Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Marseille Protéomique, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
Cell Death Dis. 2021 Jun 25;12(7):649. doi: 10.1038/s41419-021-03920-4.
Endothelial-mesenchymal transition (EndMT) is an important source of cancer-associated fibroblasts (CAFs), which facilitates tumour progression. PDAC is characterised by abundant CAFs and tumour necrosis factor-α (TNF-α). Here, we show that TNF-α strongly induces human endothelial cells to undergo EndMT. Interestingly, TNF-α strongly downregulates the expression of the endothelial receptor TIE1, and reciprocally TIE1 overexpression partially prevents TNF-α-induced EndMT, suggesting that TNF-α acts, at least partially, through TIE1 regulation in this process. We also show that TNF-α-induced EndMT is reversible. Furthermore, TNF-α treatment of orthotopic mice resulted in an important increase in the stroma, including CAFs. Finally, secretome analysis identified TNFSF12, as a regulator that is also present in PDAC patients. With the aim of restoring normal angiogenesis and better access to drugs, our results support the development of therapies targeting CAFs or inducing the EndMT reversion process in PDAC.
内皮-间质转化（EndMT）是癌症相关成纤维细胞（CAFs）的重要来源，有助于肿瘤的进展。PDAC 的特点是富含 CAFs 和肿瘤坏死因子-α（TNF-α）。在这里，我们表明 TNF-α 强烈诱导人内皮细胞发生 EndMT。有趣的是，TNF-α 强烈地下调内皮受体 Tie1 的表达，而反之 Tie1 的过表达部分阻止了 TNF-α 诱导的 EndMT，表明 TNF-α 在这个过程中至少部分地通过 Tie1 调节起作用。我们还表明，TNF-α 诱导的 EndMT 是可逆的。此外，TNF-α 处理原位小鼠导致基质（包括 CAFs）的大量增加。最后，分泌组分析鉴定出 TNFSF12 作为一种调节剂，也存在于 PDAC 患者中。为了恢复正常的血管生成并更好地利用药物，我们的结果支持针对 CAFs 或诱导 PDAC 中 EndMT 逆转过程的治疗方法的开发。
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