Wang Saisai, Yao Yuanyuan, Li Huixia, Zheng Gang, Lu Sen, Chen Wenbin
Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou, P. R. China.
Department of Colorectal Surgery, The Central Hospital of Lishui City Lishui, P. R. China.
Am J Cancer Res. 2019 Sep 1;9(9):1957-1969. eCollection 2019.
Tumor associated macrophages (TAMs) in tumor microenvironment can interact with tumor cells and are related to tumor progression. However, the mechanisms that drive the anti-tumor functions of TAMs are not fully understood. The Src homology 2 domain-containing tyrosine phosphatase 2 (Shp2) has been reported to have tumor-suppressing roles in colorectal cancer (CRC). However, a role for Shp2 on TAMs in CRC has not been studied. Here we report that in CRC, Shp2 expression on TAMs is negatively associated with liver metastasis. TAMs require Shp2 for their anti-tumor functions in a cell-cell co-culture system and a mouse model of CRC. Mechanistically, absence of Shp2 on TAMs induces their polarization toward M2 phenotype through the activation of p-STAT3 and inhibition of p-NF-κB p65. The findings of our study imply that Shp2 is a key factor in the tumor microenvironment to facilitate the TAMs' tumor-suppressing functions in colorectal cancer.
肿瘤微环境中的肿瘤相关巨噬细胞（TAM）可与肿瘤细胞相互作用，并与肿瘤进展相关。然而，驱动TAM发挥抗肿瘤功能的机制尚未完全明确。据报道，含Src同源2结构域的酪氨酸磷酸酶2（Shp2）在结直肠癌（CRC）中具有肿瘤抑制作用。然而，Shp2在CRC的TAM中的作用尚未得到研究。在此我们报告，在CRC中，TAM上的Shp2表达与肝转移呈负相关。在细胞-细胞共培养系统和CRC小鼠模型中，TAM发挥抗肿瘤功能需要Shp2。机制上，TAM上缺乏Shp2会通过激活p-STAT3和抑制p-NF-κB p65诱导其向M2表型极化。我们的研究结果表明，Shp2是肿瘤微环境中促进TAM在结直肠癌中发挥肿瘤抑制功能的关键因素。
