title: Molecular profiles of cancer stem-like cell populations in aggressive thyroid cancers.
abstract: A substantial proportion of patients with advanced thyroid carcinoma fail to respond to or at some point become refractory to conventional therapies. This resistance and the phenomena of thyroid cancer progression and metastasis themselves are thought to be related to tumor-cell sub-populations with stem-like properties. We isolated thyrospheres from four advanced thyroid carcinomas that were resistant to radioiodine therapy and analyzed their molecular profiles. ALDH activity and proteomic profile of main stem cell markers were used to assess stem cell properties. The TaqMan Low Density Array approach was used to evaluate the expression of several genes involved in the EMT process. The phosphorylation status of tyrosine kinase receptors (RTKs) was analyzed to identify potential markers for targeted therapies. We then investigated the effects of the EMT-inhibitor crizotinib on both cell proliferation and phosphorylation status of RTK targets. The cancer stem-like properties of a subset of cells from primary cultures of each tumor were demonstrated. A wide variability among thyrospheres arising from the four thyroid cancers in terms of ALDH activity, stem cell marker expression, and phosphoproteome profiling was present. Dysregulated expression of genes involved in the EMT was observed in all four thyrosphere lines. Treatment with crizotinib was ineffective in cancer stem-like cells, suggesting the presence of a mechanism of resistance in thyrospheres. Collectively, our data indicate that thyroid cancer stem-like populations vary markedly from tumor to tumor and require detailed molecular and biological characterization if they are to be used as the basis of "personalized" treatment of aggressive disease.
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Mariavittoria
authors.initials: M
authors.lastname: Dima
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pecce
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomopatologiche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Cira Rosaria Tiziana
authors.initials: CR
authors.lastname: Di Gioia
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.affiliation: Dipartimento di Scienze Chirurgiche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rosignolo
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, Università di Udine, Udine, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.affiliation: Dipartimento di Scienze della Salute, Università di Catanzaro "Magna Graecia", Viale Europa, 88100, Catanzaro, Italy. d.russo@unicz.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Rome, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D006801:Humans; D014411:Neoplastic Stem Cells; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D000444:Aldehyde Dehydrogenase
keywords: Cancer stem cells; Drug resistance; Epithelial-mesenchymal transition; Metastatic thyroid cancer