Jaroszewski Agustina, Geysels Romina C, Volpini Ximena, Pellizas Claudia G, Motran Claudia C, Stempin Cinthia C, Nicola Juan P, Cheng Sheue-Yann, Fozzatti Laura
Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba Córdoba, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología, CONICET Córdoba, Argentina.
Am J Cancer Res. 2024 Jul 15;14(7):3626-3638. doi: 10.62347/BHFA4606. eCollection 2024.
Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatment options. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated with a poor prognosis. We have previously shown that paracrine signals released by ATC cells induced pro-tumor M2-like polarization of human monocytes. However, which soluble factors derived from ATC cells drive monocyte activation, are largely unknown. In this study we investigated the participation of transforming growth factor β1 (TGFβ1) on the phenotype of macrophage activation induced by ATC cell-derived conditioned media (CM). THP-1 cells exposed to CM derived from ATC cells and recombinant human TGFβ1 induced M2-like macrophage polarization, showing high CD163 and Dectin1 expression. Moreover, we showed that TGFβ1 induced the messenger RNA (mRNA) and protein expression of the transcription factors SNAIL and SLUG. Accordingly, increased TGFβ1 secretion from ATC cells was confirmed by enzyme-linked immunosorbent assay (ELISA). Addition of SB431542, a TGFβ receptor inhibitor, significantly decreased the Dectin1, CD163, SNAIL and SLUG expression stimulated by ATC cell-derived CM. We validated the clinical significance of the expression of TGFβ ligands, their receptors, as well as SNAIL and SLUG in human ATC by analyzing public microarray datasets. We found that the expression of the main TGFβ ligands, TGFβ1 and TGFβ3, along with their receptors, TGFR1 and TGFR2, as well as SLUG, was significantly higher in human ATC tissue samples than in normal thyroid tissues. Our findings indicate that ATC cell-secreted TGFβ1 may play a key role in M2-like macrophage polarization of human monocytes and in the up-regulation of SNAIL and SLUG transcription factors. Thus, ours results uncovered a novel mechanism involved in the activation of TAMs by soluble factors released by ATC cells, which suggest potential therapeutic targets for ATC.
间变性甲状腺癌（ATC）是一种临床侵袭性的未分化甲状腺癌，治疗选择有限。肿瘤相关巨噬细胞（TAM）占ATC浸润细胞的50%以上，其存在与预后不良相关。我们之前已经表明，ATC细胞释放的旁分泌信号可诱导人类单核细胞向促肿瘤的M2样极化。然而，ATC细胞衍生的哪些可溶性因子驱动单核细胞活化，在很大程度上尚不清楚。在本研究中，我们调查了转化生长因子β1（TGFβ1）在ATC细胞衍生的条件培养基（CM）诱导的巨噬细胞活化表型中的作用。暴露于ATC细胞衍生的CM和重组人TGFβ1的THP-1细胞诱导了M2样巨噬细胞极化，表现出高CD163和Dectin1表达。此外，我们表明TGFβ1诱导了转录因子SNAIL和SLUG的信使核糖核酸（mRNA）和蛋白质表达。因此，通过酶联免疫吸附测定（ELISA）证实了ATC细胞中TGFβ1分泌增加。添加TGFβ受体抑制剂SB431542可显著降低ATC细胞衍生的CM刺激的Dectin1、CD163、SNAIL和SLUG表达。通过分析公共微阵列数据集，我们验证了TGFβ配体、其受体以及SNAIL和SLUG在人类ATC中的表达的临床意义。我们发现，主要TGFβ配体TGFβ1和TGFβ3及其受体TGFR1和TGFR2以及SLUG在人类ATC组织样本中的表达明显高于正常甲状腺组织。我们的研究结果表明，ATC细胞分泌的TGFβ1可能在人类单核细胞的M2样巨噬细胞极化以及SNAIL和SLUG转录因子的上调中起关键作用。因此，我们的结果揭示了一种由ATC细胞释放的可溶性因子激活TAM的新机制，这为ATC提示了潜在的治疗靶点。
