趋化因子与肿瘤侵袭转移

趋化因子是一类具有趋化作用的分泌型小分子蛋白质,其受体属于G蛋白偶联的7次跨膜受体超家族.越来越多的证据表明趋化因子与肿瘤生长、侵袭和转移密切相关.现综述趋化因子在肿瘤细胞增殖、迁移、粘附、降解细胞外基质、肿瘤血管生成及肿瘤器官特异性转移等过程中的作用.     

趋化因子及其受体在肿瘤侵袭转移中的作用

近年来陆续发现了许多新的趋化因子和受体，研究发现趋化因子及其受体参与机体的多种生理和病理过程，并在肿瘤的侵袭转移中通过不同机制发挥着重要作用。本文对其进行简要综述。     

趋化因子受体与肿瘤转移

目前认为肿瘤细胞转移和淋巴细胞迁移具有相似机制,但趋化因子及其受体参与肿瘤转移的机制尚未完全阐明。由于其在肿瘤细胞器官选择性转移中的重要作用,趋化因子受体有希望成为肿瘤治疗的靶标并具有预后价值。现综述趋化因子受体与肿瘤侵袭和转移的研究进展。     

趋化因子受体与肿瘤转移

目前认为肿瘤细胞转移和淋巴细胞迁移具有相似机制,但趋化因子及其受体参与肿瘤转移的机制尚未完全阐明。由于其在肿瘤细胞器官选择性转移中的重要作用,趋化因子受体有希望成为肿瘤治疗的靶标并具有预后价值。现综述趋化因子受体与肿瘤侵袭和转移的研究进展。     

姜黄素抗肿瘤侵袭与转移研究进展

姜黄素是从姜黄中提取的一种酚类色素,来源广泛,高效低毒,具有多种药理活性,不但具有显著的抗诱变、抗肿瘤作用,而且具有抗肿瘤侵袭与转移作用.姜黄素抗肿瘤侵袭和转移的作用可以通过抑制基质金属蛋白酶（MMP）、核因子-κB（NF-κB）、尿激酶型纤溶酶原激活物（u-PA）、血管生成、细胞粘附和运动等多种机制来实现.     

趋化因子与肿瘤的定向转移

肿瘤转移预后不良，其形成涉及许多病理机制。近来研究表明，肿瘤细胞表达特定的趋化因子受体，而其转移好发部位高表达相应的配体，后者对肿瘤细胞有化学趋向性，由此形成了肿瘤细胞定向转移的“归巢”理论。这一理论提示，通过干预受体与配体问的相互作用，可能成为抗肿瘤转移治疗的新途径。     

姜黄素抗肿瘤侵袭与转移研究进展

姜黄素是从姜黄中提取的一种酚类色素,来源广泛,高效低毒,具有多种药理活性,不但具有显著的抗诱变、抗肿瘤作用,而且具有抗肿瘤侵袭与转移作用.姜黄素抗肿瘤侵袭和转移的作用可以通过抑制基质金属蛋白酶(MMP)、核因子-κB(NF-κB)、尿激酶型纤溶酶原激活物(u-PA)、血管生成、细胞粘附和运动等多种机制来实现.     

趋化因子与肿瘤生长和转移

趋化因子是一个促炎多肽细胞因子的超家族，具有激活和趋化白细胞的作用，许多疾病的发生发展均需趋化因子的参与。在肿瘤的发生发展过程中，趋化因子表现出两方面的作用：一部分趋化因子可能增强宿主抗肿瘤侵入的固有或特异性免疫反应，另一部分可能通过促进肿瘤细胞的增殖和肿瘤组织中血管的生成，而促进肿瘤的生长和转移。本文主要     

信号传导与转录激活因子3与肿瘤侵袭和转移

信号传导与转录激活因子3(STAT3)在各种癌组织中表达均明显增高,STAT3蛋白通过对下游基因的调节发挥抑制调亡、促进细胞增殖、增加肿瘤细胞侵袭力的作用.STAT3有可能成为肿瘤治疗中一个新的治疗靶位,阻断STAT3信号传导通路可能降低肿瘤细胞的侵袭和转移、抑制肿瘤细胞生长,可为肿瘤治疗提供新的思路.     

趋化因子与肿瘤的定向转移

肿瘤转移预后不良,其形成涉及许多病理机制.近来研究表明,肿瘤细胞表达特定的趋化因子受体,而其转移好发部位高表达相应的配体,后者对肿瘤细胞有化学趋向性,由此形成了肿瘤细胞定向转移的"归巢"理论.这一理论提示,通过干预受体与配体间的相互作用,可能成为抗肿瘤转移治疗的新途径.     

SHP2与乳腺癌侵袭转移相关性的研究进展

含Src同源区2蛋白质酪氨酸磷酸酶（Src homology 2 domain containing protein tyrosine phosphatases,SHP2）是一种跨膜型蛋白酪氨酸磷酸酶,通过调节细胞内蛋白质的酪氨酸磷酸化水平,在细胞信号转导通路及控制细胞活性中发挥重要的作用。其活化状态与乳腺癌发生发展过程中的Ras/ERK,PI3K/Akt/mTOR等信号通路、激素水平、侵袭转移、肿瘤干细胞的生物学行为等密切相关。SHP2基因的敲除或抑制SHP2蛋白表达,可不同程度阻断与乳腺癌侵袭、转移相关的信号通路,从而抑制肿瘤生长,甚至不可逆地使肿瘤丧失重新获得干细胞特性的能力。因此,SHP2很可能为抗肿瘤药物的研发提供一个新的靶点。本文就SHP2与乳腺癌侵袭转移的相关研究进展进行综述。      

尿激酶纤溶酶原激活物系统与肿瘤侵袭转移

恶性肿瘤合成分泌大量胞外蛋白水解酶,降解细胞外基质及基底膜,是恶性肿瘤侵袭转移的重要基础.尿激酶纤溶酶原激活物(uPA)系统作为主要的蛋白水解酶在其中发挥重要作用.本简述uPA系统的结构、功能及其在侵袭、转移中的作用.     

Hyperforin inhibits cancer invasion and metastasis

Hyperforin (Hyp), the major lipophilic constituent of St. John's wort, was assayed as a stable dicyclohexylammonium salt (Hyp-DCHA) for cytotoxicity and inhibition of matrix proteinases, tumor invasion, and metastasis. Hyp-DCHA triggered apoptosis-associated cytotoxic effect in both murine (C-26, B16-LU8, and TRAMP-C1) and human (HT-1080 and SK-N-BE) tumor cells; its effect varied, with B16-LU8, HT-1080, and C-26 the most sensitive (IC50 = 5 to 8 micromol/L). At these concentrations, a marked and progressive decline of growth was observed in HT-1080 cells, whereas untransformed endothelial cells were only marginally affected. Hyp-DCHA inhibited in a dose-dependent and noncompetitive manner various proteinases instrumental to extracellular matrix degradation; the activity of leukocyte elastase was inhibited the most (IC50 = 3 micromol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC50 > 100 micromol/L. Nevertheless, inhibition of extracellular signal-regulated kinase 1/2 constitutive activity and reduction of MMP-2 and MMP-9 secretion was triggered by 0.5 micromol/L Hyp-DCHA to various degrees in different cell lines, the most in C-26. Inhibition of C-26 and HT-1080 cell chemoinvasion (80 and 54%, respectively) through reconstituted basement membrane was observed at these doses. Finally, in mice that received i.v. injections of C-26 or B16-LU8 cells, daily i.p. administration of Hyp-DCHA-without reaching tumor-cytotoxic blood levels-remarkably reduced inflammatory infiltration, neovascularization, lung weight (-48%), and size of experimental metastases with C-26 (-38%) and number of lung metastases with B16-LU8 (-22%), with preservation of apparently healthy and active behavior. These observations qualify Hyp-DCHA as an interesting lead compound to prevent and contrast cancer spread and metastatic growth.     

miRNA与肿瘤侵袭转移

目前,microRNA (miRNA)已成为肿瘤研究中最基本的参与者,主要通过与靶标基因3 'UTR(非翻译区)的完全或不完全配对,降解靶标基因mRNA或抑制其翻译,从而参与调控个体发育、细胞凋亡、增殖及分化等生命活动.miRNA作为调控基因表达的重要分子在肿瘤侵袭转移中的作用越来越受到重视,表明miRNA在肿瘤侵袭和转移中的作用机制具有重要的理论意义,同时也可为肿瘤的诊断和治疗提供新方法.本文就miRNA通过调控上皮间质转化及肿瘤干细胞导致肿瘤侵袭转移的最新研究进展作一综述.     

Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response

The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8⁺ and CD4⁺ T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. ( Cancer Sci 2007; 98: 1652–1658)     

Extracellular matrix--regulation of cancer invasion and metastasis

Cancer cell invasion comprises steps in the destruction of the basement membrane and migration of cells into the connective tissue. These cells further migrate into lymph ducts and small vessels to reach metastasis. The extracellular matrix (ECM) provides a microenvironment for cells, and its destruction is associated with cancer cell invasion. Among matrix metalloproteinases (MMPs), both MMP-2 and 9 digest type IV collagen, a major component of the basement membrane, and MMP-14/MT1-MMP, a membrane-type MMP, activates MMP-2. Thus, these MMPs play a central role in cancer cell invasion. MMPs also cleave latent forms of growth factors and signaling molecules, releasing and activating them, which influence neo-vascularization and cancer apoptosis. Like proteins, carbohydrates are known to be involved in cancer invasion. Hyaluronan is known to both stimulate and inhibit cancer invasion, depending on its molecular size. Heparanase, which digests heparan sulfate, is known to facilitate cancer invasion and metastasis. In summary, ECM provides a microenvironment that regulates cell behavior and its structure altered by MMPs affects cancer cell invasion.     

Role of intermediate filaments in migration, invasion and metastasis

Summary The expression of intermediate filament proteins is remarkably tissue-specific which suggests that the intermediate filament (IF) type(s) present in cells is somehow related to their biological function. However, in some cancers-particularly malignant melanoma and breast carcinoma, there is a strong indication that vimentin and keratin IFs are coexpressed, thus presenting as a dedifferentiated or interconverted (between epithelial and mesenchymal) phenotype. In this review, twoin vitro models are presented which recapitulate the interconverted phenotype in human melanoma and breast carcinoma, and allow, for the first time, unique observations to be made with respect to the role of IFs in cancer progression.These studies have provided direct evidence linking overexpression of keratin IFs in human melanoma with increased migratory and invasive activityin vitro, which can be down-regulated by substituting dominant-negative keratin mutants. Overexpression of vimentin IFs in the breast carcinoma model leads to augmentation of motility and invasivenessin vitro, which can be transiently down-regulated by treatment with antisense oligonucleotides to vimentin. Additional experimental evidence suggests that the mechanism(s) responsible for the differential expression of metastatic properties associated with the interconverted phenotype rest(s) in the unique interaction, either direct or indirect, of IFs with specific integrins interacting with the extracellular matrix.In this review, we discuss the observations derived from the human melanoma and breast carcinoma models to address the hypothesis that the ability to coexpress vimentin and keratins confers a selective advantage to tumor cells in their interpretation of and response to signaling cues from the extracellular matrix. The ramifications of these observations are discussed with respect to the patholophysiology of the respectivein situ tumors.