The tumor microenvironment contains various components, including cancer cells, tumor vessels, and cancer-associated fibroblasts, the latter of which are comprised of tumor-promoting myofibroblasts and tumor-suppressing fibroblasts. Multiple lines of evidence indicate that transforming growth factor-β (TGF-β) induces the formation of myofibroblasts and other types of mesenchymal (non-myofibroblastic) cells from endothelial cells. Recent reports show that fibroblast growth factor 2 (FGF2) modulates TGF-β-induced mesenchymal transition of endothelial cells, but the molecular mechanisms behind the signals that control transcriptional networks during the formation of different groups of fibroblasts remain largely unclear. Here, we studied the roles of FGF2 during the regulation of TGF-β-induced mesenchymal transition of tumor endothelial cells (TECs). We demonstrated that auto/paracrine FGF signals in TECs inhibit TGF-β-induced endothelial-to-myofibroblast transition (End-MyoT), leading to suppressed formation of contractile myofibroblast cells, but on the other hand can also collaborate with TGF-β in promoting the formation of active fibroblastic cells which have migratory and proliferative properties. FGF2 modulated TGF-β-induced formation of myofibroblastic and non-myofibroblastic cells from TECs via transcriptional regulation of various mesenchymal markers and growth factors. Furthermore, we observed that TECs treated with TGF-β were more competent in promoting in vivo tumor growth than TECs treated with TGF-β and FGF2. Mechanistically, we showed that Elk1 mediated FGF2-induced inhibition of End-MyoT via inhibition of TGF-β-induced transcriptional activation of α-smooth muscle actin promoter by myocardin-related transcription factor-A. Our data suggest that TGF-β and FGF2 oppose and cooperate with each other during the formation of myofibroblastic and non-myofibroblastic cells from TECs, which in turn determines the characteristics of mesenchymal cells in the tumor microenvironment.

中文翻译：

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成纤维细胞生长因子信号通过Elk1调节转化生长因子-β诱导的肿瘤内皮细胞从内皮向成肌纤维细胞的转化。

肿瘤微环境包含各种成分，包括癌细胞，肿瘤血管和与癌症相关的成纤维细胞，后者由促进肿瘤的成纤维细胞和抑制肿瘤的成纤维细胞组成。多种证据表明，转化生长因子-β（TGF-β）诱导了成纤维细胞和内皮细胞其他类型的间充质（非肌成纤维细胞）细胞的形成。最近的报道表明，成纤维细胞生长因子2（FGF2）调节TGF-β诱导的内皮细胞间充质转化，但是在不同组成纤维细胞形成过程中控制转录网络的信号背后的分子机制仍然不清楚。在这里，我们研究了FGF2在调节TGF-β诱导的肿瘤内皮细胞（TECs）的间质转化过程中的作用。我们证明了TECs中的自身/旁分泌FGF信号抑制了TGF-β诱导的内皮细胞向成肌纤维细胞的转化（End-MyoT），从而抑制了收缩性成肌纤维细胞的形成，但另一方面，它也可以与TGF-β协同作用促进具有迁移和增殖特性的活性成纤维细胞的形成。FGF2通过各种间充质标记物和生长因子的转录调控，调节TGF-β诱导的TECs的肌成纤维细胞和非肌成纤维细胞形成。此外，我们观察到，用TGF-β处理的TECs比用TGF-β和FGF2处理的TEC更能促进体内肿瘤的生长。机械上，我们表明，Elk1通过抑制TGF-β诱导的心肌相关转录因子A对α-平滑肌肌动蛋白启动子的转录激活而介导FGF2诱导的End-MyoT抑制。我们的数据表明，在TECs形成肌成纤维细胞和非肌成纤维细胞的过程中，TGF-β和FGF2相互对抗并协同作用，这反过来又决定了肿瘤微环境中间充质细胞的特性。