Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial–mesenchymal transition-like state in breast cancer cells in vitro

Gao, Ming; Kim, Baek Gil; Kang, Suki; Choi, Yoon Young; Park, Hangran; Kang, Kyu Sub; Cho, Nam Hoon

doi:10.1242/jcs.072900

Cited by 122 publications

(117 citation statements)

References 28 publications

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“…TNC and TGF-␤ produced by the fibroblasts may be partially responsible for the EMT process of the co-culture, whereas the transcriptional alteration is caused by other substances. 50 An interaction of cancer and stromal cells in the invading border may provide a microenvironment that induces the EMT.…”

Section: Discussionmentioning

confidence: 99%

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

Nagaharu

Zhang

Yoshida

et al. 2011

The American Journal of Pathology

119

110

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Tenascin C (TNC) is an extracellular matrix glycoprotein up-regulated in solid tumors. Higher TNC expression is shown in invading fronts of breast cancer, which correlates with poorer patient outcome. We examined whether TNC induces epithelial-mesenchymal transition (EMT) in breast cancer. Immunohistochemical analysis of invasive ductal carcinomas showed that TNC deposition was frequent in stroma with scattered cancer cells in peripheral margins of tumors. The addition of TNC to the medium of the MCF-7 breast cancer cells caused EMT-like change and delocalization of E-cadherin and ␤-catenin from cell-cell contact. Although amounts of E-cadherin and ␤-catenin were not changed after EMT in total lysates, they were increased in the Triton X-100-soluble fractions, indicating movement from the membrane into the cytosol. In wound healing assay, cells were scattered from wound edges and showed faster migration after TNC treatment. The EMT phenotype was correlated with SRC activation through phosphorylation at Y418 and phosphorylation of focal adhesion kinase ( Epithelial cells are polarized and tightly interconnected by cellular junctions, whereas mesenchymal cells never form stable intercellular contacts in adult tissues. Epithelial-mesenchymal transition (EMT) is a process whereby polarized epithelial cells are converted into mesenchymal cells during embryogenesis and in diseased tissues. 1-4 EMT events also take place during tumor progression in association with invasion and metastasis, when carcinoma cells stably or transiently lose their epithelial polarity and intercellular connections, allowing them to escape the surrounding epithelium and acquire higher locomotive behavior like mesenchymal cells. 2,[5][6][7][8] Many recent studies have demonstrated that EMT is controlled by complex signaling pathways initiated from tyrosine-receptor kinases, transforming growth factor-␤ (TGF-␤) receptors, Wnt pathways, Notch pathways, and integrins, which are triggered by various extracellular signals. 2,4,9 The activated pathways, including RAS/ mitogen-activated protein kinase, phosphoinositol 3 kinase, SRC, and focal adhesion kinase (FAK), also induce cytoskeletal reorganization, causing dissociation of E-cadherin from the membrane, loss of epithelial morphology, and increased cell motility. 2,4,9,10 Expression of transcriptional regulators such as SNAI1/2 and TWIST, followed by transcriptional switching from epithelial markers to mesenchymal ones, also has been reported. 2,11,12

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Section: Discussionmentioning

confidence: 99%

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

Nagaharu

Zhang

Yoshida

et al. 2011

The American Journal of Pathology

119

110

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“…A unique example of cells which are able to provide EMT triggering signals, mostly TGF-β [19,70,71] during the whole metastatic cascade, within and outside of the primary tumor, are cancer-associated fibroblasts (CAFs). CAFs are not only part of the primary tumor niche, as CTCs were observed in heterotypic clusters with CAFs [46,72] .…”

Section: Staying Mesenchymal -Cooperation With Other Cellsmentioning

confidence: 99%

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

Markiewicz

Żaczek²

2017

Pathobiology

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The metastatic spread of cancer accounts for the vast majority of cancer-related deaths. It is mediated by tumor cells circulating in blood (called circulating tumor cells, CTCs), which escaped from their established niches. CTCs give a unique opportunity to look into the metastatic cascade and to study the molecular processes supporting the spread of tumor cells throughout the body. As current therapies are not sufficiently effective in treating metastatic disease, it is important to determine cellular and molecular features of cancer cells that “seed” new tumors in distant organs at early stages. In this review we focus on the role of the epithelial-mesenchymal transition program in providing a survival advantage to metastasizing tumor cells, especially CTCs, and put it in the context of clinical findings.

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“…There have been studies linking CAFs to chemoresistance in prostate cancer cells (38) and to epithelial-mesenchymal transition (39), which has been linked to the inhibition of anoikis through the activity of the protein NRAGE (40). However, a direct connection between CAFs and anoikis protection has yet to be conclusively demonstrated.…”

Section: Discussionmentioning

confidence: 99%

CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis

Weigel¹,

Jakimenko²,

Conti³

et al. 2014

Molecular Cancer Research

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Carcinoma-associated fibroblasts (CAFs) are now widely appreciated for their contributions to tumor progression. However, the ability of CAFs to regulate anoikis, detachment-induced cell death, has yet to be investigated. Here, a new role for CAFs in blocking anoikis in multiple cell lines, facilitating luminal filling in three-dimensional cell culture, and promoting anchorage-independent growth is defined. In addition, a novel mechanism underlying anoikis inhibition is discovered. Importantly, it was demonstrated that CAFs secrete elevated quantities of insulinlike growth factor-binding proteins (IGFBPs) that are both necessary for CAF-mediated anoikis inhibition and sufficient to block anoikis in the absence of CAFs. Furthermore, these data reveal a unique antiapoptotic mechanism for IGFBPs: the stabilization of the antiapoptotic protein Mcl-1. In aggregate, these data delineate a novel role for CAFs in promoting cell survival during detachment and unveil an additional mechanism by which the tumor microenvironment contributes to cancer progression. These results also identify IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells.

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Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial–mesenchymal transition-like state in breast cancer cells in vitro

Cited by 122 publications

References 28 publications

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis

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