Kimura Takahito, Kruhlak Michael, Zhao Li, Hwang Eunmi, Fozzatti Laura, Cheng Sheue-Yann
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA.
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA.
Am J Cancer Res. 2024 Dec 15;14(12):5812-5825. doi: 10.62347/QUWQ3794. eCollection 2024.
Anaplastic thyroid cancer (ATC) is a lethal endocrine malignancy. It has been shown that tumor-associated macrophages (TAMs) contribute to the aggressiveness of ATC. However, stimulatory factors that could facilitate the induction and infiltration of TAMs in the ATC tumor microenvironment (TME) are not fully elucidated. In this study, we used a human leukemia monocytic cell line (THP-1) to study the differentiation of THP-1 into M2-like macrophages (M2) by conditioned media (CM) derived from each of the three human ATC cells: 8505C, THJ-11T (11T), and THJ-16T (16T). The capacity of CM to induce M2 was in the order of 16T>8505C>11T cells as determined by the expression of M2 markers (CD163, CD204, and CCL13). Cytokine arrays and ELISA assays revealed five commonly enriched cytokines (IL-6, IL-8, MCP-1, TIMP-1, and TGF-β1) in the CM derived from each of the three ATC cells. These cytokines, individually, had weak activity, but together, they mimicked full CM activity in the induction of M2. Further, they collaboratively activated STAT3, ERK, and PI3K-AKT signaling to facilitate the induction of M2 as found in CM. Importantly, we found that the CM-induced M2 could secrete soluble growth factors to promote ATC cell proliferation as evidenced by the increased Ki-67, cMYC, and cyclin D1 protein levels. Our studies identified the major stimulatory cytokines which acted collaboratively to induce M2 in the TME. Importantly, the present studies indicate that when using inhibitors to target TAMs, combination therapies would be required for effective treatment of ATC.
间变性甲状腺癌（ATC）是一种致命的内分泌恶性肿瘤。研究表明，肿瘤相关巨噬细胞（TAM）促成了ATC的侵袭性。然而，能够促进TAM在ATC肿瘤微环境（TME）中诱导和浸润的刺激因子尚未完全阐明。在本研究中，我们使用人白血病单核细胞系（THP-1），通过源自三种人ATC细胞（8505C、THJ-11T（11T）和THJ-16T（16T））各自的条件培养基（CM）来研究THP-1向M2样巨噬细胞（M2）的分化。根据M2标志物（CD163、CD204和CCL13）的表达确定，CM诱导M2的能力顺序为16T>8505C>11T细胞。细胞因子阵列和ELISA分析揭示了源自三种ATC细胞各自的CM中五种共同富集的细胞因子（IL-6、IL-8、MCP-1、TIMP-1和TGF-β1）。这些细胞因子单独作用时活性较弱，但共同作用时，它们在诱导M2方面模拟了完整CM的活性。此外，它们协同激活STAT3、ERK和PI3K-AKT信号传导，以促进如在CM中发现的M2诱导。重要的是，我们发现CM诱导的M2可以分泌可溶性生长因子来促进ATC细胞增殖，Ki-67、cMYC和细胞周期蛋白D1蛋白水平升高证明了这一点。我们的研究确定了在TME中协同作用诱导M2的主要刺激细胞因子。重要的是，目前的研究表明，在使用抑制剂靶向TAM时，需要联合治疗才能有效治疗ATC。
