Abstract
Thyroid tumors are extremely heterogeneous varying from almost benign tumors with good prognosis as papillary or follicular tumors, to the undifferentiated ones with severe prognosis. Recently, several models of thyroid carcinogenesis have been described, mostly hypothesizing a major role of the thyroid cancer stem cell (TCSC) population in both cancer initiation and metastasis formation. However, the cellular origin of TCSC is still incompletely understood. Here, we review the principal epigenetic mechanisms relevant to TCSC origin and maintenance in both well-differentiated and anaplastic thyroid tumors. Specifically, we describe the alterations in DNA methylation, histone modifiers, and microRNAs (miRNAs) involved in TCSC survival, focusing on the potential of targeting aberrant epigenetic modifications for developing novel therapeutic approaches. Moreover, we discuss the bidirectional relationship between TCSCs and immune cells. The cells of innate and adaptive response can promote the TCSC-driven tumorigenesis, and conversely, TCSCs may favor the expansion of immune cells with protumorigenic functions. Finally, we evaluate the role of the tumor microenvironment and the complex cross-talk of chemokines, hormones, and cytokines in regulating thyroid tumor initiation, progression, and therapy refractoriness. The re-education of the stromal cells can be an effective strategy to fight thyroid cancer. Dissecting the genetic and epigenetic landscape of TCSCs and their interactions with tumor microenvironment cells is urgently needed to select more appropriate treatment and improve the outcome of patients affected by advanced differentiated and undifferentiated thyroid cancers.
Highlights
Veronica Veschi 1†, Francesco Verona 1†, Melania Lo Iacono 1†, Caterina D’Accardo 2, Gaetana Porcelli 1, Alice Turdo 2, Miriam Gaggianesi 1, Stefano Forte 3, Dario Giuffrida 3, Lorenzo Memeo 3 and Matilde Todaro 2*
This model is supported by scientific evidence, such as the presence of TP53 and BRAF mutations in differentiated and undifferentiated carcinomas, including anaplastic thyroid carcinoma (ATC) [13], but it cannot explain the presence of specific RET/papillary thyroid carcinoma (PTC) rearrangements and PAX8/PPARγ gene fusion that may occur in ATCs [14]
Thyroid cancers (TCs): (i) Thyroid-specific differentiation and tumor suppressor genes aberrantly methylated in their promoter regions along with altered expression of miRNAs represent the most frequent epigenetic features in well-differentiated thyroid tumors, as PTC and follicular thyroid carcinoma (FTC), while the amount of reports regarding the histone modifications are very limited. (ii) The most common altered epigenetic mechanisms that contribute to well-differentiated TC initiation and progression, lead to the activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival pathways, which sustain thyroid cancer stem cell (TCSC) origin and maintenance. (iii) In undifferentiated TC (UTC) in addition to MAPK and PI3K/AKT pathways, other signaling pathways, as Wnt/β-catenin and Notch, crucial for the survival of TCSCs are epigenetically compromised
Summary
Thyroid cancers (TCs) are highly heterogeneous and represent the most frequent tumors among the endocrine neoplasms [1, 2]. The risk of thyroid proliferative diseases is increased during pregnancy, while the specific risk for TC is decreased after menopause According to their histopathological features, it is possible to distinguish four subtypes of thyroid carcinoma: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), anaplastic thyroid carcinoma (ATC), and medullary thyroid carcinoma (MTC). The existence of cancer stem cell (CSC) population explains the aggressiveness of TCs and their resistance to the clinical treatments. CSCs are a small subset of cancer cells within tumors that exhibit exclusive self-renewal ability, clonogenic, and metastatic potential. They show a key role during the initiation, progression, drug resistance, and cancer recurrence or metastasis [9, 10]. Nowadays, dissecting the role of TCSCs in TC initiation, progression, and invasiveness may lead to the development of more effective therapies in advanced TCs
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