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J Natl Cancer Inst DOI:10.1093/jnci/dju182

Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment.

Publication TypeJournal Article
Year of Publication2014
AuthorsSadow, PM, Priolo, C, Nanni, S, Karreth, FA, Duquette, M, Martinelli, R, Husain, A, Clohessy, J, Kutzner, H, Mentzel, T, Carman, CV, Farsetti, A, Henske, EPetri, Palescandolo, E, MacConaill, LE, Chung, S, Fadda, G, Lombardi, CPio, De Angelis, AM, Durante, O, Parker, JA, Pontecorvi, A, Dvorak, HF, Fletcher, C, Pandolfi, PPaolo, Lawler, J, Nucera, C
JournalJ Natl Cancer Inst
Volume106
Issue8
Date Published2014 Aug
ISSN1460-2105
KeywordsAngiogenesis Inhibitors, Biomarkers, Tumor, Cell Line, Tumor, Cell Proliferation, Genotype, Glutamic Acid, Hemangiopericytoma, Humans, Indoles, Mass Spectrometry, Mutation, Neoplasm Recurrence, Local, Pericytes, Proto-Oncogene Proteins B-raf, Sulfonamides, Thyroid Neoplasms, Valine, Xenograft Model Antitumor Assays
Abstract

Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell-like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAF(WT/V600E); 33.3% (1 of 3 samples) of BRAF(WT/V600E)-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAF(WT/V600E), were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAF(WT/V600E)-positive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAF(V600E) therapy with vemurafenib disrupted angiogenic and metabolic properties (~3-fold decrease) with down-regulation (~2.2-fold decrease) of some extracellular-matrix (ECM) factors and ECM-associated long non-coding RNA (LincRNA) expression, with no effects in BRAF(WT)-pericytes. Vemurafenib also inhibited (~3-fold decrease) cell viability in vitro and in BRAF(WT/V600E)-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAF(WT/V600E)-dependent thyroid MPC cell culture. Our findings identify BRAF(WT/V600E) as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAF(V600E) agents may be useful adjuvant therapy in BRAF(WT/V600E)-MPC patients. Patients with BRAF(WT/V600E)-MPC should be closely followed because of the risk for multifocality/recurrence.

URLhttp://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25063326
DOI10.1093/jnci/dju182
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25063326?dopt=Abstract

Alternate JournalJ. Natl. Cancer Inst.
PubMed ID25063326
PubMed Central IDPMC4155429
Grant ListR01 CA181183 / CA / NCI NIH HHS / United States
T32 HL007893 / HL / NHLBI NIH HHS / United States
1R01CA181183-01A1 / CA / NCI NIH HHS / United States
1R21CA165039-01A1 / CA / NCI NIH HHS / United States