Cancer Stem Cells in Thyroid Tumors: From the Origin to Metastasis

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.

Keywords: cancer stem cells; epigenetic alterations; immune system; microenvironment; thyroid tumors.

Figure 1

Thyroid tumors and thyroid cancer stem cell genetic model. Thyroid cancers (TCs) are heterogeneous diseases varying from well-differentiated [papillary thyroid carcinomas (PTCs), follicular thyroid carcinomas (FTCs)] to undifferentiated tumors (UTCs). According to the most recent thyroid cancer stem cell model, the cell of origin of TC may be represented by the same cancer stem cell, which is subjected to different types of genetic mutations, leading to the development of PTC (80% of cases), FTC (15%), and UTC (2%), respectively. The model shown represents the microscopic structure of thyroid follicles, in which walls of follicular cells surround the follicle lumen filled with colloid, the center of thyroid hormone production. Moreover, following this model, thyroid cancer stem cells (TCSCs) along with thyroid differentiated cancer cells may populate the thyroid follicle. Parafollicular “C” cells are the cells of origin of medullary thyroid carcinoma (MTC).

Figure 2

Epigenetic mechanisms relevant in thyroid cancer stem cells (TCSCs). Altered epigenetic mechanisms crucial for the survival of TC cells and, in particular for TCSCs, have not completely elucidated yet. The majority of aberrant epigenetic events in TCs are based on (1) DNA methylation: the promoters of thyroid-specific differentiation as transcriptional thyroid factor 1 (TTF1) and sodium iodide symporter (NIS) and of tumor suppressor genes as tissue inhibitor of metalloproteinase-3 (TIMP3), phosphatase and tensin homolog (PTEN), Ras association domain family 1 isoform A (RASSF1A) are silenced by hypermethylation; (2) histone modifications: several histone-modifying enzymes are aberrantly expressed in TCs as bromodomain-containing protein 4 (BRD4), lysine demethylase 1A (KDM1A), enhancer of zeste homolog 2 (EZH2), and histone deacetylase (HDAC); (3) non-coding RNA (miRNAs, lnRNAs): many non-coding RNAs are up- or downregulated in both well-differentiated and undifferentiated TCs, influencing the transcription and the posttrancriptional regulation of several oncogenes and/or tumor suppressor genes.

Figure 3

Cross-talk between immune system and thyroid cancer stem cells (TCSCs). The schematic picture describes the interactions between TCSCs and different innate and adaptive immune cells. TCSCs escape from immune response by different mechanisms: recruiting macrophages M2, mast cells, neutrophils with protumorigenic roles promoting the immunosuppressive response through the release of interleukin (IL)-10 by MDSCs and iDCs, suppressing the NK cells response by PGE2, and upregulating CTLA-4 and PD-1. Conversely, the immune response contrasts the TCSC growth and proliferation by CD8+ T lymphocyte and NK cells cytotoxic activity. EMT, epithelial-to-mesenchymal transition; iDC, immature dendritic cells; IL-6, interleukin-6; IL-10, interleukin-10; CXCL-8, C–X–C motif chemokine ligand-8; CXCL16, C–X–C motif chemokine ligand 16; TGF-β, tumor growth factor-β; VEGF-A, vascular endothelial growth factor A; TNF-α, tumor necrosis factor-α; PGE2, prostaglandin-E2; CXCR3, CXC chemokine receptor; CCL-2, C–C motif chemokine ligand-2; csf-1, colony stimulating factor-1; NK cells, natural killer cells.

Figure 4

Tumor microenvironment (TME) interactions and therapeutic strategies in thyroid cancer stem cells (TCSCs). The principal interactions between TCSCs and tumor microenvironment (TME) cells, along with the novel potential therapeutic targets, are shown. Cancer-associated fibroblasts (CAFs) produce FGF-21, which favors a more aggressive TC cells phenotype. TC cells secrete chemokines as CSF1, CCL15, and CCL2 to recruit tumor-associated macrophage (TAM) in order to sustain TC progression. CXCL8 secreted by TC cells guarantees stemness through an auto-paracrine loop by binding CXCR1. CXCL16 is secreted by TAMs favoring the migration and invasiveness of TC cells. Interleukin-6 (IL-6) supports stemness, colony formation and proliferation, in TC cells through JAK1/STAT3 phosphorylation. Reparixin (CXCR1 inhibitor) decreases thyrospheroid survival and epithelial–mesenchymal transition (EMT). The use of the CSFR1 inhibitor, LY3022855, hampers TAM recruitment. CXCL16-neutralizing antibody counteracts TC progression. Immunotherapy is based on the use of anti-PD1 antibodies as Pembrolizumab and Nivolumab, whereas epigenetic therapy nowadays is limited to histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors alone or in combination with conventional approaches in TCs.