title: RET mutation and increased angiogenesis in medullary thyroid carcinomas.
abstract: Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors.
authors.affiliation: Department of Internal Medicine and Medical Specialties'Sapienza' University of Rome, Rome, Italy antonella.verrienti@uniroma1.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.affiliation: Department of Medicine (DIMES)Anatomic Pathology-Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.affiliation: Department of Diagnostics and Public HealthUniversity and Hospital Trust of Verona, Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Colato
authors.affiliation: Laboratoire de Recherche Translationnelle etCentre de Ressources Biologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Boichard
authors.affiliation: Laboratory of Molecular PathologyDepartment of Medico-Surgical and Biotechnology, 'Sapienza' University of Rome, Latin, Italy.
authors.forename: Saula
authors.initials: S
authors.lastname: Checquolo
authors.affiliation: Department of Internal Medicine and Medical Specialties'Sapienza' University of Rome, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pecce
authors.affiliation: Department of Internal Medicine and Medical Specialties'Sapienza' University of Rome, Rome, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.affiliation: Department of Internal Medicine and Medical Specialties'Sapienza' University of Rome, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rosignolo
authors.affiliation: Department of Pharmacology and Biotechnology (FaBiT)University of Bologna, Bologna, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: de Biase
authors.affiliation: Department of Medicine (DIMEC)Medical Genetics Unit, University of Bologna School of Medicine, Bologna, Italy.
authors.forename: Kerry
authors.initials: K
authors.lastname: Rhoden
authors.affiliation: Anatomic Pathology UnitAUSL di Bologna-Maggiore Hospital, Bologna, Italy.
authors.forename: Gian Piero
authors.initials: GP
authors.lastname: Casadei
authors.affiliation: Department of Health SciencesUniversity of Catanzaro 'Magna Graecia', Catanzaro, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.affiliation: Department of Medicine (DIMES)Anatomic Pathology-Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Bologna, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Visani
authors.affiliation: Department of Medicine (DIMES)Anatomic Pathology-Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Bologna, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Acquaviva
authors.affiliation: Department of Diagnostics and Public HealthUniversity and Hospital Trust of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ferdeghini
authors.affiliation: Department of Internal Medicine and Medical Specialties'Sapienza' University of Rome, Rome, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
authors.affiliation: Department of Internal Medicine and Medical Specialties'Sapienza' University of Rome, Rome, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
mesh_terms: D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055806:Microvessels; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; C581309:FLT4 protein, human; C000588866:KDR protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: RET mutations; angiogenesis; medullary thyroid cancer; pericyte