Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

Li, Dongbo; Ji, Hongfei; Niu, Xingjian; Yin, Lei; Wang, Yiran; Gu, Yucui; Wang, Jinlu; Zhou, Xiaoping; Zhang, Han; Zhang, Qingyuan

Solid tumors such as breast cancer usually contain heterogeneous populations of neoplastic cells, immune cells, and collections of tissue-specific resident and recruited stromal cell types, which together form the TME. 7, 8 The relevance of this tumor heterogeneity is linked to various hallmarks of cancer including drug resistance. [9] [10] [11] [12] [13] [14] Macrophages are diverse cells that show distinct phenotypes depending on their anatomical location and activating stimuli. 15, 16 In breast cancer, macrophages can comprise up to 50% of the TME. 17 Among them, M2-type macrophages, commonly referred to as TAM, are associated with tumor malignancy. 18, 19 CD163, a scavenger receptor, is regarded as a highly specific monocyte/macrophage marker for M2 polarization. 20 Escamilla et al reported that TAM are involved in the resistance of patients with prostate cancer to androgen blockade therapy. 21 In our previous study, we found a correlation between TAM and tamoxifen resistance in patients with breast cancer, but the underlying mechanism has not been elucidated. 22 Tumor-associated macrophages secrete a variety of chemokines into the TME including CCL2, which is secreted mainly by macrophages when cocultured with MCF7 cells. 23 CCL2 is also known as MCP-1 and small inducible cytokine A2. CCL2 belongs to the CC chemokine family that recruits monocytes, memory T cells, and dendritic cells to sites of inflammation. 24, 25 Several studies have reported that CCL2 and the inflammatory environment promote the malignant behavior of different tumors. [26] [27] [28] Xu et al found that CCL2 recruits monocytes to the TME and polarizes macrophages into the M2 type. 25 Secretion of CCL2 is also an important manifestation of TAM polarization in macrophages. 29 Ueno et al showed that a high level of CCL2 expression is a significant indicator of earlier relapse. 30 However, there have been only a few studies on the role of CCL2 in endocrine resistance of breast cancer.