上皮间质转化与肿瘤转移研究进展

上皮细胞间质转化是一种基本的生理病理变化,其在胚胎发育、慢性炎症、纤维化和肿瘤浸润转移中发挥重要作用。近年来,人们发现EMT与肿瘤的发生及转移可能存在关联,使其迅速成为肿瘤研究的焦点。对于EMT的研究不但能进一步了解其影响肿瘤的机制,而且可促进EMT生物标记物及靶向治疗的研究,这对侵袭性肿瘤的诊治具有重大意义。1 EMT概述     

MicroRNA在胃癌上皮-间质转化中的研究进展

上皮-间质转化不仅参与正常胚胎发育过程中器官和组织的生成,而且也有助于提高癌细胞的侵袭及转移.当上皮-间质转化受到刺激时,细胞和细胞之间黏附及极性由于黏附分子如E-钙黏蛋的消失而被打乱,导致细胞之间的相互作用发生改变,导致细胞发生间充质表型的改变,最终激活癌细胞的迁移和侵袭.研究证明部分转录因子、生长因子以及相关信号通路参与上皮-间质转化过程,而miRNA可通过调控癌基因或抑癌基因参与胃癌细胞的增殖、凋亡、侵袭及转移过程,其中也涉及上皮-间质转化的调控.本文就近年来miRNA在胃癌EMT过程中的具体调控机制予以综述.     

胃癌细胞奥沙利铂耐药与上皮-间质转化关系研究

目的：探讨胃癌细胞奥沙利铂（oxaliplatin,L-OHP）耐药与上皮-间质转化（EMT）的关系。 方法：采用逐步递增L-OHP浓度持续体外诱导人胃癌SGC-7901细胞,建立L-OHP耐药细胞系SGC-7901/L-OHP;通过形态学、群体倍增时间、药物敏感性检测确定SGC-7901/L-OHP成功建立;比较SGC-7901/L-OHP细胞与亲代细胞EMT相关标记物N-cadherin和E-cadherin表达差异。 结果：经6个月诱导,L-OHP耐药细胞系SGC-7901/L-OHP成功建立,表现为该细胞的形态由上皮表型转变为间质样细胞表型;群体倍增时间较亲代细胞明显延长（P<0.05）;L-OHP的IC50为亲代细胞的9.7倍。与亲代细胞SGC-790比较,SGC-7901/L-OHP细胞中N-cadherin mRNA和蛋白表达明显上调,E-cadherin mRNA和蛋白表达明显下调（均P<0.05）。 结论：EMT可能是人胃癌细胞对L-OHP产生耐药的重要机制。     

细胞核Snail因子在胰腺癌上皮-间质转化中的作用

目的：探讨细胞核因子Snail在胰腺癌组织中的表达及与胰腺癌上皮-间质转化（EMT）过程的相关性。 方法：采用免疫组织化学方法检测77例胰腺癌组织（研究组）与13例正常胰腺组织（对照组）中的Snail、Slug、E-cadherin、vimentin的表达。 结果：研究组中胰腺癌患者胰腺组织中Snail、Slug、E-cadherin、vimentin的表达阳性率为70.13%、68.83%、36.36%、72.73%。对照组13例正常胰腺组织中Snail、Slug均不表达,E-cadherin、vimentin的表达阳性率分别为92.31%、7.69%。胰腺癌组织中Snail表达与E-cadherin表达呈负相关（r=-0.225,P=0.025）,与vimentin表达呈正相关（r=0.493,P<0.01）;Slug表达与vimentin表达呈正相关（r=0.358,P=0.001）。Slug的表达与肿瘤分化程度及肿瘤TNM分期有关、E-cadherin的表达与淋巴结的转移与肿瘤分化程度有关、vimentin的表达与淋巴结转移、肿瘤分化程度及肿瘤TNM分期有关（均P<0.01）。 结论：Snail的高表达可能通过调控EMT过程在胰腺癌的发展过程中发挥作用,是胰腺癌浸润和转移的重要生物学指标。     

上皮-间质转化在胃肠道肿瘤中的研究进展

目的 介绍上皮-间质转化(EMT)在胃肠道肿瘤中的研究现状.方法 收集近年来国内、外有关EMT及其调节因子与胃肠道肿瘤关系的文献并作综述.结果 EMT是胚胎发育的一个基本过程,在成熟上皮细胞中EMT的异常激活可以降低细胞间黏附分子表达进而促进肿瘤的转移.上皮细胞表面标志物E-钙黏素表达抑制和EMT发生密切相关,E-钙黏素转录抑制因子可能在调节EMT过程中起重要作用,并且这些转录抑制因子在胃肠道肿瘤中呈明显高表达.此外,EMT的发生可能在胃肠道肿瘤干细胞形成过程中起重要作用.结论 EMT及其调节因子在胃肠道肿瘤发生、侵袭和转移过程中起了重要作用,对于EMT及其调节因子的研究可以为肿瘤发生机理提供新的视角,为肿瘤治疗提供新的靶点.     

上皮间质转化在前列腺癌中的研究进展

前列腺癌（PCa）是一种最常见的恶性肿瘤,据2010年美国癌症协会估计每年新发病例在各种肿瘤中最多,死亡率仅次于肺癌。未发生远处转移的PCa患者的5年生存率已接近100％,但是,发生转移的PCa患者的预后很差。因此研究肿瘤转移的机制尤其是肿瘤细胞如何从原位脱离就显得非常重要。在本文中,我们将讨论目前最流行的转移机制上皮间质转化的作用及其在PCa转移中的潜在作用。我们也将进一步讨论了间质上皮转化及其在肿瘤转移中的作用,最后是两者的相互作用在肿瘤转移全过程中的作用。     

上皮间质转化在结直肠癌侵袭转移中的作用机制

上皮间质转化是在一定的微环境中,上皮细胞向间质细胞转化的现象,从而获得间质细胞不易黏附、运动能力增强、抗凋亡等特性.在胚胎发育和肿瘤发展过程中均发现上皮细胞向间质细胞转化的现象.研究表明,上皮间质转化在结直肠癌侵袭转移过程中发挥着重要作用,其作用机制涉及多种信号通路和相关分子.     

上皮-间质转化及其调控基因Snail在肿瘤侵袭转移中的作用

上皮间质转化(EMT)和锌指转录因子Snail在肿瘤的侵袭和远处转移过程中起重要作用。笔者就两者在肿瘤侵袭转移中的作用结合文献进行综述。     

上皮-间质转化在肝癌非手术治疗后促进残癌侵袭、转移的研究进展

上皮-间质转化(EMT)以上皮表型的缺失伴随上皮间质特性的获得为主要特征。上皮-间质转化现象与肝癌非手术治疗后残癌的侵袭、转移能力增加关系密切。本文对近年来有关EMT在各种肝癌非手术治疗后,促进残癌侵袭、转移的研究进展进行综述。     

有氧糖酵解和上皮-间充质转化在肿瘤转移机制中的作用

有氧糖酵解是恶性肿瘤的特征之一,该能量代谢方式的改变可缩短供能周期,提高供能速率,而葡萄糖不完全氧化导致的中间产物富余又能使肿瘤细胞从中获益。上皮-间充质转化(EMT)则作为介导肿瘤侵袭转移的初始步骤,期间常伴有各种标志蛋白和转录因子的改变。此外,有氧糖酵解除了为肿瘤细胞供给能量,还可以通过该过程中的限速酶和创造肿瘤微...     

Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer.     

肿瘤干细胞与胃肠道癌发生和转移

目的 介绍肿瘤干细胞在胃肠道肿瘤发生和转移中的研究进展.方法 收集国内、外近年来有关肿瘤干细胞与胃肠道肿瘤发生与转移的研究进展的文献并作综述. 结果近年来的研究已发现在肿瘤细胞中存在着少量的具有干细胞样特性的肿瘤细胞.这些肿瘤干细胞利用机体的干细胞-巢系统而在肿瘤的发生、维持生长、增殖、转移和复发中起着重要作用.此外,在耐受抗肿瘤药物而导致的复发中发挥重要作用.在胃肠道肿瘤中,特别是在结直肠癌中,这些肿瘤起始细胞通常具有CD133+的特征.CD133+结肠癌细胞具有克隆形成能力、增殖能力、分化能力以及转移瘤形成能力.同时,在骨转移患者的外周血中也已发现有高含量的CD133 mRNA存在.结论 CD133+肿瘤细胞的分子生物学特性以及肿瘤干细胞-巢系统的机理是开发更有效的肿瘤诊治方法的基础,并为靶向治疗等新途径提供理论依据.     

Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model

Epithelial mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Transforming growth factor beta (TGF-β) is associated with this malignancy by having the ability to induce EMT. Metformin, has been shown to inhibit EMT in breast cancer cells. Based on this evidence we hypothesize that treatment with metformin and the silencing of TGF-β, inhibits the EMT in cancer cells. Canine metastatic mammary tumor cell line CF41 was stably transduced with a shRNA-lentivirus, reducing expression level of TGF-β1. This was combined with metformin treatment, to look at effects on cell migration and the expression of EMT markers. For in vivo study, unmodified or TGF-β1sh cells were injected in the inguinal region of nude athymic female mice followed by metformin treatment. The mice’s lungs were collected and metastatic nodules were subsequently assessed for EMT markers expression. The migration rate was lower in TGF-β1sh cells and when combined with metformin treatment. Metformin treatment reduced N-cadherin and increased E-cadherin expression in both CF41 and TGF-β1sh cells. Was demonstrated that metformin treatment reduced the number of lung metastases in animals bearing TGF-β1sh tumors. This paralleled a decreased N-cadherin and vimentin expression, and increased E-cadherin and claudin-7 expression in lung metastases. This study confirms the benefits of TGF-β1 silencing in addition to metformin as potential therapeutic agents for breast cancer patients, by blocking EMT process. To the best of our knowledge, we are the first to report metformin treatment in cells with TGF-β1 silencing and their effect on EMT.     

Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer

Matrix metalloproteinases (MMPs) degrade and modify the extracellular matrix (ECM) as well as cell-ECM and cell-cell contacts, facilitating detachment of epithelial cells from the surrounding tissue. MMPs play key functions in embryonic development and mammary gland branching morphogenesis, but they are also upregulated in breast cancer, where they stimulate tumorigenesis, cancer cell invasion and metastasis. MMPs have been investigated as potential targets for cancer therapy, but clinical trials using broad-spectrum MMP inhibitors yielded disappointing results, due in part to lack of specificity toward individual MMPs and specific stages of tumor development. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells take on the characteristics of invasive mesenchymal cells, and activation of EMT has been implicated in tumor progression. Recent findings have implicated MMPs as promoters and mediators of developmental and pathogenic EMT processes in the breast. In this review, we will summarize recent studies showing how MMPs activate EMT in mammary gland development and in breast cancer, and how MMPs mediate breast cancer cell motility, invasion, and EMT-driven breast cancer progression. We also suggest approaches to inhibit these MMP-mediated malignant processes for therapeutic benefit.     

Dendritic Cells Coinjected with Tumor Cells Treated with an Anticancer Drug to Induce Tumor Rejection

Purpose: We examined whether bone marrow-derived dendritic cells (DCs) could induce antitumor immunity when a chemotherapeutic drug was added. Methods: CT26 (a murine colon cancer cell line syngeneic with BALB/c) and CT26-bearing mice were treated with mitomycin C (MMC) intraperitoneally (i.p.). Next, mice immunized with a coinjection of DCs and MMC-treated CT26 (i.p.) were given an intradermal inoculation of CT26. Finally, CT26-bearing mice were treated with MMC (i.p.) with or without DCs, given peritumorally. Results: Although the inoculated tumor was not rejected in the control mice, CT26 was rejected in 50% of the mice injected with MMC alone. Apoptosis was observed in the MMC-treated CT26 cells in vitro and in vivo. Immunization with DCs and apoptotic CT26 cells, but not with apoptotic CT26 alone, gave protection against tumor challenge in 7 of 13 mice. A significantly higher level of cytotoxic T-cell activity and interferon-γ production was seen in the protected mice. When MMC (i.p.) treatment was followed by peritumoral DC injection in the CT26-bearing mice, remarkable therapeutic effects were observed. Conclusion: DCs can collaborate with chemotherapy-induced apoptotic tumor cells and elicit improved antitumor immunity, probably through the acquisition of tumor-associated antigens from apoptotic tumor cells. Received: January 7, 2002 / Accepted: September 3, 2002 Acknowledgments. We thank Dr. Kazuo Kinoshita for his useful advice on using flow cytometry. This research was partly supported by the Ministry of Education, Culture, Sports, Science and Technology (No. 11671160). Reprint requests to: S. Yamasaki     

SnoN as a Key Regulator of the High Glucose-Induced Epithelial-Mesenchymal Transition in Cells of the Proximal Tubule

Background/Aims: Ski-related protein N (SnoN) suppression is essential to transforming growth factor-β1 induction and the epithelial-mesenchymal transition (EMT) in several cancer cells. The role of SnoN in diabetic nephropathy is unknown. We aimed to determine the role of SnoN in the EMT of proximal tubule cells (PTCs) maintained under high glucose conditions. Methods: Immunohistochemistry, immunocytochemistry, Western blotting, small interfering RNA gene silencing, viral transduction and RT-PCR were used to assess changes in SnoN, E-cadherin, cytokeratin-18, α-smooth muscle actin and fibronectin expression using an in vivo streptozotocin-induced rat diabetic nephropathy model, and PTCs exposed to high glucose (25 mmol/l). Results: High glucose induced EMT in vitro and in vivo. Exposure of PTCs to a high concentration of glucose suppressed SnoN expression in a time-dependent manner compared with normal glucose and high osmolarity-treated groups. SnoN gene silencing under high glucose conditions appears to enhance the transition of PTC phenotype. Conversely, ectopic expression of exogenous SnoN after transfection conferred tubular epithelial cell resistance to high glucose-induced EMT. Conclusion: SnoN plays a negative role in high glucose-induced EMT in PTCs. The effect of SnoN downregulation in vivo and in vitro suggests that SnoN may be a potential therapeutic target.     

Sirolimus Attenuates Calcineurin Inhibitor-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

BackgroundCalcineurin inhibitors (CNIs), which are potent immunosuppressants (ISs), increase the risk for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LTx). Epithelial-mesenchymal transition (EMT) is a key process in which epithelial cancer cells lose their polarity, resulting in cancer progression and metastasis. The aim of this study was to evaluate the effect of sirolimus (SRL) individually and in combination with other ISs to reduce EMT.MethodsHCC SK-Hep1 cells were used and various ISs (SRL, tacrolimus, cyclosporine A, or mycophenolate mofetil) were administered at 2 dosages and in combination therapies. Mice were transplanted with SK-Hep1 cells (in the liver) and were monitored after 2 weeks.ResultsThe in vitro treatment with SRL showed a dose-dependent attenuation of cell proliferation and migration in case of the individual and IS combination treatments; further, decreased levels of pro-EMT proteins, namely, N-cadherin, transforming growth factor-β, ZEB1, Slug, and Snail were observed. In contrast, E-cadherin expression was upregulated after both the individual and IS combination treatments. These results were also observed in the samples from mice transplanted with the SK-Hep1 cells.ConclusionThe present study demonstrated that SRL reduced HCC metastasis by inhibiting EMT. Thus, our findings provide a rationale for the use of SRL in combination with ISs in HCC LTx patients.