Senescent thyrocytes and thyroid tumor cells induce M2-like macrophage polarization of human monocytes via a PGE2-dependent mechanism

Thyroidcarcinoma includes several variants characterized by different biological and clinical features: from indolent microcarcinoma to undifferentiated and aggressive anaplastic carcinoma. Inflammation plays a critical role in thyroid tumors. Conditions predisposing to cancer, as well as oncogene activity, contribute to the construction of an inflammatory microenvironment that facilitates thyroid tumorprogression. Moreover, oncogene-induced senescence, a mechanism tightly connected with inflammation, and able to restrain or promote cancer progression, is involved in thyroidcancer. The interactions between thyroid tumorcells and the microenvironment are not completely clarified. We characterize in vitro the interplay between macrophages and senescent thyrocytes and tumor-derived cell lines, modeling early and late thyroid tumorstages, respectively. Purified peripheral blood-derived human monocytes were exposed to thyroidcell-derived conditioned medium (CM) and assessed for phenotype by flow cytometry. The factors secreted by thyroidcells and macrophages were identified by gene expression analysis and ELISA. The protumoral effect of macrophages was assessed by wound healing assayon K1 thyroid tumorcells. The expression of PTGS2 and M2 markers in thyroid tumorswas investigated in publicly available datasets. Human monocytes exposed to CM from senescent thyrocytes and thyroid tumorcell lines undergo M2-like polarization, showing high CD206 and low MHC II markers, and upregulation of CCL17secretion. The obtained M2-like macrophages displayed tumor-promoting activity. Among genes overexpressed in polarizing cells, we identified the prostaglandin-endoperoxide synthase enzyme (PTGS2/COX-2), which is involved in the production of prostaglandin E2 (PGE2). By using COX-2 inhibitorswe demonstrated that the M2-like polarization ability of thyroidcells is related to the production of PGE2. Co-expression of PTGS2 and M2 markers is observed a significant fraction of human thyroid tumors. Our results demonstrate that both senescent thyrocytes and thyroid tumorcell lines trigger M2-like macrophage polarizationthat is related to PGE2 secretion. This suggests that the interaction with the microenvironment occurs at both early and late thyroid tumorstages, and favors tumor progression. The co-expression of PTGS2 gene and M2 markers in human thyroidcarcinoma highlights the possibility to counteract tumor growth through COX-2 inhibition.