title: Igf-I influences everolimus activity in medullary thyroid carcinoma.
abstract: BACKGROUND
  Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells. It has been previously demonstrated that insulin-like growth factor I (IGF-I) protects MTC from the effects of antiproliferative drugs. Everolimus, an mTOR inhibitor, has shown potent antiproliferative effects in a human MTC cell line, TT, and in two human MTC primary cultures.
  
  
  OBJECTIVE
  To verify whether IGF-I may influence the effects of everolimus in a group of human MTC primary cultures.
  
  
  METHODS
  We collected 18 MTCs that were dispersed in primary cultures, treated without or with 10 nM-1 μM everolimus and/or 50 nM IGF-I. Cell viability was evaluated after 48 h, and calcitonin (CT) secretion was assessed after a 6 h incubation. IGF-I receptor downstream signaling protein expression profile was also investigated.
  
  
  RESULTS
  Everolimus significantly reduced cell viability in eight MTC [by ~20%; P < 0.01 vs. control; everolimus-responders (E-R) MTCs], while cell viability did not change in 10 MTCs [everolimus-non-responders (E-NR) MTCs]. In E-R MTCs, IGF-I blocked the antiproliferative effects of everolimus that did not affect CT secretion, but blocked the stimulatory effects of IGF-I on this parameter. IGF-I receptor downstream signaling proteins were expressed at higher levels in E-NR MTC as compared to E-R MTCs.
  
  
  CONCLUSIONS
  IGF-I protects a subset of MTC primary cultures from the antiproliferative effects of everolimus and stimulates CT secretion by an mTOR mediated pathway that, in turn, may represent a therapeutic target in the treatment of aggressive MTCs.
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy ; Laboratorio in rete del Tecnopolo "Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara , Ferrara , Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Gentilin
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy.
authors.forename: Carmelina
authors.initials: C
authors.lastname: Di Pasquale
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Tagliati
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gagliano
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova , Padova , Italy.
authors.forename: Mariarosa
authors.initials: M
authors.lastname: Pelizzo
authors.affiliation: Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova , Padova , Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Merante Boschin
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy ; Laboratorio in rete del Tecnopolo "Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara , Ferrara , Italy.
authors.forename: Ettore C
authors.initials: EC
authors.lastname: Degli Uberti
authors.affiliation: Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara , Ferrara , Italy ; Laboratorio in rete del Tecnopolo "Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara , Ferrara , Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
keywords: IGF-I; calcitonin; everolimus; mTOR; medullary thyroid carcinoma