The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer

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.

Serum sex hormones correlate with pathological features of papillary thyroid cancer

“…ERα dose-dependently stimulates the survival and growth of PTC tumor cells. E 2 has been shown to significantly elevate ERα expression in TC cell lines and promote TC proliferation via the RAS/RAF/MAPK/ERK pathway [ 6 ]. This is consistent with the results we observed.…”

“…Previous studies have identified estrogen receptors, androgen receptors, prolactin receptors, and progesterone receptors expressed in PTC lesions [ 4 , 5 ]. It is now believed that estrogens can regulate the development of PTC through genomic or non-genomic effect [ 6 ], while androgens have been suggested to inhibit the progression of PTC in recent studies [ 7 , 8 ]. These findings suggest that sex hormones may provide new clinical strategies for papillary thyroid cancer, such as prediction of diagnosis, endocrine therapy, and assessment of prognostic risk, as in breast cancer and prostate cancer.…”

Women consuming oral contraceptives containing cyproterone acetate and ethinylestradiol show a higher risk of thyroid cancer than nonusers

“…Higher levels of estrogen have been associated with larger tumor size, increased lymph node metastasis, and advanced disease stage in PTC and FTC. [ 10 ] Some studies have suggested that longer exposure to estrogen over multiple menstrual cycles may increase the risk of thyroid cancer. [ 11 ] Estrogen exposure may modify the impact of ionizing radiation, a known risk factor for thyroid cancer, potentially enhancing its carcinogenic effects.…”