title: Inhibition of Metastatic Potential in Breast Carcinoma In Vivo and In Vitro through Targeting VEGFRs and FGFRs.
abstract: Angiogenesis and lymphangiogenesis are considered to play key roles in tumor metastasis. Targeting receptor tyrosine kinases essentially involved in the angiogenesis and lymphangiogenesis would theoretically prevent cancer metastasis. However, the optimal multikinase inhibitor for metastasis suppression has yet to be developed. In this study, we evaluated the effect of NSTPBP 0100194-A (194-A), a multikinase inhibitor of vascular endothelial growth factor receptors (VEGFRs)/fibroblast growth factor receptors (FGFRs), on lymphangiogenesis and angiogenesis in a mammary fat pad xenograft model of the highly invasive breast cancer cell line 4T1-Luc(+). We investigated the biologic effect of 194-A on various invasive breast cancer cell lines as well as endothelial and lymphatic endothelial cells. Intriguingly, we found that 194-A drastically reduced the formation of lung, liver, and lymph node metastasis of 4T1-Luc(+) and decreased primary tumor growth. This was associated with significant reductions in intratumoral lymphatic vessel length (LVL) and microvessel density (MVD). 194-A blocked VEGFRs mediated signaling on both endothelial and lymphatic endothelial cells. Moreover, 194-A significantly inhibited the invasive capacity induced by VEGF-C or FGF-2 in vitro in both 4T1 and MDA-MB231 cells. In conclusion, these experimental results demonstrate that simultaneous inhibition of VEGFRs/FGFRs kinases may be a promising strategy to prevent breast cancer metastasis.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan ; Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.forename: Liang-Ming
authors.initials: LM
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Lin-Hung
authors.initials: LH
authors.lastname: Wei
authors.forename: Chih-Hau
authors.initials: CH
authors.lastname: Chen
authors.forename: Tsung-Ching
authors.initials: TC
authors.lastname: Lai
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Sun
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo