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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1198-8) contains supplementary material, which is available to authorized users.

Cancer Associated Fibroblasts and Senescent Thyroid Cells in the Invasive Front of Thyroid Carcinoma

“…Some studies have assessed the interactions between senescent cells and other cell types as platelets [20] and immune cells [21]. In addition, our laboratory has recently described an interplay between senescent thyrocytes and macrophages [22]. Several works (reviewed in reference [16]) describe the presence of senescent fibroblasts along with CAFs in tumor stroma and how both can promote tumor aggressive features.…”

“…Interesting, these factors were also identified in senescent thyroid cells. TGF-β1 [22], IL-1, and IL-6 [12,15,22] are expressed by two thyroid models of oncogene-induced senescence, as well as by senescent TC cells at the invasive border of human PTCs [12]. It is noteworthy that we found that the same mediators (TGF-β1, IL-1 and IL-6) are expressed by tumors with high LOX, collagen, CAFs, and senescent cells markers ( Figure S6), supporting the hypothesis of a possible cross-talk between CAFs and senescent TC cells.…”

Response gene to complement 32 expression in macrophages augments paracrine stimulation-mediated colon cancer progression

“…Increasing evidences show that macrophages are recruited into tumor microenvironment and polarized to M2 type to promote tumor progression [42][43][44] . Previous studies suggest that RGC-32 inhibits M1 phenotype and promotes M2 polarization.…”

CX3CR1 regulates hepatocellular carcinoma(HCC) metastasis via PI3K/AKT pathway

“…With the continuous exploration and research, the chemokine axis is becoming increasingly important. More and more attention has been paid to the role of CXCR4 [23][24], CCL20 [25], CCL2-CCR2 [26], CCR4 [27] and other chemokine axes in the occurrence and development of hepatocellular carcinoma [28][29][30]. As a chemokine receptor, CX 3 CR1 has also been proved to be involved in regulating the biological effects of various tumors.…”