Estrogens and stem cells in thyroid cancer

Abstract

Recent discoveries highlight the emerging role of estrogens in the initiation and progression of different malignancies through their interaction with stem cell (SC) compartment. Estrogens play a relevant role especially for those tumors bearing a gender disparity in incidence and aggressiveness, as occurs for most thyroid diseases. Although several experimental lines suggest that estrogens promote thyroid cell proliferation and invasion, their precise contribution in SC compartment still remains unclear. This review underlines the interplay between hormones and thyroid function, which could help to complete the puzzle of gender discrepancy in thyroid malignancies. Defining the association between estrogen receptors' status and signaling pathways by which estrogens exert their effects on thyroid cells is a potential tool that provides important insights in pathogenetic mechanisms of thyroid tumors.

Keywords: cancer stem cells; estrogens; growth factors; stem cells; thyroid cancer; thyroid hormones.

Figure 1

The cellular origin of thyroid carcinomas is shown. According to the multistep carcinogenesis model, TC originates from follicular cells as a consequence of multiple mutations accumulated throughout their life-span. Thyrocytes could give rise to PTC by RAS and BRAF mutations or RET/PTC and NTRK1 rearrangements and to FTC by point mutations of the RAS gene and PAX8/PPARγ rearrangement. ATC derive from PTC and FTC after deregulation of the p53 and the Wnt/β-catenin pathway. In fetal cell carcinogenesis model, three types of fetal thyroid cells were proposed to generate different forms of thyroid cancer. Fetal thyroid stem cells, characterized by expression of the oncofetal fibronectin (OF), generate ATC, thyroblasts, which express OF and the differentiation marker Tg, are proposed to be the cellular origin of PTC. The more differentiated prothyrocytes, expressing Tg, give rise to FTC. The cancer stem cells model proposes TC as an SC disease. The accumulation of mutations in differentiated thyrocytes leads to their transformation. A subset of these cells may (in more aggressive tumor types) dedifferentiate and assume CSC characteristics.

Figure 2

Signaling pathways in follicular cells are shown. The main regulators of thyroid proliferation and function act through TSH signaling and GF pathway. THs control the secretion of TSH, which binds to TSH-R and induces the coupling of G-proteins stimulating AC and PLC. TSH also acts via PI3K pathway. GFs act via MAPK and PI3K pathways regulating the expression of genes involved in survival, cell cycle progression, and proliferation. Estrogens regulate proliferation, cell motility, differentiation, and apoptosis through four different mechanisms: (1) genomic (or classical) estrogen-signaling: E2–ER complex translocates into the nucleus, where it binds to ERE-sequences; (2) ERE-independent genomic actions (TFs cross-talk): genes lacking in ERE-sequences are activated by other TFs in the nucleus through protein–protein interactions; (3) non-genomic (or membrane-initiated) estrogen-signaling: E2 activation of plasma membrane-associated ER and GPR30 trigger the activation of MAPK and PI3K pathways and/or increases the Ca²⁺ levels; (4) ligand-independent signaling: in absence of E2, GFs can stimulate ERs directly or indirectly through MAPK and/or PI3K pathways. THs play a critical role in development and homeostasis. Nuclear TRs activate gene expression by binding to RXR, which in turn bind to TRE-sequences. Given that EREs share a similar nucleotide sequence with TREs, ERs and TRs can interact and regulate several transcriptional responses. The cross-talk between genomic and non-genomic pathways and other integrative signaling lead to a synergic cell response.