The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer

SIMPLE SUMMARY: The composite network of stromal, immune, vascular and cancer cells, which constitutes the tumor microenvironment (TME), has emerged as a player in thyroid cancer (TC) development and progression, as well as in several other cancer settings. In this context, estrogens may also contribute to TC carcinogenesis by activating proliferative pathways (namely PI3K/AKT/mTOR and RAS/Raf/MAPK), as well as by exerting immunosuppressive, pro-carcinogenic effects. To date, the complex interactions between the TME and estrogenic pathways have not been entirely unraveled in TC. ABSTRACT: Thyroid cancer (TC) cells employ multiple signaling pathways, such as PI3K/AKT/mTOR and RAS/Raf/MAPK, fostering cell proliferation, survival and metastasis. Through a complex interplay with immune cells, inflammatory mediators and stroma, TC cells support an immunosuppressive, inflamed, pro-carcinogenic TME. Moreover, the participation of estrogens in TC pathogenesis has previously been hypothesized, in view of the higher TC incidence observed among females. In this respect, the interactions between estrogens and the TME in TC could represent a relevant, unexplored area of research. We thereby collectively reviewed the available evidence concerning the potential carcinogenic role of estrogens in TC, specifically focusing on their crosstalk with the TME.