期刊
BMC CANCER
卷 16, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s12885-016-2225-1
关键词
Angiogenesis; Breast cancer; Choline metabolism; Cytosolic phospholipase A2; Dynamic contrast enhanced MRI; Micro-CT; Prostaglandin E2; Targeted therapy
类别
资金
- liaison committee [46056806]
- Norwegian Cancer Society [2209215]
- Research Council of Norway [239940, 228879]
- Research Council of Norway (BIA) [193203]
- Avexxin AS
- Faculty of Medicine at NTNU
- Central Norway Regional Health Authority
Background: Group IVA cytosolic phospholipase A2 (cPLA2 alpha) 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 cPLA2 alpha inhibitor, AVX235, in a patient-derived triple-negative BLBC model. Methods: Mice 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 alpha-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 (alpha = 0.05) were performed on all other data. Results: Glycerophosphocholine 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 cPLA2 alpha 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. Conclusions: These results demonstrate that cPLA2 alpha inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2 alpha inhibition may be a potential new therapeutic option for triple-negative basal-like breast cancer.
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