肿瘤相关中性粒细胞（TANs）及其所产生的中性粒细胞弹性蛋白酶（NE）在肿瘤发生发展中起重要作用，NE是中性粒细胞胞外陷阱（NETs）的主要成分之一，NETs可在感染、癌症等情况下形成，并促进这些疾病的发展，但NE在NETs中的关键作用尚需证实。近年来发现TGF-β1可以促使TANs的N1型（抗肿瘤）向促肿瘤的N2极化（NE由N2型分泌），机制不明。我们前期发现几种天然产物，包括ZX-1201（三萜类）与西维来司钠（NE抑制剂）均能抑制NE的活性；ZX-1201并能逆转TGF-β1诱导肿瘤细胞的生长和迁移，分子对接显示其可直接与TβRI受体以及NE结合。本研究将比较ZX-1201与西维来司钠抑制肿瘤生长、转移作用的差异，包括它们调节TANs表型极化的作用及可能的机制；它们对NE的抑制作用；NE在NETs中的贡献；以及它们对NE上下游分子的调节及信号网络，为发展新的抗肿瘤药物提供线索和思路。

Tumor associated neutrophils (TANs) and their produced neutrophil elastase (NE) play an important role in tumor development. NE is one of the main components of neutrophil extracellular traps (NETs) , NETs can be formed in cases of infection, cancer etc., and to promote the development of these diseases, but the key role of NE in NETs needs to be confirmed. In recent years, TGF-β1 has been found to facilitate the polarization of TANs from type N1 (anti-tumor) to N2 (tumor-promoting, NE can be secreted by N2), but the mechanism is unknown. We previously found that several natural products including ZX-1201 (a single compound of triterpenes) like sivelestat (NE inhibitor) could significantly inhibit NE activities. Moreover, ZX-1201 could significantly reverse the TGF-β1 induced cancer cell growth, migration and cancer metastasis. Molecular docking showed that it could directly bind with TβRI and NE respectively. Based on our previous works, in this proposed study, we will compare the effects of ZX1201 and sivelestat on cancer growth and metastasis, including their role in regulating phenotypic polarization of TANs and their possible mechanisms; their inhibitory effect on NE, and the contribution of NE on the formation of NETs; the regulatory effect of both compounds on NE and on the upstream or downstream molecules of NE and potential signaling network. We hope our results can provide clues and experimental evidences for the development of new anti-cancer drugs.