TGF-β type I receptor inhibitor suppresses polarization of tumor-associated macrophages to the M2 phenotype and exerts antitumor effects on colorectal cancer
التفاصيل البيبلوغرافية
العنوان:
TGF-β type I receptor inhibitor suppresses polarization of tumor-associated macrophages to the M2 phenotype and exerts antitumor effects on colorectal cancer
Background: Macrophages can be classified into two main types based on their functions: pro-inflammatory M1-like and anti-inflammatory M2-like. Tumor-associated macrophages (TAMs) are macrophages that infiltrate tumor tissues and many TAM polarized to the M2 phenotype. M2-TAMs promote tumor progression through various mechanisms. Transforming growth factor (TGF)-β, which is abundant in tumor tissues and exacerbates advanced-stage tumors, has been implicated in the M2 polarization of macrophages. The study aimed to investigate whether TGF-β promotes the M2 polarization of TAMs and whether inhibiting TGF-β would reduce this polarization in the tumor environment of colorectal cancer (CRC). Methods: In this study, macrophages were prepared from THP-1 cells by treating them with phorbol 12-myristate 13-acetate, and were used to analyze the polarization of human macrophages by TGF-β and TGF-β type I receptor inhibitor SB431542. The degree of polarization was assessed using both RT-qPCR and flow cytometry. To evaluate the effect of SB431542 in vivo, a CRC model was generated by implanting CT26 cells into balb/c mice. Tumor volume and weight were measured, and the percentage of M2-TAM was analyzed using flow cytometry. Results: The TGF-β type I receptor inhibitor SB431542 suppressed the M2 polarization of THP-1–derived macrophages in CRC conditioned medium. In syngeneic mouse models of CRC SB431542 reduced tumor volume and weight with the decrease of the proportion of M2-TAMs. The antitumor effect of SB431542 was abolished under conditions of TAM depletion. Conclusions: The study suggests that TGF-β promotes the M2 polarization of TAMs in the tumor environment of solid tumors, including CRC. Therefore, the anti-tumor effect of SB431542 on CRC is attributed to the reduction of M2-TAMs. The results of this study are expected to contribute significantly to the development of therapies for CRC that regulate TAM polarity.
