Inflammatory Breast Cancer Promotes Development of M2 Tumor-Associated Macrophages and Cancer Mesenchymal Cells through a Complex Chemokine Network

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13), p.3360-3371
• Main Authors: Valeta-Magara, Amanda, Gadi, Abhilash, Volta, Viviana, Walters, Beth, Arju, Rezina, Giashuddin, Shah, Zhong, Hua, Schneider, Robert J
• Format: Article
• Language: English
• Subjects: Apoptosis; Autocrine Communication; Cell Proliferation; Chemokines - genetics; Chemokines - metabolism; Epithelial-Mesenchymal Transition; Female; Humans; Inflammatory Breast Neoplasms - genetics; Inflammatory Breast Neoplasms - metabolism; Inflammatory Breast Neoplasms - pathology; Macrophages - metabolism; Macrophages - pathology; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Paracrine Communication; Prognosis; Signal Transduction; Tumor Cells, Cultured; Tumor Microenvironment
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-2158

Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages. The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft model of IBC, we demonstrate that IBC strongly expresses IL8 and growth-regulated oncogene (GRO) chemokines that activate STAT3, which promotes development of high levels of CSC-like cells and a mesenchymal phenotype. We also show that IBC expresses high levels of many monocyte recruitment and macrophage polarization factors that attract and differentiate monocytes into tumor-promoting, immune-suppressing M2-like macrophages. The M2 macrophages in turn were found to secrete high levels of IL8 and GRO chemokines, thereby creating a feed-forward chemokine loop that further drives an IBC epithelial-to-mesenchymal transition. Our study uncovers an intricate IBC-initiated autocrine-paracrine signaling network between IBC cells and monocytes that facilitates development of this highly aggressive form of breast cancer. SIGNIFICANCE: This study uncovers a signaling network in which IBC cells commandeer macrophages to become tumor-promoting, and they in turn drive IBC cells to be more cancer stem-like, mesenchymal, and aggressive. http://cancerres.aacrjournals.org/content/canres/79/13/3360/F1.large.jpg.