Department of Medical Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, 92-216 Lodz, Poland.
Department of Medical Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, 92-216 Lodz, Poland.
Biochim Biophys Acta Mol Cell Res. 2017 Dec;1864(12):2283-2296. doi: 10.1016/j.bbamcr.2017.09.004. Epub 2017 Sep 8.
Increasing evidence indicates that the tumor microenvironment is a critical factor supporting cancer progression, chemoresistance and metastasis. Recently, cancer-associated fibroblasts (CAFs) have been recognized as a crucial tumor stromal component promoting cancer growth and invasiveness via modulation of the extracellular matrix (ECM) structure, tumor metabolism and immune reprogramming. One of the main sources of CAFs are endothelial cells undergoing the endothelial-mesenchymal transition (EndMT). EndMT is mainly promoted by the Transforming Growth Factor-β (TGF-β) family secreted by tumor cells, though the role of particular members in EndMT regulation remains poorly understood. Our findings demonstrate that TGF-β2 induces mesenchymal transdifferentiation of human microvascular endothelial cells (HMEC-1 cells) to CAF-like cells in association with elongated cell morphology, modulation of stress fiber organization, higher α-SMA protein levels and activation of RhoA and Rac-1 pathways. Such regulation is similar to that observed in cells maintained using conditioned medium from invasive colorectal cancer cell line culture. Furthermore, TGF-β2 stimulation resulted in myocardin-related transcription factor (MRTF) activation and upregulation. Our results demonstrate for the first time that such interaction is sufficient for integrin-linked kinase (ILK) overexpression. ILK upregulation also enhanced MRTF activation via RhoA and Rac-1-MMP9 via inside-out integrin activation. Herein, we propose a new ILK-MMP9-MRTF axis that appears to be critical for EndMT differentiation of endothelial to CAF-like cells. Thus, it might be an attractive target for cancer treatment.
越来越多的证据表明，肿瘤微环境是支持癌症进展、化疗耐药和转移的关键因素。最近，癌相关成纤维细胞（CAF）已被认为是一种关键的肿瘤基质成分，通过调节细胞外基质（ECM）结构、肿瘤代谢和免疫重编程来促进肿瘤生长和侵袭。CAF 的主要来源之一是内皮细胞经历内皮-间充质转化（EndMT）。EndMT 主要由肿瘤细胞分泌的转化生长因子-β（TGF-β）家族促进，尽管特定成员在 EndMT 调节中的作用仍知之甚少。我们的研究结果表明，TGF-β2 诱导人微血管内皮细胞（HMEC-1 细胞）向 CAF 样细胞的间充质转化，伴随细胞形态拉长、应力纤维组织调节、α-SMA 蛋白水平升高和 RhoA 和 Rac-1 通路的激活。这种调节类似于在含有侵袭性结直肠癌细胞系培养的条件培养基中维持的细胞中观察到的调节。此外，TGF-β2 刺激导致肌球蛋白相关转录因子（MRTF）的激活和上调。我们的研究结果首次表明，这种相互作用足以导致整合素连接激酶（ILK）的过度表达。ILK 的上调还通过 RhoA 和 Rac-1-MMP9 通过整合素的内-外激活增强了 MRTF 的激活。在此，我们提出了一个新的 ILK-MMP9-MRTF 轴，它似乎对内皮细胞向 CAF 样细胞的 EndMT 分化至关重要。因此，它可能是癌症治疗的一个有吸引力的靶点。
