miRNA-139-5p与肿瘤

转移和复发是恶性肿瘤的重要特征。肿瘤细胞的增殖、浸润、侵袭能力与肿瘤的复发和转移息息相关。非编码小RNA通过转录后水平参与肿瘤的发生和发展过程。其中,miR-139-5p成为研究热点之一。在许多肿瘤中都发现miR-139-5p的异常表达,它参与了肿瘤细胞的增殖、分化、转移和浸润,调节肿瘤细胞对化疗药物敏感性,并与肿瘤患者的预后相关。因此,miR-139-5p可能成为肿瘤治疗的一个新靶点。本文对miR-139-5p与肿瘤的关系作一综述。系统地了解它在恶性肿瘤进程中的作用,为广大研究者及临床工作者提供新思路新方法。     

肿瘤异质性：精准医学需破解的难题

肿瘤异质性是恶性肿瘤的重要特征,表现为同一种恶性肿瘤不同患者个体之间或者同一患者体内不同部位肿瘤细胞间从基因型到表型上存在的差异.这种差异可表现为不同的遗传背景、不同的病理类型、不同的分化状态、不同的基因突变谱和转录组、蛋白质组表达谱等,体现了恶性肿瘤在演进过程中的高度复杂性和多样性.肿瘤异质性给肿瘤的治疗带来极大的困难,一直是肿瘤发生发展机制研究领域重要的科学问题.本文综述了肿瘤异质性的生物学特征及其可能的形成机制,并对"精准医学"时代如何针对肿瘤异质性设计更为有效的个性化治疗方案进行了思考.     

肿瘤转移研究的现状与趋势

肿瘤转移是恶性肿瘤的主要特征,是引起癌症患者死亡的首要因素．肿瘤转移的发生涉及到肿瘤细胞及其所处的微环境中复杂的信号通路,这些信号通路的激活及相互作用介导了肿瘤的转移、侵袭和在血液/淋巴循环系统中存活,以及在转移靶部位的生长过程．肿瘤转移是一个复杂的、多因素调控的动态过程,对于肿瘤转移机制的研究将有助于深入了解转移过程,并可以鉴定到有意义的治疗靶标,为临床诊断和治疗奠定基础．     

炎症细胞因子在肿瘤微环境中的作用及其作为治疗靶点的研究进展

肿瘤相关炎症是近年来肿瘤免疫领域的研究热点。炎症被称为恶性肿瘤的第八大生物学特征,其在肿瘤发生发展、侵袭转移过程中发挥重要作用。肿瘤微环境中存在大量的炎症细胞因子,如IL-1、IL-6、IL-12、IL-17、TNF-α和TGF-β,它们不仅可以募集炎症细胞到肿瘤部位,放大炎症效应,还可促进肿瘤细胞生长和转移,促进肿瘤血管、淋巴管生成。现主要从炎症细胞因子及肿瘤微环境入手,旨在探讨炎症细胞因子介导的慢性炎症在肿瘤发生发展过程中的重要作用,及其作为肿瘤治疗靶点的转化医学的研究进展及展望。     

抑癌基因和肿瘤转移

目前肿瘤治疗最棘手的问题,莫过于肿瘤细胞对传统治疗药物的抗性和肿瘤转移,所以,进一步研究肿瘤细胞的抗药性和转移的分子基础,已成为提高肿瘤治疗和预后的热点问题。本文就肿瘤转移过程中抑癌基因变化的研究进展作一介绍。肿瘤转移是个有多种基因参与的过程。在此过...     

靶向循环肿瘤细胞治疗策略在抗肿瘤转移中的应用

转移是肿瘤治疗的主要挑战，90%的肿瘤相关死亡病例与肿瘤转移有关。循环肿瘤细胞(circulating tumor cells,CTCs)是肿瘤转移形成的关键，与肿瘤转移的形成过程密切相关。因此，靶向CTCs的治疗策略成为目前抗肿瘤转移研究的热点。基于此，本文从CTCs的产生、CTCs的播散和CTCs的远端定植三个阶段综述了CTCs参与肿瘤转移的机制，并分别从调节肿瘤转移相关基因表达和抑制EMT过程抑制肿瘤细胞脱落产生CTCs、激活自身免疫细胞和仿生细胞膜或特异性分子修饰纳米制剂在血液循环捕获消除CTCs、抑制CTCs黏附并穿过血管内皮细胞和破坏PMN处适宜肿瘤细胞生长的微环境等方面总结了控制肿瘤转移的研究进展，以期为肿瘤转移预防和治疗提供新的思路。     

PTEN:抑制肿瘤侵袭及转移的新靶点

侵袭与转移是恶性肿瘤的主要生物学特征之一,并影响肿瘤的疗效及预后.其主要通过肿瘤细胞与血管内皮细胞以及细胞基质之间的相互作用,穿透血管内皮细胞、降解细胞外基质,从而向局部及远处转移.多种信号转导分子参与了肿瘤的侵袭、转移过程.PTEN基因表达的蛋白具有蛋白磷酸酶及脂质磷酸酶双重活性,其作为抑癌基因通过对细胞内多种信号转导通路的调控,参与维持细胞的正常生理活动;负调控肿瘤细胞的生长、细胞周期;诱导肿瘤细胞凋亡;抑制肿瘤细胞的侵袭、浸润及转移.本文就PTEN如何参与抑制肿瘤细胞侵袭及转移做一综述.     

ADAM17在恶性肿瘤中的研究及其进展

去整合素-金属蛋白酶17(adisintegrin and metalloproteinase 17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrin and metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程.去整合素-金属蛋白酶17(ADAM17)又称为肿瘤坏死因子转换酶(TACE),因此除了具有解聚素和金属蛋白酶的活性,还可以将没有活性的肿瘤坏死因子(TNF-α)从细胞膜上切割下来,并与其受体相结合,从而激活TNF-α下游的EGFR信号传导,此外还可以激活多条信号传导途径如Notch传导通路等,进而影响肿瘤细胞的粘附、凋亡、转移、增殖等生物学行为.纵观ADAM17的研究,在多种恶性肿瘤中呈高表达状态,且这种高表达状态与肿瘤侵润程度及转移情况相关.随着人们对ADAM17基础科学的研究不断深入,ADAM17的临床应用前景也正被不断开发,鉴于其在多种恶性肿瘤组织中高表达的情况,可将其作为许多肿瘤的诊断标志物、及判断其转移和预后情况.靶向药物的研究给恶性肿瘤患者带来了新的福音,利用EGFR为研究扳机点成功研制出许多靶向药物,在EGFR的配体释放环节,ADAM17尤为重要.本文总结了ADAM17在恶性肿瘤发展中的作用及其机制,对其在癌症治疗的应用前景进行展望.     

TGF-β调节的EMT在肿瘤浸润、转移中作用的研究进展

恶性肿瘤的浸润转移是导致肿瘤患者死亡的主要原因,转化生长因子-β(transforming growth factor-β,TGF-β)调节的上皮间质转化(epithelial-mesenchymal transition,EMT)能使肿瘤上皮细胞转变为具有间质特性的细胞,肿瘤细胞由此获得侵袭性和迁移性,从原发灶中逸出,进而发生转移。因此,对TGF-β调节的EMT在肿瘤浸润转移中作用的深入研究能够为临床治疗肿瘤转移提供研究基础。将对TGF-β调节EMT的信号通路,及其在肿瘤浸润转移中的作用和干预研究进行综述。     

鼻咽癌转移相关分子标志物的研究进展

鼻咽癌(Nasopharyngeal carcinoma NPC)是一种来源于鼻粘膜上皮细胞的恶性肿瘤,也是我国常见的头颈部恶性肿瘤之一.由于它的解剖位置相对隐匿,且多以低分化癌为主,因此大多数的鼻咽癌患者都死于肿瘤的转移而并非原发灶.研究表明,肿瘤的侵袭与转移与细胞的异常运动有关,是肿瘤细胞的粘附、降解、运动以及血管生成等多种生物学行为互相作用的动态过程.然而,影响NPC浸润转移的分子机制至今尚未完全阐明.随着现代分子生物学的发展,许多分子标志物被发现,使我们对鼻咽癌有了更高层次的认识.深入了解这些分子标志物的表达及调控,对筛选鼻咽癌标记物、提供药物治疗新靶点及预测治疗预后具有十分重要的意义.本研究拟对近年来鼻咽癌转移相关分子标志物的研究进展做一综述.     

肿瘤转移的分子机制及靶向干预研究新进展

肿瘤转移是一个多阶段的恶性进展过程,涉及肿瘤细胞从原发部位逃逸,侵入脉管系统并在其中存活,随循环系统到达远处靶器官并穿出脉管系统播散定植,最终克隆性生长形成转移瘤。转移过程的每一阶段与肿瘤细胞本身遗传和表观遗传改变以及微环境中诸多因素的综合调控密切相关。本综述概要介绍了恶性肿瘤转移多步骤过程中所涉的分子调控机制以及肿瘤转移靶向干预新措施等方面的研究进展;同时,就未来肿瘤转移研究相关的新技术和新方向作一简单的展望。     

Revisiting the seed and soil in cancer metastasis

Metastasis remains the overwhelming cause of death for cancer patients. During metastasis, cancer cells will leave the primary tumor, intravasate into the bloodstream, arrest at a distant organ, and eventually develop into gross lesions at the secondary sites. This intricate process is influenced by innumerable factors and complex cellular interactions described in 1889 by Stephen Paget as the seed and soil hypothesis. In this review, we revisit this seed and soil hypothesis with an emerging understanding of the cancer cell (i.e. seed) and its microenvironment (i.e. soil). We will provide background to suggest that a critical outcome of the seed–soil interaction is resistance of the stresses that would otherwise impede metastasis.     

Distinct mechanisms of tumor invasion and metastasis

Most cancer deaths are caused by metastasis rather than the primary tumor. Cancer cells invade normal tissue as epithelial sheets or single cells by inducing expression of programs characteristic of developmental processes. Depending on their tissue of origin, cancer cells subsequently spread to distinct target organs where they seed secondary tumors (metastasis). Recent experimental evidence suggests that metastasis requires changes not only in cancer cells but also in the tumor microenvironment and in the metastatic target site. For example, a premetastatic niche is formed in target organs that attract cancer cells. Understanding the distinct mechanisms used by cancer cells to form metastasis will enable better patient evaluation and the design of innovative therapeutic approaches.     

PRL-3 siRNA inhibits the metastasis of B16-BL6 mouse melanoma cells in vitro and in vivo

Phosphatase of regenerating liver-3 (PRL-3) has been proposed to promote the invasion of tumor cells to metastasis sites. However, the effect of PRL-3 on spontaneous metastasis has not been clearly demonstrated, and whether PRL-3 could become a new therapeutic target in malignant tumor is still unknown. In this study, we used PRL-3 siRNA as a molecular medicine to specifically reduce the expression of PRL-3 in B16-BL6 cells, a highly metastatic melanoma cell line. In vitro, PRL-3 siRNA significantly inhibited cell adhesion and migration, but had no effect on cell proliferation. In the spontaneous metastatic tumor model in vivo, PRL-3 siRNA treatment remarkably inhibited the proliferation of primary tumor, prevented tumor cells from invading the draining lymph nodes, and prolonged the life span of mice. Therefore, our results indicate that PRL-3 plays a critical role in promoting the whole process of spontaneous metastasis and tumor growth initiation, and that inhibiting PRL-3 will improve malignant tumor therapy.     

Dynamic process of prostate cancer metastasis to bone

Prostate cancer metastasis to the bone occurs at high frequency in patients with advanced disease, causing significant morbidity and mortality. Over a century ago, the "seed and soil" theory was proposed to explain organ-specific patterns of metastases. Today, this theory continues to be relevant as we continue to discover factors involved in the attraction and subsequent growth of prostate cancer cells to the bone. These include the accumulation of genetic changes within cancer cells, the preferential binding of cancer cells to bone marrow endothelial cells, and the release of cancer cell chemoattractants from bone elements. A key mediator throughout this metastatic process is the integrin family of proteins. Alterations in integrin expression and function promote dissociation of cancer cells from the primary tumor mass and migration into the blood stream. Once in circulation, integrins facilitate cancer cell survival through interactions between other cancer cells, platelets, and endothelial cells of the target bone. Furthermore, dynamic changes in integrins and in integrin-associated signal transduction aid in the extravasation of cancer cells into the bone and in expansion to a clinically relevant metastasis. Thus, we will review the critical roles of integrins in the process of prostate cancer bone metastasis, from the escape of cancer cells from the primary tumor, to their survival in the harsh "third microenvironment" of the circulation, and ultimately to their attachment and growth at distant bone sites.     

Hydrogen peroxide fuels aging,inflammation, cancer metabolism and metastasis

In 1889, Dr. Stephen Paget proposed the “seed and soil” hypothesis, which states that cancer cells (the seeds) need the proper microenvironment (the soil) for them to grow, spread and metastasize systemically. In this hypothesis, Dr. Paget rightfully recognized that the tumor microenvironment has an important role to play in cancer progression and metastasis. In this regard, a series of recent studies have elegantly shown that the production of hydrogen peroxide, by both cancer cells and cancer-associated fibroblasts, may provide the necessary “fertilizer,” by driving accelerated aging, DNA damage, inflammation and cancer metabolism, in the tumor microenvironment. By secreting hydrogen peroxide, cancer cells and fibroblasts are mimicking the behavior of immune cells (macrophages/neutrophils), driving local and systemic inflammation, via the innate immune response (NFκB). Thus, we should consider using various therapeutic strategies (such as catalase and/or other anti-oxidants) to neutralize the production of cancer-associated hydrogen peroxide, thereby preventing tumor-stroma co-evolution and metastasis. The implications of these findings for overcoming chemo-resistance in cancer cells are also discussed in the context of hydrogen peroxide production and cancer metabolism.     

Biological impact of mechanical stimuli on tumor metastasis

Increasing evidence suggests tumor cell exposure to mechanical stimuli during the perioperative period as well as throughout the normal disease process may have a discernable impact on tumor metastasis and patient outcome. In vitro studies have demonstrated that transient exposure to increased extracellular pressure and shear forces modulates integrin binding affinity and stimulates cancer cell adhesion through a cytoskeleton- and focal adhesion complex-dependent signaling mechanism. More prolonged exposure to elevated pressures stimulates tumor cell proliferation by a distinct signaling pathway. Whether pressure effects on cell adhesion and proliferation pose biological ramifications in vivo remained unknown. We recently reported that pressure activation of malignant cells does indeed have a biological impact on surgical wound implantation, tumor development, and tumor-free survival in a murine colon tumor model. Moreover, this effect can be disrupted by preoperative administration of colchicine. Taken together with previous work from our laboratory and others, these findings suggest that further

elucidation of the mechanical signaling pathways governing pressure-stimulated tumor cell adhesion and proliferation may identify novel therapeutic targets for the treatment and prevention of tumor metastasis.     

TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4

Cells released from primary tumors seed metastases to specific organs by a nonrandom process, implying the involvement of biologically selective mechanisms. Based on clinical, functional, and molecular evidence, we show that the cytokine TGFbeta in the breast tumor microenvironment primes cancer cells for metastasis to the lungs. Central to this process is the induction of angiopoietin-like 4 (ANGPTL4) by TGFbeta via the Smad signaling pathway. TGFbeta induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases.