M2-like tumour-associated macrophage-secreted IGF promotes thyroid cancer stemness and metastasis by activating the PI3K/AKT/mTOR pathway

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.

Automated summary

The study revealed that M2-like tumour-associated macrophages (TAMs) can accelerate metastasis and increase stemness of anaplastic thyroid carcinoma (ATC) cells, potentially through the secretion of IGF that activates the IR-A/IGF1R-mediated PI3K/AKT/mTOR signalling pathway.