Thyroid stem cells: lessons from normal development and thyroid cancer

Thomas, Dylan C.; Friedman, Stanford B.; Lin, Reigh-Yi

doi:10.1677/erc-07-0210

Cited by 48 publications

(30 citation statements)

References 53 publications

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“…This result is also consistent with our data, in which we found normal mitotic activity in TshR-KO mice at birth. Taken together, this result indicates that deletion of TshR is unlikely to have depleted a putative thyroid progenitor cell population, whose existence has not been definitively established, and whose characteristics have not been fully defined (41). However, TshR-KO cells cannot be viewed as normal, and it is possible that they may have a weaker response to the transforming effects of the oncogene because of an as yet undefined differentiation handicap, such as a block in cell cycle progression that cannot be overcome by constitutive MAPK activation.…”

Section: Discussionmentioning

confidence: 94%

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Franco¹,

Malaguarnera²,

Refetoff

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

192

198

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Mutations of BRAF are found in ∼45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf V600E /TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf V600E induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-Braf V600E /TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gsα gene in LSL-Braf V600E /TPO-Cre/Gnas-E1 fl/fl mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence.T hyroid follicular cells are among a select group of cell types, which includes other endocrine cell lineages, melanocytes, and Schwann cells, in which the second messenger cAMP helps promote DNA synthesis and cell proliferation. In thyroid cells this pathway is engaged via constitutive and ligand-induced activation of the TSH receptor (TSHR), which, however, requires concomitant activation of receptor tyrosine kinase signaling for growth to ensue (1-3). It is therefore fitting that distinct subtypes of thyroid neoplasms are associated with oncogenes encoding effectors of the TSH-TSH receptor-adenylyl cyclase pathway (i.e., TSHR and GNAS) (4, 5) or with proteins that signal along canonical receptor tyrosine kinase pathways. Thus, rearrangements of genes encoding the receptor tyrosine kinases RET or NTRK, as well as point mutations of all three RAS genes and of the serine kinase BRAF, are found in a mutually exclusive manner in papillary thyroid cancers (PTC), the most prevalent form of the disease (6-8). The activating point mutation BRAF T1799A , which encodes for BRAF V600E , is the most common genetic abnormality in papillary thyroid cancer and constitutively activates the MEK-ERK pathway. Thyroid cancers with BRAF mutations have distinctive pathological and phenotypic features: i.e., they are more frequently invasive, have highe...

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Section: Discussionmentioning

confidence: 94%

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Franco¹,

Malaguarnera²,

Refetoff

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

192

198

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“…24 They mostly divide asymmetrically to generate two different daughter cells, one identical to the mother and one more differentiated that will eventually give rise to specialised cells. This mechanism allows to maintain control over the SC pool preserving tissue homeostasis.…”

Section: Normal Thyroid Stem Cellsmentioning

confidence: 99%

“…27 SCs are usually classified into three major groups according to their development potential: embryonic SCs (ESCs), adult SCs (ASCs) and fetal SCs (FSCs). 24 The fate of SCs is influenced by specific signals coming from the microenvironment niche and can be manipulated in vitro to form differentiated lineages. ESCs represent a potential source of derived thyroid cells that have a superior predilection to mutate and hence initiate thyroid diseases.…”

Section: Normal Thyroid Stem Cellsmentioning

confidence: 99%

Normal vs cancer thyroid stem cells: the road to transformation

et al. 2015

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Recent investigations in thyroid carcinogenesis have led to the isolation and characterisation of a subpopulation of stem-like cells, responsible for tumour initiation, progression and metastasis. Nevertheless, the cellular origin of thyroid cancer stem cells (SCs) remains unknown and it is still necessary to define the process and the target population that sustain malignant transformation of tissue-resident SCs or the reprogramming of a more differentiated cell. Here, we will critically discuss new insights into thyroid SCs as a potential source of cancer formation in light of the available information on the oncogenic role of genetic modifications that occur during thyroid cancer development. Understanding the fine mechanisms that regulate tumour transformation may provide new ground for clinical intervention in terms of prevention, diagnosis and therapy.Oncogene advance online publication, 11 May 2015; doi:10.1038/onc.2015.138

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“…A link between stem and cancer cells has been claimed for tumors supposedly deriving from immature progenitors/stem cells or from formerly normal cells that have acquired stem-like properties (3). So far, cancer stem cells (CSCs) have been isolated based on the expression of specific surface molecules (4)(5)(6)(7)(8), which have been associated with aggressive and metastatic behavior and not with ''stemness'' per se.…”

Section: Introductionmentioning

confidence: 99%

Multiple Pluripotent Stem Cell Markers in Human Anaplastic Thyroid Cancer: The Putative Upstream Role of SOX2

Carina

Zito

Pizzolanti

et al. 2013

Thyroid

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Background: Anaplastic thyroid carcinoma (ATC) is a rare and aggressive endocrine tumor with highly undifferentiated morphology. It has been suggested that cancer stem cells (CSCs) might play a central role in ATC. The objectives of this study were (i) to characterize CSCs from ex vivo ATC specimens by investigating the expression of several pluripotent stem cell markers, and (ii) to evaluate in vitro drug resistance modifications after specific CSC transcription factor switch-off. Methods: In ex vivo experiments, eight formalin-fixed, paraffin-embedded ATC specimens were analyzed by reverse-transcription and real-time quantitative PCR and immunohistochemistry. In in vitro experiments using ATC SW1736 cells, the expression levels of OCT-4, NANOG, and ABCG2 and the sensitivity to either cisplatin or doxorubicin were evaluated after silencing. Results: OCT-4, KLF4, and SOX2 transcription factors and C-KIT and THY-1 stem surface antigens showed variable up-regulation in all ATC cases. The SW1736 cell line was characterized by a high percentage of stem population (10.4 -2.1% of cells were aldehyde dehydrogenase positive) and high expression of several CSC markers (SOX2, OCT4, NANOG, C-MYC, and SSEA4). SOX2 silencing down-regulated OCT-4, NANOG, and ABCG2. SOX2 silencing sensitized SW1736 cells, causing a significant cell death increase (1.8-fold) in comparison to control cells with 10 lM cisplatin (93.9 -3.4% vs. 52.6 -9.4%, p < 0.01) and 2.7 fold with 0.5 lM doxorubicin (45.8 -9.9% vs. 17.1 -3.4% p < 0.01). ABCG2 silencing caused increased cell death with both cisplatin (74.9 -1.4%) and doxorubicin treatment (74.1 -0.1%) vs. no-target-treated cells (respectively, 45.8 -1.0% and 48.6 -1.0%, p < 0.001). Conclusions: The characterization of CSCs in ATC through the analysis of multiple pluripotent stem cell markers might be useful in identifying cells with a stem-like phenotype capable of resisting conventional chemotherapy. In addition, our data demonstrate that SOX2 switch-off through ABCG2 transporter down-regulation has a major role in overcoming CSC chemotherapy resistance.

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Thyroid stem cells: lessons from normal development and thyroid cancer

Cited by 48 publications

References 53 publications

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Normal vs cancer thyroid stem cells: the road to transformation

Multiple Pluripotent Stem Cell Markers in Human Anaplastic Thyroid Cancer: The Putative Upstream Role of SOX2

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