Dataset Information

Tumor Endothelial Cells with Distinct Patterns of TGF?-Driven Endothelial-to-Mesenchymal Transition.

ABSTRACT: Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGF? stimulation. Although some TECs strikingly upregulate ? smooth muscle actin (SMA), a principal marker of EndMT and activated myofibroblasts, counterpart normal mammary gland endothelial cells (NEC) showed little change in SMA expression after TGF? treatment. Compared with NECs, SMA(+) TECs were 40% less motile in wound-healing assays and formed more stable vascular-like networks in vitro when challenged with TGF?. Lineage tracing using ZsGreen(Cdh5-Cre) reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA(+) TECs, suggesting that not all endothelial cells (EC) respond identically to TGF? in vivo. Indeed, examination of 84 TGF?-regulated target genes revealed entirely different genetic signatures in TGF?-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGF?-regulated genes but operates in tandem with TGF? to upregulate others. ECs challenged with TGF? secrete bFGF, which blocks SMA expression in secondary cultures, suggesting a cell-autonomous or lateral-inhibitory mechanism for impeding mesenchymal differentiation. Together, our results suggest that TGF?-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature.

SUBMITTER: Xiao L

PROVIDER: S-EPMC4383705 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Tumor Endothelial Cells with Distinct Patterns of TGFβ-Driven Endothelial-to-Mesenchymal Transition.

Xiao Lin L Kim Dae Joong DJ Davis Clayton L CL McCann James V JV Dunleavey James M JM Vanderlinden Alissa K AK Xu Nuo N Pattenden Samantha G SG Frye Stephen V SV Xu Xia X Onaitis Mark M Monaghan-Benson Elizabeth E Burridge Keith K Dudley Andrew C AC

Cancer research 20150129 7

Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGFβ stimula ...[more]

PMID: 25634211

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Project description:Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-?, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-?1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, ?1-integrin, calponin and ?-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-? signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-?-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-?-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.

Dataset Information

Tumor Endothelial Cells with Distinct Patterns of TGF?-Driven Endothelial-to-Mesenchymal Transition.

Publications

Tumor Endothelial Cells with Distinct Patterns of TGFβ-Driven Endothelial-to-Mesenchymal Transition.

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