Abstract
<div>Abstract<p>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 stimulation. Although some TECs strikingly upregulate α 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 TGFβ treatment. Compared with NECs, SMA<sup>+</sup> TECs were 40% less motile in wound-healing assays and formed more stable vascular-like networks <i>in vitro</i> when challenged with TGFβ. Lineage tracing using <i>ZsGreen<sup>Cdh5-Cre</sup></i> reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA<sup>+</sup> TECs, suggesting that not all endothelial cells (EC) respond identically to TGFβ <i>in vivo</i>. Indeed, examination of 84 TGFβ-regulated target genes revealed entirely different genetic signatures in TGFβ-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGFβ-regulated genes but operates in tandem with TGFβ to upregulate others. ECs challenged with TGFβ 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 TGFβ-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature. <i>Cancer Res; 75(7); 1244–54. ©2015 AACR</i>.</p></div>
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