维细胞、内皮细胞、炎症细胞、脂肪细胞等。间质细胞的分布、细胞外基质的组成和代谢产物在同一肿瘤中明显不同。肿瘤细胞周围的间质细胞状态对肿瘤的转移产生重要影响,甚至可以用来预测肿瘤复发。肿瘤的发生发展包括众多成分之间的相互作用,本文论述了这一复杂网络的各个组成部分。     

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: 细胞外基质与肿瘤相关成纤维细胞

肿瘤的发生发展是一个肿瘤细胞与其微环境相互促进,共同演化的动态过程．实体肿瘤的发生发展过程伴随细胞外基质的过量沉积及其组织形式的异常以及成纤维细胞的活化和富集．细胞外基质与肿瘤相关成纤维细胞不仅是实体肿瘤的重要病理特征,同时也是恶性肿瘤发展的重要驱动力量．细胞外基质与肿瘤相关成纤维细胞通过多种机制促进了肿瘤的发生、发展和转移．针对细胞外基质与肿瘤相关成纤维细胞进行肿瘤治疗,可以为肿瘤的临床治疗提供新的思路．     

胶原样分子与肿瘤关系研究进展

细胞外基质不仅维持着体内细胞微环境的稳定,还在细胞的正常生长、增殖以及细胞之间的信号传导中起着重要作用。肿瘤发生时,基质中的分子组分发生了改变,这些改变朝着有利于肿瘤细胞生长侵袭的方向发展。在这个过程中,细胞外基质的主要成分在合成和分解上发生巨大变化,胶原分子便是其中之一,胶原分子作为细胞外基质中的主要成分,对细胞的黏附、运动、迁移等活动起着重要作用。随着研究的深入,发现越来越多的胶原分子参与了肿瘤的发生发展。基质中还存在着一些分子,它们在结构上和胶原蛋白一样含有三螺旋胶原结构域,在肿瘤的发生发展过程中同样发挥着重要作用。本文就包括胶原分子在内的含有胶原结构的分子在肿瘤中的作用做一综述。     

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。     

肿瘤微环境中微生物影响肿瘤发生发展的分子机制

肿瘤微环境呈现出一个错综复杂的生态系统,包括肿瘤细胞、非癌细胞、细胞外基质以及微生物群落等多种要素。微生物在肿瘤内广泛分布,其在空间分布上呈现出显著的特异性。这些微生物的组成成分与功能状态在肿瘤的发生和进展中发挥着至关重要的作用。本文深入阐明了肿瘤微环境内微生物菌群的特征,并探索其对肿瘤发生发展的影响机制,以期为肿瘤的诊断和治疗提供全新的策略和视角。     

成纤维细胞激活蛋白α与肿瘤发展进程的研究

肿瘤微环境对肿瘤的发生、发展具有重要的意义。选择性表达于肿瘤微环境重要组成部分——肿瘤相关成纤维细胞（carcinoma associated fibroblasts,CAFs）表面的成纤维细胞激活蛋白α（fibroblast activation protein-α,FAPα）广泛参与了肿瘤的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等过程,从而促进了肿瘤的发展进程。FAPα具有蛋白水解酶活性,并作用于细胞信号通路,但FAPα在肿瘤微环境中发挥功能的具体分子机制还有待进一步研究。由于FAPα的表达具有肿瘤组织特异性,因此,以FAPα作为肿瘤基质标志物,对肿瘤进行病理诊断和免疫治疗将成为新兴的研究靶点。对FAPα的主要生物学性状进行概述,并综述了其对肿瘤细胞的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等方面的重要影响。     

Tumor mechanics and metabolic dysfunction

Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.     

Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction

The development of atherosclerosis involves phenotypic changes among vascular smooth muscle cells (VSMCs) that correlate with stiffening and remodeling of the extracellular matrix (ECM). VSMCs are highly sensitive to the composition and mechanical state of the surrounding ECM, and ECM remodeling during atherosclerosis likely contributes to pathology. We hypothesized that ECM mechanics and biochemistry are interdependent in their regulation of VSMC behavior and investigated the effect of ligand presentation on certain stiffness-mediated processes. Our findings demonstrate that substrate stiffening is not a unidirectional stimulus—instead, the influence of mechanics on cell behavior is highly conditioned on ligand biochemistry. This “stiffness-by-ligand” effect was evident for VSMC adhesion, spreading, cytoskeletal polymerization, and focal adhesion assembly, where VSMCs cultured on fibronectin (Fn)-modified substrates showed an augmented response to increasing stiffness, whereas cells on laminin (Ln) substrates showed a dampened response. By contrast, cells on Fn substrates showed a decrease in myosin light chain (MLC) phosphorylation and elongation with increasing stiffness, whereas Ln supported an increase in MLC phosphorylation and no change in cell shape with increasing stiffness. Taken together, these findings show that identical cell populations exhibit opposing responses to substrate stiffening depending on ECM presentation. Our results also suggest that the shift in VSMC phenotype in a developing atherosclerotic lesion is jointly regulated by stromal mechanics and biochemistry. This study highlights the complex influence of the blood vessel wall microenvironment on VSMC phenotype and provides insight into how cells may integrate ECM biochemistry and mechanics during normal and pathological tissue function.     

Cells Actively Stiffen Fibrin Networks by Generating Contractile Stress

During wound healing and angiogenesis, fibrin serves as a provisional extracellular matrix. We use a model system of fibroblasts embedded in fibrin gels to study how cell-mediated contraction may influence the macroscopic mechanical properties of their extracellular matrix during such processes. We demonstrate by macroscopic shear rheology that the cells increase the elastic modulus of the fibrin gels. Microscopy observations show that this stiffening sets in when the cells spread and apply traction forces on the fibrin fibers. We further show that the stiffening response mimics the effect of an external stress applied by mechanical shear. We propose that stiffening is a consequence of active myosin-driven cell contraction, which provokes a nonlinear elastic response of the fibrin matrix. Cell-induced stiffening is limited to a factor 3 even though fibrin gels can in principle stiffen much more before breaking. We discuss this observation in light of recent models of fibrin gel elasticity, and conclude that the fibroblasts pull out floppy modes, such as thermal bending undulations, from the fibrin network, but do not axially stretch the fibers. Our findings are relevant for understanding the role of matrix contraction by cells during wound healing and cancer development, and may provide design parameters for materials to guide morphogenesis in tissue engineering.     

Cells Actively Stiffen Fibrin Networks by Generating Contractile Stress

During wound healing and angiogenesis, fibrin serves as a provisional extracellular matrix. We use a model system of fibroblasts embedded in fibrin gels to study how cell-mediated contraction may influence the macroscopic mechanical properties of their extracellular matrix during such processes. We demonstrate by macroscopic shear rheology that the cells increase the elastic modulus of the fibrin gels. Microscopy observations show that this stiffening sets in when the cells spread and apply traction forces on the fibrin fibers. We further show that the stiffening response mimics the effect of an external stress applied by mechanical shear. We propose that stiffening is a consequence of active myosin-driven cell contraction, which provokes a nonlinear elastic response of the fibrin matrix. Cell-induced stiffening is limited to a factor 3 even though fibrin gels can in principle stiffen much more before breaking. We discuss this observation in light of recent models of fibrin gel elasticity, and conclude that the fibroblasts pull out floppy modes, such as thermal bending undulations, from the fibrin network, but do not axially stretch the fibers. Our findings are relevant for understanding the role of matrix contraction by cells during wound healing and cancer development, and may provide design parameters for materials to guide morphogenesis in tissue engineering.     

Tumor Growth Modeling from the Perspective of Multiphase Porous Media Mechanics

Multiphase porous media mechanics is used for modeling tumor growth, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT). This approach incorporates the interaction of more phases than legacy tumor growth models. The tumor is treated as a multiphase system composed of an extracellular matrix, tumor cells which may become necrotic depending on nutrient level and pressure, healthy cells and an interstitial fluid which transports nutrients. The governing equations are numerically solved within a Finite Element framework for predicting the growth rate of the tumor mass, and of its individual components, as a function of the initial tumor-to-healthy cell ratio, nutrient concentration, and mechanical strain. Preliminary results are shown.     

TGF-β对肿瘤微环境中免疫监视及细胞外基质的调控作用

转化生长因子β(transforming growth factorβ,TGF-β)是一种多功能的细胞因子,能够调控细胞增殖、分化、黏附、迁移及凋亡等行为,在胚胎发育过程和成体组织稳态维持中发挥重要的作用。而在许多疾病状态下,特别是在癌症中,TGF-β不仅能够影响肿瘤细胞的增殖与转移,其对于肿瘤微环境的调控与塑造也受到越来越多的关注。肿瘤微环境是指肿瘤在发生和发展过程中所处的内环境,由肿瘤细胞本身、相邻正常组织中的间质细胞,以及这些细胞所释放的众多细胞因子等共同组成。肿瘤微环境是肿瘤发展的重要机制,也是肿瘤临床治疗领域亟待探索的关键问题。TGF-β是调节肿瘤微环境组成和功能的主要参与者之一。在本综述中,将着重讨论TGF-β对于肿瘤微环境中的免疫监视机制及肿瘤细胞外基质的主要影响。即TGF-β对于构成先天性和获得性抗肿瘤免疫应答的各种类群的免疫细胞具有广泛的调控作用,从而削弱宿主的肿瘤免疫监视功能。同时,TGF-β通过促进肿瘤相关成纤维细胞的产生,以及肿瘤细胞外基质的纤维化,有助于肿瘤的恶变和转移。此外,还介绍了通过阻断肿瘤微环境中TGF-β信号通路进行肿瘤治疗的主要策略及独特优势。而未来进一步解析TGF-β信号在肿瘤微环境中的复杂调控作用,并建立有效的靶向干预方法对于开发高效的抗肿瘤药物具有重要的意义。     

Tumor stroma-associated antigens for anti-cancer immunotherapy

Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell survival seem to be more suitable therapeutic targets. However, even such antigens may be subject to immune evasion due to impaired processing and cell surface expression. Since development and progression of tumors is not only dependent on cancer cells themselves but also on the active contribution of the stromal cells, e.g. by secreting growth supporting factors, enzymes degrading the extracellular matrix or angiogenic factors, the tumor stroma may also serve as a target for immune intervention. To this end several antigens have been identified which are induced or upregulated on the tumor stroma. Tumor stroma-associated antigens are characterized by an otherwise restricted expression pattern, particularly with respect to differentiated tissues, and they have been successfully targeted by passive and active immunotherapy in preclinical models. Moreover, some of these strategies have already been translated into clinical trials.     

Reciprocal interactions between cells and extracellular matrix during remodeling of tissue constructs

Cells remodel extracellular matrix during tissue development and wound healing. Similar processes occur when cells compress and stiffen collagen gels. An important task for cell biologists, biophysicists, and tissue engineers is to guide these remodeling processes to produce tissue constructs that mimic the structure and mechanical properties of natural tissues. This requires an understanding of the mechanisms by which this remodeling occurs. Quantitative measurements of the contractile force developed by cells and the extent of compression and stiffening of the matrix describe the results of the remodeling processes. Not only do forces exerted by cells influence the structure of the matrix but also external forces exerted on the matrix can modulate the structure and orientation of the cells. The mechanisms of these processes remain largely unknown, but recent studies of the regulation of myosin-dependent contractile force and of cell protrusion driven by actin polymerization provide clues about the regulation of cellular functions during remodeling.     

重组PAI－2对肿瘤细胞降解细胞外基质的影响

重组ＰＡＩ－２对肿瘤细胞降解细胞外基质的影响曹祥荣（南京师范大学生物系,２１００２４）关键词纤溶酶原激活剂抑制剂－２,基因重组,细胞外基质降解肿瘤细胞转移过程中最重要的因素是肿瘤细胞侵袭能力,其生化过程即为细胞外基质（ＥＯＭ）降解作用。纤溶酶系统（纤...