Liu Li, Ye Ting Hong, Han Yuan Ping, Song Hang, Zhang Yong Kui, Xia Yong, Wang Ning Yu, Xiong Ying, Song Xue Jiao, Zhu Yong Xia, Li De Liang, Zeng Jun, Ran Kai, Peng Cui Ting, Wei Yu Quan, Yu Luo Ting
Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, China.
Cell Physiol Biochem. 2014;33(3):633-45. doi: 10.1159/000358640. Epub 2014 Mar 4.
AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment.
First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor.
Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4(+) and CD8(+) T-cells were significantly increased in tumor and spleens.
Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.
AZD4547是一种靶向成纤维细胞生长因子受体（FGFRs）酪氨酸激酶的小分子抑制剂，目前正处于针对乳腺癌患者的II期临床研究阶段，但其潜在机制仍不清楚。本研究旨在探讨AZD4547在肿瘤微环境水平上抑制乳腺肿瘤肺转移的潜在机制。
首先，通过体外实验，我们研究了FGFRs抑制剂AZD4547对4T1肿瘤细胞增殖、凋亡、迁移和侵袭的作用。其次，通过体内动物实验，我们评估了AZD4547对4T1荷瘤小鼠肿瘤生长和肺转移的影响。最后，我们检测了AZD4547对肺、脾、外周血和肿瘤中髓源性抑制细胞（MDSCs）浸润的影响。
通过本研究我们发现，AZD4547可通过抑制4T1肿瘤细胞的增殖、阻断其迁移和侵袭以及诱导其体外凋亡来有效抑制肿瘤细胞。在动物模型中我们还证明，AZD4547能够抑制肿瘤生长和肺转移，这分别与肿瘤和肺组织中MDSCs积累的减少相一致。此外，在接受AZD4547治疗的小鼠中，外周血和脾脏中的MDSCs数量也减少。重要的是，通过AZD4547治疗后，肿瘤和脾脏中的CD4(+)和CD8(+) T细胞显著增加。
我们的研究表明，AZD4547在体外可抑制乳腺癌细胞增殖、诱导其凋亡并阻断其迁移和侵袭，在体内可通过调节肿瘤免疫微环境来抑制肿瘤生长和肺转移。
