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

• Published in: Journal of experimental & clinical cancer research Vol. 38; no. 1; p. 208
• Main Authors: Mazzoni, Mara, Mauro, Giuseppe, Erreni, Marco, Romeo, Paola, Minna, Emanuela, Vizioli, Maria Grazia, Belgiovine, Cristina, Rizzetti, Maria Grazia, Pagliardini, Sonia, Avigni, Roberta, Anania, Maria Chiara, Allavena, Paola, Borrello, Maria Grazia, Greco, Angela
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21-05-2019; BioMed Central; BMC
• Subjects: Analysis; Breast cancer; Carcinoma; Cell aging; Cell cycle; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Polarity - drug effects; Cellular Senescence - drug effects; Cellular Senescence - genetics; Chemokine CCL17 - genetics; Chemokines; COX-2; COX-2 inhibitors; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - pharmacology; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 Inhibitors - pharmacology; Cytokines; Development and progression; Enzyme-linked immunosorbent assay; Enzymes; Flow Cytometry; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genetic research; Genotype & phenotype; HRAS; Humans; Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - pathology; Macrophages; Macrophages - drug effects; Macrophages - pathology; Medical prognosis; Melanoma; Metastasis; Monocytes - drug effects; Oncogene-induced senescence; Physiological aspects; Prostaglandins; Prostaglandins E; Senescence; Signal Transduction - drug effects; Thyrocytes; Thyroid cancer; Thyroid carcinoma; Thyroid diseases; Thyroid Epithelial Cells - drug effects; Thyroid Epithelial Cells - pathology; Thyroid gland; Thyroid Gland - drug effects; Thyroid Gland - pathology; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Tumors; Wound care; Wound healing; Wounds; United Kingdom; United States > US; PGE2; COX-2; Thyrocytes; Macrophages; Oncogene-induced senescence; HRAS; Thyroid carcinoma
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-019-1198-8

Thyroid carcinoma 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 tumor progression. Moreover, oncogene-induced senescence, a mechanism tightly connected with inflammation, and able to restrain or promote cancer progression, is involved in thyroid cancer. The interactions between thyroid tumor cells 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 tumor stages, respectively. Purified peripheral blood-derived human monocytes were exposed to thyroid cell-derived conditioned medium (CM) and assessed for phenotype by flow cytometry. The factors secreted by thyroid cells and macrophages were identified by gene expression analysis and ELISA. The protumoral effect of macrophages was assessed by wound healing assay on K1 thyroid tumor cells. The expression of PTGS2 and M2 markers in thyroid tumors was investigated in publicly available datasets.
Human monocytes exposed to CM from senescent thyrocytes and thyroid tumor cell lines undergo M2-like polarization, showing high CD206 and low MHC II markers, and upregulation of CCL17 secretion. 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 inhibitors we demonstrated that the M2-like polarization ability of thyroid cells 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 tumor cell lines trigger M2-like macrophage polarization that is related to PGE2 secretion. This suggests that the interaction with the microenvironment occurs at both early and late thyroid tumor stages, and favors tumor progression. The co-expression of PTGS2 gene and M2 markers in human thyroid carcinoma highlights the possibility to counteract tumor growth through COX-2 inhibition.