Abstract
Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. We show that the tumorigenic capacity in thyroid cancer is confined in a small subpopulation of stem-like cells with high aldehyde dehydrogenase (ALDH(high)) activity and unlimited replication potential. ALDH(high) cells can be expanded indefinitely in vitro as tumor spheres, which retain the tumorigenic potential upon delivery in immunocompromised mice. Orthotopic injection of minute numbers of thyroid cancer stem cells recapitulates the behavior of the parental tumor, including the aggressive metastatic features of undifferentiated thyroid carcinomas, which are sustained by constitutive activation of cMet and Akt in thyroid cancer stem cells. The identification of tumorigenic and metastagenic thyroid cancer cells may provide unprecedented preclinical tools for development and preclinical validation of novel targeted therapies.
Highlights
Thyroid cancer is the most frequent endocrine malignancy with a global increasing incidence
A small population of thyroid carcinoma cells retains clonogenic capacity We measured the clonogenic activity of tumor cells freshly isolated from thyroid tumors
We found some CD133 transcripts in normal thyroid and UTC cells, clonogenic thyrosphere cultures expressed ALDH1 and CD44 at the protein level, whereas CD133 and cytokeratin 19 (CK19) were essentially negative in all the cases examined (Fig. 1C; Supplementary Fig. S1A–B)
Summary
Thyroid cancer is the most frequent endocrine malignancy with a global increasing incidence. Papillary (PTC), follicular (FTC), and anaplastic (UTC) thyroid carcinomas arise from endodermal-derived follicular cells, which represent the most abundant cellular population of the thyroid gland. PTC comprises 80% to 85% of all thyroid neoplasms, whereas FTC is the second most common thyroid cancer, accounting for approximately 10% to 15% of cases [1]. The least common (1–2%) histotype is UTC, which has a fast progression and a very poor prognosis [2, 3]. Tyrosine kinase receptors play a major role in the regulation of tumor initiation and progression [4, 5]. In response to hepatocyte growth factor/scatter factor, the Met tyrosine kinase receptor triggers intracellular signals that positively regulate cell survival differentiation and invasion [6, 7].
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