ANAPLASTIC THYROID CANCER-DERIVED CONDITIONED MEDIUM INDUCES POLARIZATION OF HUMAN MONOCYTES THROUGH UPREGULATION OF THE IL-6/STAT3 PATHWAY.

FOZZATTI, LAURA; PARK, SUNMI; GEYSELS ROMINA; STEMPIN, CINTHIA; NICOLA, JUAN PABLO; CHENG SHEUE-YANN; PELLIZAS, CLAUDIA GABRIELA

Bethesda

Simposio; Laboratory of Molecular Biology Reunion Symposium. Science in the Laboratory of Molecular Biology, NCI: Lessons from History and Prospects for the Future.; 2019

National Institutes of Health

Introduction: Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. Characterized by its undifferentiated cells, it spreads quickly to distant organs and does not respond well to standardized therapy. Tumor-associated macrophages (TAMs) are the most evident cells in all ATC representing more than 50% of the nucleated cells and there is a correlation between the number of TAMs and poor prognosis. Macrophage phenotype has been classified in pro-inflammatory (M1) and anti-inflammatory (M2). TAMs mostly have a tumor-promoting M2 phenotype. How tumor cytokines reprogram macrophage phenotype during the developing of ATC is poorly understood.Aim: To investigate the effect of soluble factors secreted by ATC cells on the modulation of macrophage phenotype.Methods: THP-1 cells (human monocytes) were exposed to conditioned media (CM) produced by human ATC cells. Macrophage proliferation and polarization were assessed by flow cytometry, RT-qPCR and Western blot analysis. Results: ATC cell-derived CM strongly influenced the phenotype of THP-1 cells. The changes involved increased expression of CCL13, CLEC7A and CD206, widely considered as M2 markers of TAMs. However, the levels of classical M1 markers were not modified. Moreover, the ATC cell-derived CM decreased the proliferation of THP-1 cells delaying their cell cycle progression from the G0/G1 phase to the S phase. Interestingly, the ATC cell-derived CM also increased mRNA expression and secreted levels of the pro-inflammatory cytokine IL-6 in THP-1 cells. It has been previously described that IL-6 activates STAT3. Indeed, increased phosphorylation of STAT3 in THP-1 cells was observed by the treatment with ATC cell-derived CM. We investigated the relevance of our findings for human ATC. In humans, high STAT3 signaling expression was associated with poor prognosis.Conclusions and Discussion: These studies suggest that ATC cells produce soluble factors that can reprogram macrophage phenotype, most probably into M2 TAMs. A better understanding of these events may represent a promising basis for the development of new therapies for ATC.