title: Generation of Novel Thyroid Cancer Stem-Like Cell Clones: Effects of Resveratrol and Valproic Acid.
abstract: Anaplastic thyroid cancer is an aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Cancer stem-like cells (CSCs) represent a small fraction of cells in the cancer that are resistant to chemotherapy and radiation therapy and are responsible for tumor reoccurrence and metastasis. We characterized CSCs in thyroid carcinomas and generated clones of CSC lines. Our study showed that anaplastic thyroid cancers had significantly more CSCs than well-differentiated thyroid cancers. We also showed that Aldefluor-positive cells revealed significantly higher expression of stem cell markers, self-renewal properties, thyrosphere formation, and enhanced tumorigenicity. In vivo passaging of Aldefluor-positive cells resulted in the growth of larger, more aggressive tumors. We isolated and generated two clonal spheroid CSC lines derived from anaplastic thyroid cancer that were even more enriched with stem cell markers and more tumorigenic than the freshly isolated Aldefluor-positive cells. Resveratrol and valproic acid treatment of one of the CSC lines resulted in a significant decrease in stem cell markers, Aldefluor expression, proliferation, and invasiveness, with an increase in apoptosis and thyroid differentiation markers, suggesting that these cell lines may be useful for discovering new adjuvant therapies for aggressive thyroid cancers. For the first time, we have two thyroid CSC lines that will be useful tools for the study of thyroid CSC targeted therapies.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Heather
authors.initials: H
authors.lastname: Hardin
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: April D
authors.initials: AD
authors.lastname: Harrison
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Carolina
authors.initials: C
authors.lastname: Larrain
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Ranran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Jidong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; Department of Surgery, University of Alabama-Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Electronic address: rvlloyd@wisc.edu.
authors.forename: Ricardo V
authors.initials: RV
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000473:pathology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D013267:Stilbenes; D014635:Valproic Acid; D000077185:Resveratrol