Discovery of a natural small-molecule compound that suppresses tumor EMT, stemness and metastasis by inhibiting TGFβ/BMP signaling in triple-negative breast cancer
Discovery of a natural small-molecule compound that suppresses tumor EMT, stemness and metastasis by inhibiting TGFβ/BMP signaling in triple-negative breast cancer
复制标题
发现一种天然小分子化合物，通过抑制三阴性乳腺癌中的 TGF beta/BMP 信号传导来抑制肿瘤 EMT、干性和转移
DOI：
10.1186/s13046-019-1130-2
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发表时间：
2019-03-21
影响因子：
11.3
通讯作者：
Wu, Zhao-Qiu
中科院分区：
文献类型：
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作者：
Di, Lei;Liu, Li-Juan;Wu, Zhao-Qiu
背景资料：转化生长因子β（TGF β）和骨形态发生蛋白（BMP）信号通路在三阴性乳腺癌（TNBC）中均被组成性激活。我们有兴趣分离天然来源的小分子抑制剂，可以同时靶向TGF β/BMP通路，并进一步研究其在多种肿瘤模型中的抗增殖/转移作用以及潜在机制。使用多种基于体外细胞的测定来检查化合物对TNBC细胞生长、干性、上皮-间充质转化（EMT）、通过靶向TGF β/BMP信号传导途径的侵袭和迁移。结果：ZL 170通过特异性靶向TNBC细胞中典型的TGF β/BMP-SMADs通路，在体外呈剂量依赖性地抑制TNBC细胞的增殖、EMT、干细胞、侵袭和迁移。该化合物显著阻碍溶骨性骨转移和异种移植肿瘤生长，而对荷瘤裸鼠的重要器官没有毒性。ZL 170强烈抑制MMTV-PyMT转基因小鼠的原发性肿瘤生长和肺转移。ZL 170治疗的肿瘤在上皮和间质区室中均表现出受损的TGF β/BMP信号通路，从而产生抑制性肿瘤微环境，其特征在于细胞外基质沉积减少和间质细胞浸润减少。ZL 170抑制肿瘤EMT，并可进一步开发为一种有效的抗肿瘤药物。本发明涉及与细胞毒性药物组合用于治疗TNBC和其它晚期转移性癌症的转移性药剂。
Background: The transforming growth factor beta (TGF beta) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGF beta/BMP pathways and further studying its anti-proliferative/-metastatic effects as well as the underlying mechanisms in multiple tumor models.Methods: Multiple in vitro cell-based assays are used to examine the compound's inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGF beta/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170's effects on TNBC growth and metastasis potentials in vivo.Results: ZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGF beta/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGF beta/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells.Conclusions: ZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers.