title: Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF(V600E).
abstract: Cachexia is the result of complex metabolic alterations which cause morbidity and mortality in patients with advanced cancers including undifferentiated (anaplastic) thyroid carcinoma (ATC). ATC is a lethal disease with limited therapeutic options and unclear etiology for cachexia. We hypothesize that the BRAF(V600E) oncoprotein triggers microvascular endothelial cell tubule formation (in vitro angiogenesis) by means of factors which play a crucial role in angiogenic switch, inflammation/immune response and cachexia. We use human ATC cells and applied multiplex ELISA assay to screen for and measure angiogenic/cachectic and pro-inflammatory factors in the ATC-derived secretome. We find that vemurafenib anti-BRAF(V600E) therapy significantly reduces secreted VEGFA, VEGFC and IL6 protein levels compared to vehicle-treated ATC cells. As a result, the secretome from vemurafenib-treated ATC cells inhibits microvascular endothelial cell-related in vitro angiogenesis. Furthermore, ATC clinical samples express VEGFA, VEGFC and IL6 proteins. Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAF(V600E)-positive human ATC aggressiveness. Understanding the extent to which microenvironment-associated angiogenic factors participate in cachexia and cancer metabolism in advanced thyroid cancers will reveal new biomarkers and foster novel therapeutic approaches.
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA.
authors.forename: Amjad
authors.initials: A
authors.lastname: Husain
authors.affiliation: Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Sadow
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA; Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: cnucera@bidmc.harvard.edu.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Nucera
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism*; D002100:Cachexia / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D009154:Mutation; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D065646:Thyroid Carcinoma, Anaplastic / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D013964:Thyroid Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D000077484:Vemurafenib
chemical_list: D042501:Angiogenic Proteins; D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; D020738:Leptin; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C467484:VEGFA protein, human; C467486:VEGFC protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Anaplastic thyroid cancer; Angiogenesis; BRAF(V600E); Cachexia; Cytokines; Inflammation