Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer

Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.     

上皮-间充质转化与非小细胞肺癌EGFR-TKIs获得性耐药关系的研究进展

目前,表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitors,EGFR-TKIs)在非小细胞肺癌中的获得性耐药机制已经成为研究的热点,且针对相应机制治疗EGFR-TKIs获得性耐药非小细胞肺癌的药物也已被研发应用,然而部分获益的患者最终仍然出现了耐药的现象,更多未知的耐药机制仍有待研究探索.近期研究发现,上皮-间充质转化(epithelial to mesenchymal transition,EMT)也与非小细胞肺癌EGFR-TKIs获得性耐药具有—定的相关性,它是一个可诱发肿瘤细胞获得迁移和侵袭能力、促进肿瘤进展的生物学过程.因此,本文主要就EMT的发生机制、EMT与EGFR-TKIs获得性耐药相关关系的研究进展进行详细综述.     

High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells

Background

The neurotrophic receptor tropomyosin related kinase (TrkB) is associated with tumor progression in neuroblastoma and certain human malignancies. Recent reports indicate TrkB may participate in the epithelial–mesenchymal transition (EMT). This study investigates whether TrkB expression is associated with the clinical outcome of colorectal cancer (CRC) patients and whether TrkB induces EMT in CRC cells.

Methods

TrkB and E-cadherin expression in surgical tissue samples and clinicopathological data from 102 CRC patients were analyzed by real-time polymerase chain reaction and immunohistochemistry. The biological role of TrkB in CRC was analyzed using RNA interference against TrkB in the CRC cell line SW480 to assess tumor progression and the correlation between TrkB and E-cadherin expression.

Results

Patients with high TrkB mRNA expression in clinical samples had a significantly poorer prognosis relative to those with low TrkB levels (p?=?0.03). TrkB was inversely correlated with E-cadherin at both the mRNA and protein levels. In vitro, cell proliferation (p?=?0.02), migration (p?p?Conclusions High TrkB expression is associated with poor prognosis in CRC patients and enhanced malignant potential in terms of proliferation, migration, invasion, and anoikis inhibition in CRC cells. These results indicate TrkB could induce EMT and play an important role in CRC progression to metastasis.     

Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle?

The lethal consequences of prostate cancer are related to its metastasis to other organ sites. Epithelial-to-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm to explain invasive and metastatic behavior during cancer progression. EMT is a normal physiologic process by which cells of epithelial origin convert into cells bearing mesenchymal characteristics. It has been proposed that EMT is co-opted by cancer cells during their metastatic dissemination from a primary organ to secondary sites, but the extent to which this recapitulates physiologic EMT remains uncertain. However, there is ample evidence that EMT-like states occur in, and may contribute to, prostate cancer progression and metastasis, and so has become a very active area of research. Here we review this evidence and explore recent studies that have aimed to better define the role and mechanisms of EMT in prostate cancer. While definitive evidence of something akin to physiologic EMT is still lacking in human prostate cancer, this area of research has nonetheless provided new avenues of investigation into the longstanding puzzles of metastasis, therapeutic resistance, and prognostic biomarkers.     

Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: Sensitivity and resistance

Gefitinib and erlotinib, which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), are highly effective against lung tumors with EGFR activating mutations. However, in 20–30% of cases, there is intrinsic resistance, and even if the treatment is effective, resistance is acquired in one to several years. Possible mechanisms of acquired resistance to EGFR-TKI, thus far, include a gatekeeper mutation of EGFR, activation of an alternate pathway, activation of EGFR downstream signals, transformation to small cell lung cancer, and epithelial–mesenchymal transition (EMT). Recently, BIM (BCL2L11), which is a BH3-only proapoptotic member of the Bcl-2 protein family, was shown to play a central role in inducing apoptosis in response to EGFR-TKI treatment in EGFR mutant lung cancer cells. Moreover, when the expression of active BIM protein was low, there was resistance to apoptosis induction by EGFR-TKI treatment and early disease progression.A polymorphism of the BIM gene unique to East Asian people has been detected and is now attracting attention as a factor causing resistance to EGFR-TKI due to decreased BIM activity.     

活化血管内皮生长因子受体-1诱导肝癌细胞MHCC97-H上皮-间叶表型转化的实验研究

目的 探讨血管内皮生长因子受体1(VEGFR-1)促肝细胞癌(HCC)侵袭转移的作用机制.方法 用VEGFR-1的特异性配体血管内皮生长因子-B(VEGF-B)诱导活化肝癌细胞MHCC97-H,观察MHCC97-H细胞形态学改变,RT-PCR和Western blot检测MHCC97 H细胞上皮标志物钙黏蛋白(E-cad)、连环蛋白-a(a-cat)和间叶标志物波形蛋白、神经钙黏蛋白(N-cad)的mRNA和蛋白质表达改变,细胞荧光免疫组织化学法检测E-cad、a-cat和波形蛋白、N-cad表达部位改变,细胞侵袭和迁移试验检测MHCC97-H细胞侵袭和运动能力的改变.组间比较采用单因素方差分析.结果 VEGFR-1活化后MHCC97-H细胞变成梭形、纺锤状,细胞间隙增宽,有的伸出伪足;活化前上皮标志物E-cad、a-cat的mRNA吸光度值(A值)分别为12.55±2.98、14.23±1.36,活化后E-cad、a-cat的A值分别为6.78±3.66、6.18±0.92,活化后上皮标志物的mRNA表达显著下调,F=17.21,P＜0.05.活化前上皮标志物E cad、a-cat蛋白的A值分别为20 878±11.54、7520.45±8.66,活化后E cad、a-cat的A值分别为8031.23±10.44、5425.15±7.37,活化后上皮标志物的蛋白表达显著下调,F=30.49,P＜0.05.波形蛋白、Ncad mRNA的A值分别为0.72±1.77、4.46±6.50,活化后的分别为26.58±7.97、26.98±10.79,活化后间叶标志物的mRNA表达显著上调,F=26.24,P＜0.05.活化前波形蛋白、Ncad蛋白的A值分别为6100.22±12.73、1244.64±10.27,活化后的分别为12836.99±9.67、4586.70±8.58,活化后间叶标志物的蛋白表达显著上调,F=19.16,P＜0.05.上皮标志物E-cad和a-cat在胞膜表达减少,胞质中的表达增加,波形蛋白和N-cad在胞质中表达显著增加;MHCC97-H细胞运动和侵袭能力显著增强,与活化前相比,F=20.13,P＜0.05,差异有统计学意义.结论 VEGFR-1促进肝细胞癌侵袭和转移是通过诱导肝癌细胞发生上皮-间叶表型转化实现的.     

p38 MAPK和JNK信号通道在TGF-β1诱导的肺泡上皮细胞上皮-间质转化中的意义

目的 探讨p38丝裂原活化蛋白激酶（p38 MAPK）和c-Jun氨基端激酶（JNK）信号通道在转化生长因子β1 （TGF-β1）诱导的人肺泡上皮细胞上皮-间质转化（epithelial to mesenchymal transition,EMT）中的意义,从而进一步揭示肺纤维化的发病机制.方法 使用TGF-β1诱导A549细胞EMT,分别在蛋白水平（使用p38 MAPK抑制剂SB203580和JNK抑制剂SP600125）和RNA水平（RNA干扰）抑制p38 MAPK和JNK信号通道,检测抑制后A549细胞的p38 MAPK和JNK的蛋白和mRNA,以及间质细胞表型蛋白包括结蛋白、波形蛋白、α-平滑肌肌动蛋白和上皮细胞表型蛋白包括E-钙黏素、紧密连接蛋白-1、水通道蛋白-5的表达.结果 TGF-β1可以诱导A549细胞EMT,表现为间质细胞表型蛋白表达的增加和上皮细胞表型蛋白表达的减少,这一过程p38 MAPK和JNK通道表达也增加,无论蛋白水平抑制或基因沉默p38 MAPK和JNK均可减轻A549细胞的EMT.结论 p38 MAPK和JNK信号通道在TGF-β1诱导的A549细胞EMT过程中起重要作用.     

Specific glycosphingolipids mediate epithelial-to-mesenchymal transition of human and mouse epithelial cell lines

Epithelial-to-mesenchymal cell transition (EMT) is a basic process in embryonic development and cancer progression. The present study demonstrates involvement of glycosphingolipids (GSLs) in the EMT process by using normal murine mammary gland NMuMG, human normal bladder HCV29, and human mammary carcinoma MCF7 cells. Treatment of these cells with d-threo-1-(3′,4′-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4), the glucosylceramide (GlcCer) synthase inhibitor, which depletes all GSLs derived from GlcCer, (i) down-regulated expression of a major epithelial cell marker, E-cadherin; (ii) up-regulated expression of mesenchymal cell markers vimentin, fibronectin, and N-cadherin; (iii) enhanced haptotactic cell motility; and (iv) converted epithelial to fibroblastic morphology. These changes also were induced in these cell lines with TGF-β, which is a well-documented EMT inducer. A close association between specific GSL changes and EMT processes induced by EtDO-P4 or TGF-β is indicated by the following findings: (i) The enhanced cell motility of EtDO-P4-treated cells was abrogated by exogenous addition of GM2 or Gg4, but not GM1 or GM3, in all 3 cell lines. (ii) TGF-β treatment caused changes in the GSL composition of cells. Notably, Gg4 or GM2 was depleted or reduced in NMuMG, and GM2 was reduced in HCV29. (iii) Exogenous addition of Gg4 inhibited TGF-β-induced changes of morphology, motility, and levels of epithelial and mesenchymal markers. These observations indicate that specific GSLs play key roles in defining phenotypes associated with EMT and its reverse process (i.e., mesenchymal-to-epithelial transition).