Epithelial-Mesenchymal Transition-Derived Cells Exhibit Multilineage Differentiation Potential Similar to Mesenchymal Stem Cells  

Abstract

Summary The epithelial-to-mesenchymal transition (EMT) is an embryonic process that becomes latent in most normal adult tissues. Recently, we have shown that induction of EMT endows breast epithelial cells with stem cell traits. In this report, we have further characterized the EMT-derived cells and shown that these cells are similar to mesenchymal stem cells (MSCs) with the capacity to differentiate into multiple tissue lineages. For this purpose, we induced EMT by ectopic expression of Twist, Snail or TGF-β in immortalized human mammary epithelial cells (HMECs). We found that the EMT-derived cells and MSCs share many properties including the antigenic profile typical of MSCs, i.e. CD44+, CD24− and CD45−. Conversely, MSCs express EMT-associated genes, such as Twist, Snail and FOXC2. Interestingly, CD140b (PDGFR-β), a marker for naive MSCs, is exclusively expressed in EMT-derived cells and not in their epithelial counterparts. Moreover, functional analyses revealed that EMT-derived cells but not the control cells can differentiate into Alizarin Red S-positive mature osteoblasts, Oil Red O-positive adipocytes and Alcian Blue-positive chondrocytes similar to MSCs. We also observed that EMT-derived cells but not the control cells invade and migrate towards MDA-MB-231 breast cancer cells similar to MSCs. In vivo wound homing assays in nude mice revealed that the EMT-derived cells home to wound sites similar to MSCs. In conclusion, we have demonstrated that the EMT-derived cells are similar to MSCs in gene expression, multi-lineage differentiation, and ability to migrate towards tumor cells and wound sites.

Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis

“…The identification of GD2 as a marker for breast CSCs is based on our recent work linking EMT-derived breast epithelial cells with bone marrow-derived multipotent MSCs (13). In support of this notion, Weissman's group recently demonstrated that CD271, another bone marrow-derived MSC marker, is also highly expressed on melanoma-initiating cells (28), suggesting that a number of cell surface markers expressed on MSCs may also be shared by CSCs from different tumor types.…”

“…We recently reported that, following the induction of EMT, human mammary epithelial cells show functional properties similar to those of human bone marrowderived MSCs (13). Therefore, we hypothesized that the cell markers expressed on the surface of MSCs could also be expressed on the surface of breast CSCs.…”

“…HMECs (also known as HMLE cells) expressing H-Ras oncogene (HMLER) were cultured as described previously (13). In brief, HMECs obtained from Clonetics were immortalized with the catalytic subunit of human telomerase and SV40 large T antigen.…”

“…The assay for GD3S was Hs00268157; the assay for GD2S was B4GALNT1; and the assay for nestin was Hs00707120_s1. qRT-PCR for E-cadherin, N-cadherin, vimentin, Snail, and Twist was performed as described before (13).…”

Twist2 contributes to breast cancer progression by promoting an epithelial–mesenchymal transition and cancer stem-like cell self-renewal

“…Yin et al (2010) reported that Twist1 may be an important regulator of stemness in epithelial ovarian cancer cells. The EMT-derived cells, which are induced by Twist1 in human mammary epithelial cells, exhibited the potential for multilineage differentiation similar to mesenchymal stem cells (Battula et al, 2010). Twist2, similar to Twist1, is a potential mediator of mesenchymal stem cell self-renewal and lineage commitment.…”