E7130 is a novel anti-cancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAFs) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry (cytometry by time-of-flight [CyTOF]) analysis, multiplex-immunohistochemical (IHC) analysis, and magnetic resonance imaging (MRI). Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGF-β1 production, a precursor of TGF-β1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGF-β1 in plasma. To our best knowledge this is the first report to show a reduction of TGF-β1 production in TME. Furthermore, Multiplex-IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a non-invasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers.

中文翻译：

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使用 E7130 通过血管重塑和 CAF 抑制改善肿瘤促进微环境：通过多模态成像方式进行生物标志物分析

E7130 是一种新型抗癌药物，通过天然化合​​物去甲软海绵素 B 的全合成研究而产生。除了抑制微管动力学外，E7130 还通过抑制癌症相关成纤维细胞 (CAF) 来改善肿瘤微环境 (TME) 的促肿瘤作用并促进肿瘤脉管系统的重塑。在这里，我们使用多种成像方式证明了 E7130 对 TME 的改善作用，包括多重质谱流式细胞术（飞行时间细胞术 [CyTOF]）分析、多重免疫组织化学 (IHC) 分析和磁共振成像 (MRI)。使用 E7130 治疗以 TME 中存在大量 CAF 为特征的实验性实体瘤。E7130 在 CAF 中抑制 LAP-TGF-β1（TGF-β1 的前体）的产生，但在癌细胞中则不然；这种效应伴随着血浆中循环 TGF-β1 的减少。据我们所知，这是第一份显示 TME 中 TGF-β1 产量减少的报告。此外，多重 IHC 分析显示，E7130 处理的异种移植物中细胞结构减少，TUNEL 阳性凋亡细胞增加。在 TME 中还观察到微血管密度 (MVD) 和胶原蛋白 IV (Col IV) 增加，胶原蛋白 IV 是一种与内皮细胞相关的细胞外基质 (ECM) 成分，并且 E7130 治疗也增加了血浆 Col IV 水平。MRI 显示异种移植物中造影剂的积累增加。此外，E7130 治疗后的弥散加权 MRI 显示肿瘤细胞结构和间质液压力减少。总体而言，我们的研究结果强烈支持 E7130 以治疗有益的方式改变 TME 的作用机制。重要的是，从转化的角度来看，我们的数据证明 MRI 作为一种非侵入性生物标志物，可以检测 E7130 对 TME 的改善，并得到血浆生物标志物一致变化的支持。