Abstract
Abstract
Angiogenesis is a key process in tumor propagation, progression, and metastasis. This process is tightly modulated by a wide range of growth factors, receptor tyrosine kinases, cytokines, matrix metalloproteinases, and transcription factors. Distinctively, vascular endothelial growth factor (VEGF) and their receptors have been identified as prominent stimulators of tumor angiogenesis. Therefore, inhibiting VEGF-induced tumor angiogenesis has been explored extensively for cancer therapy. In this context, F16, a novel small molecule possessing a unique molecular configuration to block VEGFR2, has been subjected to intensive preclinical investigations. The F16 molecule exhibits in vitro antiangiogenic activity via inhibiting endothelial cell proliferation, migration, and tube formation. In addition, F16 was found to significantly inhibit the in vivo angiogenesis in chick chorioallantoic membranes as well as in athymic nude mice with xenograft tumors. As a consequence of the antiangiogenic effects, F16 was able to effectively control the tumor growth in mice with xenograft tumors. In the present study, we aimed to comprehensively interrogate the impact of F16 treatment on the expression of a panel of angiogenesis-related genes to gain insight into the underlying molecular mode of action. We analyzed the expression of 84 genes that are known to be associated with angiogenesis in human umbilical vein endothelial cells (HUVECs). Our pilot study identified upregulation of some key genes in response to F16 treatment which include tissue inhibitor of metalloproteinase 1 (TIMP1), angiopoietin-like 4 (ANGPTL 4), chondromodulin 1 (LECT 1), and placenta growth factor (PIGF). On the other hand, several genes involved in promoting angiogenesis were downregulated, which include matrix metallopeptidase 9 (MMP9), integrin subunit beta 3 (ITGβ 3), insulin growth factor 1 (IGF 1), transforming growth factor alpha (TGF α), interleukin 6 (IL 6), leptin (LEP), thrombospondin -1, -2 (THBS -1, -2), tyrosine kinase (TEK), VEGF B and C. The differential genes expression related to pro- and anti-angiogenic growth factors coincide very well with our previous observation of F16 inhibiting endothelial cell proliferation, migration and tube formation. Based on the Gene Expression Profile (GEP) observed in our experiments, we speculate that F16 can induce TIMP1 which in turn could suppress the MMP9 signaling leading to the inhibition of endothelial cell migration. This disruption of TIMP1/MMP9 pathway offers an interesting foundation for functional studies that can be performed to confirm the role of F16 as a potential MMP9 inhibitor, which may provide extended benefits during the use of this drug for treating highly metastatic cancers. (This project was supported by The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida).
Citation Format: Khalid Alhazzani, Ali Alaseem, Thiagarajan Venkatesan, Appu Rathinavelu. Angiogenesis-related gene expression profile of a novel antiangiogenic agent F16 in human vascular endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1535. doi:10.1158/1538-7445.AM2017-1535