Open AccessM2‑like tumour‑associated macrophage‑secreted IGF promotes thyroid cancer stemness and metastasis by activating the PI3K/AKT/mTOR pathway
Author(s) -
Juan Lv,
Chao Liu,
Fukun Chen,
Zhiping Feng,
Jia Li,
Pengjie Liu,
Zhixian Yang,
Fei Hou,
ZhongLiang Deng
Publication year - 2021
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2021.12249
Subject(s) - cancer research , pi3k/akt/mtor pathway , epithelial–mesenchymal transition , sox2 , vimentin , metastasis , biology , protein kinase b , thyroid carcinoma , cancer , thyroid , endocrinology , immunohistochemistry , signal transduction , transcription factor , immunology , microbiology and biotechnology , biochemistry , genetics , gene
M2‑like tumour‑associated macrophages (TAMs) have been demonstrated to promote the growth of anaplastic thyroid carcinoma (ATC). However, the underlying mechanism of M2‑like TAMs in ATC remains unclear. Thus, in the present study, the role and mechanism of M2‑like TAMs in ATC were investigated. M2‑like TAMs were induced by treatment with PMA, plus IL‑4 and IL‑13, and identified by flow cytometry. Transwell and sphere formation assays were applied to assess the invasion and stemness of ATC cells. The expression levels of insulin‑like growth factor (IGF)‑1 and IGF‑2 were examined by ELISA and reverse transcription‑quantitative PCR. Proteins related to the epithelial‑mesenchymal transition (EMT), stemness and the PI3K/AKT/mTOR pathway were examined via western blotting. Immunohistochemistry (IHC) was used to detect the expression of the M2‑like TAM markers CD68 and CD206 in ATC tissues and thyroid adenoma tissues. It was found that treatment with PMA plus IL‑4 and IL‑13 successfully induced M2‑like TAMs. Following co‑culture with M2‑like TAMs, the invasive ability and stemness of ATC cells were significantly increased. The expression levels of the EMT‑related markers N‑cadherin and Vimentin, the stemness‑related markers Oct4, Sox2 and CD133, and the insulin receptor (IR)‑A/IGF1 receptor (IGF1R) were markedly upregulated, whereas E‑cadherin expression was significantly decreased. In addition, the production of IGF‑1 and IGF‑2 was significantly increased. Of note, exogenous IGF‑1/IGF‑2 promoted the invasion and stemness of C643 cells, whereas blocking IGF‑1 and IGF‑2 inhibited metastasis and stemness by repressing IR‑A/IGF‑1R‑mediated PI3K/AKT/mTOR signalling in the co‑culture system. IHC results showed that the expression of CD68 and CD206 was obviously increased in ATC tissues. To conclude, M2‑like TAMs accelerated the metastasis and increased the stemness of ATC cells, and the underlying mechanism may be related to the section of IGF by M2‑like TAMs, which activates the IR‑A/IGF1R‑mediated PI3K/AKT/mTOR signalling pathway.