dc.contributor.author | Kim, Eugene | |
dc.contributor.author | Tunset, Hanna Maja | |
dc.contributor.author | Cebulla, Jana | |
dc.contributor.author | Vettukattil, Muhammad Riyas | |
dc.contributor.author | Helgesen, Heidi | |
dc.contributor.author | Feuerherm, Astrid Jullumstrø | |
dc.contributor.author | Engebråten, Olav | |
dc.contributor.author | Mælandsmo, Gunhild | |
dc.contributor.author | Johansen, Berit | |
dc.contributor.author | Moestue, Siver Andreas | |
dc.date.accessioned | 2016-09-07T08:45:39Z | |
dc.date.accessioned | 2016-09-09T08:50:50Z | |
dc.date.available | 2016-09-07T08:45:39Z | |
dc.date.available | 2016-09-09T08:50:50Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | BMC Cancer 2016, 16(191) | nb_NO |
dc.identifier.issn | 1471-2407 | |
dc.identifier.uri | http://hdl.handle.net/11250/2405671 | |
dc.description.abstract | Background:
Group 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.
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 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.
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 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.
Conclusions:
These 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. | nb_NO |
dc.language.iso | eng | nb_NO |
dc.publisher | BioMed Central | nb_NO |
dc.rights | Navngivelse 3.0 Norge | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/no/ | * |
dc.title | Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model | nb_NO |
dc.type | Journal article | nb_NO |
dc.type | Peer reviewed | nb_NO |
dc.date.updated | 2016-09-07T08:45:39Z | |
dc.source.volume | 16 | nb_NO |
dc.source.journal | BMC Cancer | nb_NO |
dc.source.issue | 191 | nb_NO |
dc.identifier.doi | 10.1186/s12885-016-2225-1 | |
dc.identifier.cristin | 1341469 | |
dc.description.localcode | © Kim et al. 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | nb_NO |