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dc.contributor.authorKim, Eugene
dc.contributor.authorTunset, Hanna Maja
dc.contributor.authorCebulla, Jana
dc.contributor.authorVettukattil, Muhammad Riyas
dc.contributor.authorHelgesen, Heidi
dc.contributor.authorFeuerherm, Astrid Jullumstrø
dc.contributor.authorEngebråten, Olav
dc.contributor.authorMælandsmo, Gunhild
dc.contributor.authorJohansen, Berit
dc.contributor.authorMoestue, Siver Andreas
dc.date.accessioned2016-09-09T08:23:37Z
dc.date.available2016-09-09T08:23:37Z
dc.date.issued2016-03-07
dc.description.abstract<b>Background</b> <br> 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.<br> <b>Methods</b> <br> 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. <br> <b>Results</b> <br> 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. <br> <b>Conclusions</b> <br> 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.en_US
dc.descriptionPublisher's version, source: <a href=http://doi.org/10.1186/s12885-016-2225-1>http://doi.org/10.1186/s12885-016-2225-1</a>.en_US
dc.identifier.citationBMC Cancer 2016, 16(191)en_US
dc.identifier.cristinIDFRIDAID 1341469
dc.identifier.doi10.1186/s12885-016-2225-1
dc.identifier.issn1471-2407
dc.identifier.urihttps://hdl.handle.net/10037/9654
dc.language.isoengen_US
dc.publisherBioMed Centralen_US
dc.relation.projectIDSamarbeidsorganet mellom Helse Midt-Norge og NTNU: 46056806
dc.relation.projectIDKreftforeningen: 2209215
dc.relation.projectIDNorges forskningsråd: 239940
dc.relation.projectIDNorges forskningsråd: 228879
dc.relation.projectIDNorges forskningsråd: 193203
dc.rights.accessRightsopenAccess
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762en_US
dc.subjectAngiogenesisen_US
dc.subjectBreast canceren_US
dc.subjectCholine metabolismen_US
dc.subjectCytosolic phospholipase A2en_US
dc.subjectDynamic contrast enhanced MRIen_US
dc.subjectMicro-CTen_US
dc.subjectProstaglandin E2en_US
dc.subjectTargeted therapyen_US
dc.titleAnti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer modelen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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