Consequences Of Epithelial-mesenchymal Transition Research Articles

Oxidative stress drives endometrial fibrosis via TGF-β1/MAPK signaling pathway in breast cancer.

Breast cancer patients have high serum reactive oxygen species (ROS) levels, which exert toxicity on the ovary. However, it is still unclear whether tumor-derived ROS play a role in endometrial development and function in breast cancer. Breast cancer patients and healthy controls were recruited and endometrial thickness was measured by transvaginal ultrasound (TVUS). Xenograft tumors of the breast cancer cell line MDA-MB-231 in a female BALB/c nude mice model were established, and the therapeutic mechanism of vitamin C (VC) was investigated on uterine pathology invivo and the contribution of co-culture of breast cancer cell and endometrial epithelial cell on this process was examined invitro. Median thickness in endometria was lower in breast cancer patients and tumor-bearing mice compared to controls. A gene signature of uteri in tumor-bearing mice demonstrated differential expression of genes (DEGs) regulating extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT), and activation of TGF-β and MAPK signaling pathways. In addition, ROS, EMT- and ECM-related protein levels were enhanced in uteri in tumor-bearing mice, as well as in Ishikawa cells which were co-cultured with MDA-MB-231 cells compared to controls. Supplementation with VC reduced endometrial damage, inhibited the EMT process and collagen deposition, and maintained better histologic architecture of uteri in tumor-bearing mice via inactivation of the TGF-β1/p38MAPK pathway. In women with breast cancer oxidative stress in the endometrium results in a fibrotic response as a consequence of EMT. VC could alleviate endometrial fibrosis via TGF-β1/p38MAPK pathway and provide new predictive and therapeutic targets for fertility preservation in younger breast cancer patients.

In Silico Analysis of Ion Channels and Their Correlation with Epithelial to Mesenchymal Transition in Breast Cancer.

Simple SummaryBreast cancer involves changes in the healthy cells of the breast resulting in rapid and abnormal division of cells that later spread to other parts of the body through the process of metastasis, which involves epithelial mesenchymal transition (EMT). Ion channels play a significant role in the switch from epithelial to mesenchymal transition through their contributions to cellular motility, cell volume regulation and cell cycle progression. Comprehensive computational analyses were performed to understand the role of ion channels in tumor/metastatic samples of breast cancer and their correlation with EMT.Uncontrolled growth of breast cells due to altered gene expression is a key feature of breast cancer. Alterations in the expression of ion channels lead to variations in cellular activities, thus contributing to attributes of cancer hallmarks. Changes in the expression levels of ion channels were observed as a consequence of EMT. Additionally, ion channels were reported in the activation of EMT and maintenance of a mesenchymal phenotype. Here, to identify altered ion channels in breast cancer patients, differential gene expression and weighted gene co-expression network analyses were performed using transcriptomic data. Protein–protein interactions network analysis was carried out to determine the ion channels interacting with hub EMT-related genes in breast cancer. Thirty-two ion channels were found interacting with twenty-six hub EMT-related genes. The identified ion channels were further correlated with EMT scores, indicating mesenchymal phenotype. Further, the pathway map was generated to represent a snapshot of deregulated cellular processes by altered ion channels and EMT-related genes. Kaplan–Meier five-year survival analysis and Cox regressions indicated the expression of CACNA1B, ANO6, TRPV3, VDAC1 and VDAC2 to be potentially associated with poor survival. Deregulated ion channels correlate with EMT-related genes and have a crucial role in breast cancer-associated tumorigenesis. Most likely, they are potential candidates for the determination of prognosis in patients with breast cancer.

Human lung epithelial BEAS-2B cells exhibit characteristics of mesenchymal stem cells

BEAS-2B was originally established as an immortalized but non-tumorigenic epithelial cell line from human bronchial epithelium. Because of general recognition for its bronchial epithelial origin, the BEAS-2B cell line has been widely used as an in vitro cell model in a large variety of studies associated with respiratory diseases including lung carcinogenesis. However, very few studies have discussed non-epithelial features of BEAS-2B cells, especially the features associated with mesenchymal stem cells (MSCs), which represent a group of fibroblast-like cells with limited self-renewal and differentiation potential to various cell lineages. In this study, we compared BEAS-2B with a human umbilical cord-derived MSCs (hMSCs) cell line, hMSC1, which served as a representative of hMSCs in terms of expressing common features of hMSCs. It was observed that both BEAS-2B and hMSC1 shared the same expression profile of surface markers of hMSCs and exhibited similar osteogenic and adipogenic differentiation potential. In addition, like hMSC1, the BEAS-2B cell line exhibited suppressive activities on proliferation of mitogen-activated total T lymphocytes as well as Th1 lymphocytes, and IFNγ-induced expression of IDO1, all thus demonstrating that BEAS-2B cells exhibited an almost identical characteristic profile with hMSCs, even though, there was a clear difference between BEAS-2B and hMSCs in the effects on type 2 macrophage polarization. Most importantly, the hMSCs features of BEAS-2B were unlikely a consequence of epithelial-mesenchymal transition. Therefore, this study provided a set of evidence to provoke reconsideration of epithelial origin of BEAS-2B.

Immunological Consequences of Epithelial-Mesenchymal Transition in Tumor Progression.

Microenvironments that tumor cells encounter are different during the stages of cancer progression-primary tumor, metastasis, and at the metastatic site. This suggests potential differences in immune surveillance of primary tumor and metastasis. Epithelial-mesenchymal transition (EMT) is a key reversible process in which cancer cells transition into highly motile and invasive cells for dissemination. Only a tiny proportion successfully metastasize, supporting the notion of metastasis-specific immune surveillance. EMT involves extensive molecular reprogramming of cells conferring many clinically relevant features to cancer cells and affects tumor cell interactions within the tumor microenvironment. We review the impact of tumor immune infiltrates on tumor cell EMT and the consequences of EMT in shaping the immune microenvironment of tumors. The usefulness of EMT as a model to investigate metastasis-specific immune surveillance mechanisms are also explored. Finally, we discuss potential implications of EMT for tumor immunogenicity, as well as current immunotherapies and future strategies.

Abstract LB-296: Allikrein 14 induces epithelial-mesenchymal transition-like changes in colon cancer cells

Abstract Accumulating evidence indicates that serine proteinase family of the kallikrein-related-peptidases (KLK1-KLK15) are deregulated in cancer and their up-regulation is often associated with poor patient prognosis. Although primarily known as cancer biomarkers, recent evidence implicates KLKs in many cancer-related processes, including cell-growth, angiogenesis, invasion and metastasis. In addition, KLKs have emerged as signalling molecules by selectively targeting members of a unique subfamily of cell surface G-protein coupled receptors termed, proteinase-activated receptors (PARs). PARs are now considered important players in the development of human colon cancer. Indeed, we have previously demonstrated that in colonic tumours, upregulated PAR-2 and aberrantly expressed PAR-1 and PAR-4 control human colon cancer cell migration and proliferation. Recently, we showed that some members of the aberrantly expressed KLKs mediate these responses by signalling of through PARs. We hypothesized that KLK14 induced-cell migration and colonic tumour invasion are the consequence of epithelial-mesenchymal transition. We focused on KLK14 for which morphological changes were observed when colon cancer cells were treated with KLK14. We found that: 1) microscopic analysis showed redistribution of perijunctional F-actin in KLK14 treated HT29 cells, a colon cancer derived adenocarcinmoma; 2) HT29 cell treatment with KLK14 induced loss of E-cadherin-mediated cell-cell adhesion; 3) Biochemical studies showed down regulation of epithelial markers and upregulation of mesenchymal markers, the molecular mechanisms involved are under investigation. These results suggest for the first time that some KLKs are key mediators of induced ETM in human colonic tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-296. doi:1538-7445.AM2012-LB-296

Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition

Fibrosis of epithelial parenchymal organs and end-stage organ failure represent the final common pathway of many chronic diseases and are a major determinant of morbidity and mortality worldwide. Fibrosis is a complex response initiated to protect the host from an injurious event; nevertheless, it leads to serious organ damage when it becomes independent from the initiating stimulus. It involves massive deposition of matrix by an expanded pool of fibrogenic cells, disruption of the normal tissue architecture, and parenchymal destruction. Fibroblasts, the effector cells of matrix production, when engaged in fibrogenesis, display the highly activated phenotype characteristic of myofibroblasts. These cells are present in a large number in sites with ongoing inflammation, reparative reaction, and fibrosis, but their origin has not yet been definitely elucidated. Although proliferation of preexisting stromal fibroblasts and, probably, recruitment of bone marrow-derived fibrogenic cells may account for a portion of them, emerging evidence seems to indicate that an important number of matrix-producing fibroblasts/myofibroblasts arises through a mechanism of epithelial-mesenchymal transition. Through this process, epithelial cells would lose intercellular cohesion and would translocate from the epithelial compartment into the interstitium where, gaining a full mesenchymal phenotype, they could participate in the synthesis of the fibrotic matrix. Epithelial-mesenchymal transition is induced by the integrated actions of many stimuli including transforming growth factor-beta and matrix-generated signals that are also known to be implicated in inflammation, repair responses, and fibrosis. The consequences of epithelial-mesenchymal transition in chronic fibrosing diseases could be two-fold as follows: on one hand, by supplementing new mesenchymal cells, it might feed the expanding pool of interstitial fibroblasts/myofibroblasts responsible for the matrix accumulation; on the other hand, it could cause loss of epithelial cells, thus, contributing to the parenchyma destruction seen in advanced fibrosis. Markers of epithelium undergoing epithelial-mesenchymal transition include loss of E-cadherin and cytokeratin; de novo expression of fibroblast-specific protein 1/S100A4, vimentin, and alpha-smooth muscle actin; basement membrane component loss; and production of interstitial-type matrix molecules such as fibronectin and type I/III collagen. Evidence of epithelial-mesenchymal transition has been reported in the kidney, lung, liver, eye, and serosal membranes suggesting that epithelial-mesenchymal transition could be involved in the pathogenesis of fibrotic disorders in these organs. Thus, because of its fibrogenic potential, the detection of epithelial-mesenchymal transition in biopsy specimens could be useful diagnostically and represent a new biomarker of progression in chronic fibrosing diseases.