Moreover, dysregulation in signaling pathways of stem cell renewal (Wnt/β-catenin, Hedgehog and Notch pathways) may contribute to malignant transformation of normal thyroid resident cells. The existence of CSCs has been considered Celecoxib COX inhibitor in several thyroid cell lines. Mistutake et al[26] reported ability of SP cells to efflux Hoechst 33342, a DNA-binding dye. They demonstrated that SP cells

were enriched with stem-cell like characteristics. These cells were clonogenic that could give rise to both SP and non-SP cells. Additionally, SP cells showed up-regulation of “stemness” genes including those found in Notch and Wnt signaling pathways. However, both sub-population of cells (SP and non-SP cells) were tumorigenic on injection in a nude mice[26]. A research demonstrated a function role of CSCs in human ATC cell line (THJ-11T, THJ-16T, THJ-21T, THJ-29T). In their study, 3%-9% of cells formed thyrospheres expressing NANOG and Oct4 markers, which possessed the ability to self-renew. On orthotopic thyroid transplantation of thyrospheres in NOD/SCID Il2rg-/- mice, aggressive and metastatic tumors were

generated depicting that thyroid provides the niche for these thyrospheres derived cells[3]. Another such results were recently displayed by Todaro et al[8] using 3 histological variants (PTC, FTC, ATC). They demonstrated that only a small population of cells (1.2-3.5%) retains tumorigenic potential in thyroid cancer. Cells with ALDH(high) expression were associated with unlimited replication potential and self-renewing property in serum-free media with highest percentage in ATC tissues. On orthotopic thyroid injection of thyrospheres in immunodeficient mice, these cells were able to reproduce similar

phenotypic characteristics of parental tumor cells with ALDH(high) UTC spheres exhibiting cervical nodal and distant metastasis[8]. Accordingly, these results were also reported by Shimamura where their results displayed higher sphere forming ability with ALDHpos in FRO, KTC3 and ACT1 and CD326high in FRO cell lines[27]. Although PTC Batimastat accounts for majority of thyroid cancers, the data on CSCs existence in PTC cell lines is currently limited. A recent in vivo model has been designed by our group, where we described a subcutaneous mouse model of metastatic human thyroid cancer by combining human adipose-derived stromal/stem cells (ASCs) with the human mutant BRAF V600E PTC cell line K1 (Figure ​(Figure1A).1A). Over a period of six weeks, we observed development of large tumors with distant metastasis in mice that were concomitantly injected with ASCs (5 × 105 cells) and K1 cells (5 × 105 cells). About 100% of lung metastasis was identified in ASCs + K1 group (Figure ​(Figure1B)1B) compared to 40% in mice receiving only K1 cells. Tumors in ASCs + K1 were significantly larger (P < 0.