Mesenchymal stromal cells induce epithelial‐to‐mesenchymal transition in human colorectal cancer cells through the expression of surface‐bound TGF‐β

Abstract

Mesenchymal stem/stromal cells (MSC) are multipotent precursors endowed with the ability to home to primary and metastatic tumor sites, where they can integrate into the tumor-associated stroma. However, molecular mechanisms and outcome of their interaction with cancer cells have not been fully clarified. In this study, we investigated the effects mediated by bone marrow-derived MSC on human colorectal cancer (CRC) cells in vitro and in vivo. We found that MSC triggered epithelial-to-mesenchymal transition (EMT) in tumor cells in vitro, as indicated by upregulation of EMT-related genes, downregulation of E-cadherin and acquisition of mesenchymal morphology. These effects required cell-to-cell contact and were mediated by surface-bound TGF-β newly expressed on MSC upon coculture with tumor cells. In vivo tumor masses formed by MSC-conditioned CRC cells were larger and characterized by higher vessel density, decreased E-cadherin expression and increased expression of mesenchymal markers. Furthermore, MSC-conditioned tumor cells displayed increased invasiveness in vitro and enhanced capacity to invade peripheral tissues in vivo. Thus, by promoting EMT-related phenomena, MSC appear to favor the acquisition of an aggressive phenotype by CRC cells.

MicroRNA-451 induces epithelial–mesenchymal transition in docetaxel-resistant lung adenocarcinoma cells by targeting proto-oncogene c-Myc

“…Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells, and tamoxifenresistant MCF7 breast cancer cells showed EMT characteristics with altered b-catenin phosphorylation [30,31]. Similarly, paclitaxel-resistant ovarian cancer cells displayed decreased E-cadherin expression, and increased expression of mesenchymal markers consistent with EMT phenotype [32]. Also, chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway [33].…”

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…We cannot exclude that other inflammatory cytokines secreted by MSC, such as TNFa, might potentiate TGFb effets. 46 Numerous reports underlined that through TGFb secretion MSC promote a malignant phenotype in tumor cells of different histotype 10,21 The higher level of TGFb secreted by acidic MSC does not prevent proliferation of LpH-MSC-adapted melanoma cells, a condition that might be related to SMAD/NF-kB signaling interplays, as suggested by Freudlsperger et al's findings in head and neck cancers. 32 We also found that esomeprazole, a proton pump inhibitor activated by acidic medium, inhibits TGFb of acidic MSC, which corresponds to a MET program in melanoma cells grown in LpH-esomeprazole-treated MSC medium.…”

“…4 MSC also trigger in human colorectal cancer cells an increased invasiveness, which requires a cell-to-cell contact mediated by TGFb. 10 A prooncogenic role of MSC was demonstrated in human prostate cancer cells; in particular, medium conditioned by MSC stimulates proliferation, migration and MMP-dependent invasion. 11 Thus, MSC-tumor cell interaction acquires a particular importance and further understanding of these interactions is required to determine their role in tumor progression.…”

Fatty Acids Induce Stemness in the Stromal Cells of a CT26 Mouse Tumor Model

“…This interaction is known to promote the metastatic ability of cancer cells by causing an increase in cancer stemness [2][3][4] , acquisition of the epithelial-mesenchymal transition phenotype via secretion of CXCR4, SDF-1, or TGF-β from stromal stem cells [28] , induction of regulatory T cells by stromal stem cells [2][3][4] , fusion of cancer cells with stromal stem cells [29] , and multicellular sphere formation of cancer cells and stromal cells [30] .…”