The Interaction between Macrophages and Triple‐negative Breast Cancer Cells Induces ROS‐Mediated Interleukin 1α Expression to Enhance Tumorigenesis and Metastasis

Abstract

Triple‐negative breast cancer (TNBC) has higher mortality than non‐TNBC because of its stronger metastatic capacity. Increasing studies reported that TNBC tumors had more macrophage infiltration than non‐TNBC tumors, which promoted the metastasis of TNBC cells. However, how TNBC cells become more malignant after interacting with macrophages is less reported. In this study, it is observed that when TNBC cells are co‐cultured with macrophages, they display higher viability and stronger metastatic ability than non‐TNBC cells. Mechanistic studies reveal that TNBC cells acquired these abilities via interactions with macrophages in three phases. First, within 12 h of co‐culture with macrophages, some TNBC cells have significantly elevated levels of reactive oxygen species (ROS), which upregulate interleukin 1α (IL1α) expression in ERK1/2‐c‐Jun‐ and NF‐κB‐dependent manners at 24−48 h. Second, the secreted IL1α bound to IL1R1 activates the ERK1/2‐ZEB1‐VIM pathway which increases metastasis. Third, IL1α/IL1R1 facilitates its own synthesis and induces the expression of IL1β and IL8 at 72−96 h through the MKK4‐JNK‐c‐Jun and NF‐κB signaling pathways. Moreover, a higher level of IL1α is positively correlated with more macrophage infiltration and shorter overall survival in breast cancer patients. Thus, reducing ROS elevation or downregulating IL1α expression can serve as new strategies to decrease metastasis of TNBC.

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation

“…Of note, in experiments on cell interactions a number of cancer cells exceeded that of monocytes or THP1 cells 40-fold, which is a realistic value for cancer stroma. In very recent work, Hao et al used a ratio cancer cells: macrophage 30:1, and demonstrated that co‐culturing with macrophages greatly increased triple-negative breast cancer cell migration, tumor growth, and cancer metastasis [ 44 ]. This led us to suggest that such a system of tumor engagement by macrophages should function even in the beginning of tumor growth.…”

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple‐negative breast cancer

“…TNBC has more macrophage infiltration which often results in localized inflammation and hypoxia (Morrison & Okines, 2023). Compared with other cancers, TNBC exhibits high levels of ROS during metastasis, thus increasing ROS consumption may serve as a new strategy to reduce TNBC metastasis (Hao et al, 2023). As cancer cells metastasize, they undergo significant physiological changes, including the activation of matrix metalloproteases (MMPs), the initiation of epithelial-mesenchymal transition (EMT), and variations in signaling pathways.…”