血小板促进肿瘤转移的相关机制研究

肿瘤转移是导致肿瘤患者死亡的主要原因,也是肿瘤难以治疗的关键所在.肿瘤转移过程包括肿瘤细胞穿越肿瘤组织的血管内皮细胞从原发部位迁出、肿瘤细胞随血液运行以及肿瘤细胞在转移部位的植入三个主要环节,转移过程涉及多种细胞黏附分子、细胞外基质以及其他血细胞间的相互作用.研究发现血小板能够促进肿瘤转移,血小板数目增多与肿瘤转移具有正相关性[1-2],而降低血小板数目或者抑制其功能可以明显抑制肿瘤转移[3-4].     

血小板促进肿瘤转移的研究进展

肿瘤转移是导致肿瘤患者死亡的主要原因,也是肿瘤难以治疗的关键所在。肿瘤转移过程包括肿瘤细胞穿越肿瘤组织的血管内皮细胞从原发部位迁出、肿瘤细胞随血液运行以及肿瘤细胞在转移部位的植入三个主要环节,转移过程涉及多种细胞黏附分子、细胞外基质以及其他血细胞间的相互作用。研究发现血小板能够促进肿瘤转移,血小板数目增多与肿瘤转移具有正相关性,而降低血小板数目或者抑制其功能可以明显抑制肿瘤转移。虽然已证实血小板可参与肿瘤转移,但其具体作用机制目前还不十分明确。近年来的研究结果揭示,     

VEGF、survivin、bcl-2在膀胱移行细胞癌中的表达和意义

肿瘤血管形成过程复杂,其中血管内皮细胞生长因子（VEGF）发挥重要作用。膀胱移行细胞癌发生、发展受多种基因调控。survivin蛋白作为凋亡抑制蛋白（inhibitor of apoptosis protein,IAP）家族中的IAP蛋白,其结构独特,与多种肿瘤的恶性程度和预后密切相关。bcl-2基因具有抑制细胞凋亡和延长细胞存活的功能,它不加速细胞分裂、增殖,而是促进细胞生存。我们用免疫组化技术研究VEGF、survivin、bcl-2在膀胱移行细胞癌组织中表达,并分析其相关性,为膀胱移行细胞癌的诊断治疗及预后判断提供依据。[第一段]     

外泌体在肿瘤微环境中的免疫抑制作用

外泌体(exosome)作为一种纳米级囊泡,在细胞间的信息传递中起着重要作用。越来越多的研究表明,肿瘤细胞来源外泌体(tumor-derived exosomes,TEXs)携带有与亲代肿瘤细胞相似的免疫抑制性分子,介导了肿瘤细胞与NK细胞、树突状细胞、髓源性抑制细胞、巨噬细胞、效应性T细胞、调节性T细胞和调节性B细胞的通讯,从而抑制肿瘤微环境中的抗肿瘤免疫应答。此外,近年来研究发现免疫细胞来源的外泌体在免疫抑制性肿瘤微环境的形成过程中也起一定作用。现针对外泌体的生物学特征及其在免疫抑制性肿瘤微环境形成过程中的作用进行综述。     

化疗药物诱导的肿瘤细胞凋亡和相关因子的调控

细胞凋亡是不同类型的细胞受到程序化因素控制而发生的细胞死亡过程 ,而这一过程在多个环节受多个因素调节。研究证明 ,细胞凋亡不仅与肿瘤的发生有关 ,而且与肿瘤细胞的耐药性关系密切。如果肿瘤细胞凋亡受到抑制 ,则表现为耐药。同样 ,通过各种方式促进肿瘤细胞凋亡的发生 ,则可增强肿瘤细胞的化疗敏感性。研究肿瘤化疗引起的细胞凋亡机制及其调控、对于指导临床化疗有重要意义。     

RGD肽在肿瘤诊断与治疗中的应用

RGD( Arg - Gly- Asp)肽存在于多种生物细胞外基质中,能特异性识别肿瘤细胞表面的整合素并与之结合,可作为体内RGD肽类物质的竞争性抑制剂,从而能抑制肿瘤细胞与细胞外基质的黏附与迁移、抑制肿瘤血管形成、诱导肿瘤细胞凋亡.RGD肽可以作为载体在肿瘤靶向治疗中发挥重要作用,且在肿瘤显像及肿瘤治疗有潜在应用价值.该文主要介绍RGD肽在肿瘤显像中的应用、在肿瘤治疗中作为载体的应用、对肿瘤的直接抑制作用、在抗栓药物中的应用、对血小板功能的影响、诱导骨组织再生的应用研究与新进展.     

化疗药物诱导的肿瘤细胞凋亡和相关因子的调控

细胞凋亡是不同类型的细胞受到程序化因素控制而发生的细胞死亡过程，而这一过程在多个环节受多个因素调节。研究证明，细胞凋亡不仅与肿瘤的发生有关，而且与肿瘤细胞的耐药性关系密切。如果肿瘤细胞凋亡受到抑制，则表现为耐药。同样，通过各种方式促进肿瘤细胞凋亡的发生，则可增强肿瘤细胞的化疗敏感性。研究肿瘤化疗引起的细胞凋亡机制及其调控、对于指导临床化疗有重要意义。     

Caveolin-1在肿瘤发生发展及耐药机制中的作用

Caveolin-1是细胞膜微囊（caveolae）的重要组成结构,在大多数正常的细胞中表达丰富。通过其脚手架区域,在多种信号分子向胞内传递信息的过程中发挥着重要作用,其功能研究是生物学研究的热点。而近来研究表明caveolin-1在大多数肿瘤细胞中表达下降甚至缺如,过表达caveolin-1能抑制其恶性生长性状。近来的癌细胞转化及基因敲除等实验结果倾向于caveolin-1就是7q31位点的肿瘤抑制基因。但在少数肿瘤如前列腺癌、乳腺癌患者的细胞中检测到caveolin-1高表达。在纤维原细胞和上皮细胞的凋亡中起促进作用。Caveolin-1与多种肿瘤细胞的增殖、分化、侵袭、转移以及凋亡关系密切,且可能是肿瘤细胞多药耐药逆转的一个新靶点,以类似于介导胆固醇流出途径的方式将药物排出细胞导致细胞耐药性增强。     

MDSC在恶性肿瘤发生、发展中的作用

骨髓来源的抑制性细胞(myeloid-derived suppressor cell, MDSC)是一种未成熟的髓细胞，主要在致病性和炎症性免疫反应中发挥重要作用。MDSC具有强大的免疫抑制功能，它能够抑制相应的T细胞反应，限制炎症的发生发展，从而促进伤口愈合。然而，在癌症中，肿瘤细胞通常改变骨髓的生成，影响祖细胞的分化过程，最终致使MDSC积累，甚至会降低肿瘤免疫治疗的疗效。MDSC是多种恶性肿瘤发生发展过程中的关键组分，综述就其多种作用机制的相关研究进展进行总结，着重就MDSC对T细胞的抑制功能以及它在多种恶性肿瘤中的作用机制展开叙述。     

细胞凋亡抑制蛋白:肿瘤治疗的障碍与靶点

细胞凋亡抑制蛋白(inhibitor of apoptosis protein,IAP)主要通过结合并抑制细胞凋亡执行分子caspase蛋白家族而抑制细胞凋亡。肿瘤细胞高表达IAP是其获得抗凋亡特性的原因之一,成为肿瘤传统治疗(放疗,化疗等)的障碍。但特异的在肿瘤细胞内高表达而在正常细胞特别是高分化细胞中低表达或无表达也为肿瘤治疗提供了新靶点。干涉IAP分子在肿瘤细胞内的表达或功能已被作为肿瘤传统治疗方法的辅助治疗方法来研究。     

Osteopontin has a protective role in prostate tumor development in mice

Osteopontin (OPN) is a protein, generally considered to play a pro‐tumorigenic role, whereas several reports have demonstrated the anti‐tumorigenic function of OPN during tumor development. These opposing anti‐ and pro‐tumorigenic functions are not fully understood. Here, we report that host‐derived OPN plays an anti‐tumorigenic role in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model and a TRAMP tumor transplant model. Tumor suppression mediated by OPN in Rag2^?/? mice suggests that OPN is dispensable in the adaptive immune response. We found that host‐derived OPN enhanced infiltration of natural killer (NK) cells into TRAMP tumors. The requirement of OPN in NK cell migration towards TRAMP cells was confirmed by an ex vivo cell migration assay. In contrast to TRAMP cells, in vivo B16 tumor development was not inhibited by OPN, and B16 tumors did not show OPN‐mediated cell recruitment. It is possible that low levels of chemokine expression by B16 cells do not allow OPN to enhance immune cell recruitment. In addition to demonstrating the anti‐tumorigenic role of OPN in TRAMP tumor development, this study also suggests that the contribution of OPN to tumor development depends on the type of tumor as well as the source and isoform of OPN.     

Role of osteopontin,a multifunctional protein,in allergy and asthma

Osteopontin (OPN) is an extracellular matrix protein and immune modulator with a wide range of functions. OPN is recognized as a key cytokine in Th1 immune responses, yet its potential involvement in allergic/asthmatic responses has been investigated only recently. Current data from molecular and cellular studies and studies of OPN‐deficient mice provide evidence that OPN plays multiple roles in the regulation of allergic responses, including regulation of IgE response, inflammatory cell migration, and the development of airway fibrosis and angiogenesis. These results suggest that OPN is a pleiotropic cytokine that functions both systemically and locally in tissue mucosa. Notably, OPN is able to exert its effects through different functional domains, and the secreted and intracellular forms of OPN may have distinct functions. Future research to elucidate all aspects of OPN function is needed to ultimately establish its role in the regulation of immune responses and various disease processes, including those critically involved in the development of allergies and asthma. Cite this as: S. Konno, M. Kurokawa, T. Uede, M. Nishimura and S.‐K. Huang, Clinical & Experimental Allergy, 2011 (41) 1360–1366.     

Osteopontin as a new player in mast cell biology

The secreted glycoprotein osteopontin (OPN) sets into motion an astounding variety of activities that range from bone remodeling via immunomodulation to the inhibition of apoptosis. In the current issue of the European Journal of Immunology, OPN now also enters mast cell biology and the regulation of IgE-dependent immune responses since it is reported that connective tissue-type mast cells from fetal murine skin constitutively secrete biologically active OPN. Moreover, it is shown that, in vitro, OPN augments IgE-mediated mast cell degranulation and migration via ligand binding to cognate OPN receptors on the mast cell surface (CD44, alpha v integrin) and that the magnitude of an IgE-mediated passive cutaneous anaphylaxis reaction is augmented by OPN in vivo. Here, we discuss why this newly discovered property of OPN fits well into the emerging concept that OPN may serve as a multi-purpose environmental damage-response protein.     

Osteopontin expression in ductal adenocarcinomas and undifferentiated carcinomas of the pancreas

Osteopontin (OPN) is a non-collagenous extracellular matrix protein with pleiotropic functions, including mediation of cell adhesion and migration. Recently, high OPN serum levels were found in pancreatic ductal adenocarcinomas (PDACs) in which OPN mRNA was identified in macrophages. We investigated OPN expression at the protein level in 15 PDACs and 10 undifferentiated pancreatic carcinomas (UCs), 4 of them with osteoclast-like giant cells (OCGCs), to find out whether the degree of OPN expression is related to tumor infiltration by macrophages and the adhesive capacity of tumor cells. With regard to its potential adhesive function, we compared OPN expression in PDACs and UCs with that of E-cadherin and -catenin, two well-known adhesive molecules. OPN positivity was observed in two-thirds of PDACs (10/15) and in 7 UCs (7/10), including all 4 UCs with OCGCs. Apart from tumor cells, OPN was expressed in macrophages and OCGCs. When we assessed the relationship between the number of OPN-positive macrophages and tumor cells, we did not find any statistically significant correlation. There was also no correlation, either positive or negative, between OPN expression and E-cadherin and -catenin expression. The results demonstrated that, in PDACs and UCs, OPN is expressed in both tumor-associated macrophages and tumor cells. The biological significance of this dual expression pattern is not yet known. It is, however, unlikely that OPN has an adhesive function, since its expression pattern differs distinctly from that of E-cadherin or -catenin.     

Osteopontin as a two-sided mediator in acute neuroinflammation in rat models

Osteopontin (OPN) plays an important role in the initiation of inflammation, affecting cell adhesion, chemotaxis, immune regulation, and protection against apoptosis, depending on its intracellular or extracellular localization. Although OPN in inflammation of the autoimmune central nervous system is proinflammatory, recent studies have shown that OPN during the induction stage of inflammation may also participate in neuroprotection and neurite growth. The present review examines the dual roles of OPN, specifically, its proinflammatory and subsequent neuroprotective roles, in acute neuroinflammation in rat models, including experimental autoimmune encephalomyelitis, brain injury, and autoimmune neuritis. All of these models are characterized by acute neuroinflammation, followed by remodeling of neural tissues.