Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model

BMC Cancer

Research Article

Berit Johansen¹  Astrid Jullumstrø Feuerherm¹  Eugene Kim²  Heidi Helgesen²  Riyas Vettukattil²  Hanna Maja Tunset²  Jana Cebulla²  Siver Andreas Moestue²  Olav Engebråten³  Gunhild Mari Mælandsmo³ 

[1] Department of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491, Trondheim, Norway;Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491, Trondheim, Norway;Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 4953 Nydalen, 0424, Oslo, Norway;

关键词: Angiogenesis;    Breast cancer;    Choline metabolism;    Cytosolic phospholipase A2;    Dynamic contrast enhanced MRI;    Micro-CT;    Prostaglandin E2;    Targeted therapy;   

DOI  :  10.1186/s12885-016-2225-1

 received in 2015-12-14, accepted in 2016-02-28,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundGroup IVA cytosolic phospholipase A2 (cPLA2α) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti-angiogenic effects of a specific cPLA2α inhibitor, AVX235, in a patient-derived triple-negative BLBC model.MethodsMice bearing orthotopic xenografts received i.p. injections of AVX235 or DMSO vehicle daily for 1 week and then every other day for up to 19 days. Six treated and six control mice were terminated after 2 days of treatment, and the tumors excised for high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and prostaglandin E2 (PGE2) enzyme immunoassay (EIA) analysis. A 1-week imaging study was performed on a separate cohort of mice. Longitudinal dynamic contrast enhanced (DCE)-MRI was performed before, after 4 days, and after 1 week of treatment. The mice were then perfused with a radiopaque vascular casting agent, and the tumors excised for micro-CT angiography. Subsequently, tumors were sectioned and stained with lectin and for Ki67 or α-smooth muscle actin to quantify endothelial cell proliferation and vessel maturity, respectively. Partial least squares discriminant analysis was performed on the multivariate HR MAS MRS data, and non-parametric univariate analyses using Mann–Whitney U tests (α = 0.05) were performed on all other data.ResultsGlycerophosphocholine and PGE2 levels, measured by HR MAS MRS and EIA, respectively, were lower in treated tumors after 2 days of treatment. These molecular changes are expected downstream effects of cPLA2α inhibition and were followed by significant tumor growth inhibition after 8 days of treatment. DCE-MRI revealed that AVX235 treatment caused a decrease in tumor perfusion. Concordantly, micro-CT angiography showed that vessel volume fraction, density, and caliber were reduced in treated tumors. Moreover, histology showed decreased endothelial cell proliferation and fewer immature vessels in treated tumors.ConclusionsThese results demonstrate that cPLA2α inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2α inhibition may be a potential new therapeutic option for triple-negative basal-like breast cancer.

【 授权许可】

CC BY   
© Kim et al. 2016