E-cadherin re-expression showsin vivoevidence for mesenchymal to epithelial transition in clonal metastatic breast tumor cells

Abstract

Substantial experimental evidence has shown that dedifferentiation from an epithelial state to a mesenchymal-like state (EMT) drives tumor cell metastasis. This transition facilitates tumor cells to acquire motility and invasive features. Intriguingly, tumor cells at the metastatic site are primarily epithelial, and it is believed that they differentiate back to an epithelial state by a process called mesenchymal to epithelial transition (MET). However, there is little in vivo evidence to support the MET process. To investigate EMT and MET in vivo, we generated two epithelial (E) and two mesenchymal (M) primary clonal cell lines from a spontaneous mouse mammary tumor (Tg MMTV/neu). These cells were labeled with reporters (GFP and luciferase), and tracked in vivo during primary tumor growth and subsequent secondary metastasis. Once E cells were implanted into the mammary fat pad, E-cadherin expression progressively decreased and continued to decrease as the primary tumor enlarged over time. A greater percentage of E tumor cells expressed E-cadherin at the secondary metastatic site as compared to the corresponding primary tumor site. Collectively, these data provide direct in vivo evidence that epithelial tumor cells have metastatic potential, undergo EMT at the primary tumor site, and MET at the metastatic site.

Evaluation of a developmental hierarchy for breast cancer cells to assess risk-based patient selection for targeted treatment

“…The premise underlying this strategy is that the loss of the initiating tumor cells will cause the bulk cancer to regress. However, this strategy needs to consider the possibility that the non-CSCs/cancer progenitors may dedifferentiate into CSCs 21 , 35 , 36 . We address these problems by developing a hierarchy of BCCs since this would be needed to study if dedifferentiation occurs, and if so, identify the ease by which the particular BCC subset can dedifferentiate.…”

The exon 38-containing ARHGEF11 splice isoform is differentially expressed and is required for migration and growth in invasive breast cancer cells

“…E-cadherin is often downregulated or lost at the primary site in metastatic cancer, while metastases often re-express E-cadherin, a phenomenon which is attributed to EMT at the primary site, and reverse EMT, mesenchymal-epithelial transition, at the site of metastasis formation [ 29 – 31 ]. Our results that the forced expression of E-cadherin potentiated the growth and survival of MDA-MB-231 cells provide an experimental model in which these differential effects can be dissected, and comparison of these cells with parallel lines in which ARHGEF11exon38(+) is manipulated (Figure 6 ), provide insight into the differential effect of these two proteins on cancer cell phenotype.…”

The role of cancer-associated fibroblast MRC-5 in pancreatic cancer

“…Recently, it has been proposed that CSCs can be generated by EMT 22 , 23 , whereby epithelial cells lose their epithelial properties and acquire a mesenchymal-like phenotype and stem cell-like features 24 , 25 . Classical EMT is a dynamic and reversible program that is often activated during tumor invasion and metastasis and is characterized by the expression of EMT-inducing transcription factors, such as snail, slug, twist-1, ZEB-1, and ZEB-2; upregulation of vimentin and N-cadherin; and downregulation of E-cadherin, alpha-catenin, and P120-catenin 26 . During EMT, while front-rear polarity develops, apico-basal polarity is disrupted.…”