Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells

Abstract

Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are purported to be responsible for tumor initiation, maintenance, metastases, and disease recurrence. Interleukin-8 (IL-8) is upregulated in breast cancer compared with normal breast tissue and is associated with poor prognosis. IL-8 is reported to promote breast cancer progression by increasing cell invasion, angiogenesis, and metastases and is upregulated in HER2-positive cancers. Recently, we and others have established that IL-8 via its cognate receptors, CXCR1 and CXCR2, is also involved in regulating breast CSC activity. Our work demonstrates that in metastatic breast CSCs, CXCR1/2 signals via transactivation of HER2. Given the importance of HER2 in breast cancer and in regulating CSC activity, a pathway driving the activation of these receptors would have important biological and clinical consequences, especially in tumors that express high levels of IL-8 and other CXCR1/2-activating ligands. Here, we review the IL-8 signaling pathway and the role of HER2 in maintaining an IL-8 inflammatory loop and discuss the potential of combining CXCR1/2 inhibitors with other treatments such as HER2-targeted therapy as a novel approach to eliminate CSCs and improve patient survival.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…The IL8-CXCR2 pathway has been shown to be important in the pathogenesis of solid tumors, and preclinical studies have demonstrated a role for this pathway in the breast cancer microenvironment. 22,27,28,30,45 Various small molecule CXCR2 inhibitors are being developed clinically, and one is being tested in a clinical trial in breast cancer. Our results demonstrate that this pathway is also functionally important for the viability of leukemic stem cell compartments in AML and MDS.…”

“…To determine aberrantly expressed genes in MDS and AML stem and progenitor cells, we previously conducted a parallel transcriptional study comparing LT-HSCs, ST-HSCs, and GMPs from AML samples with deletion of chromosome 7 (27) to healthy control counterparts 10 ( Figure 1A). A small set of 7 genes was found to be consistently overexpressed in all compartments (LT-HSCs, ST-HSCs, and GMPs) and included IL8.…”

“…Extensive work in solid tumors has shown that IL8 is critical in survival, invasion, and proliferation of cancer cells [21][22][23][24] and might be an important regulator of cancer stem cell activity. [25][26][27] Activation of multiple pathways by IL8, including phosphatidylinositol 3-kinase/protein kinase B (AKT), phospholipase C/protein kinase C, and mitogen-activated protein kinase (MAPK) signaling, leads to increased expression of various The online version of this article contains a data supplement.…”

“…21 Blocking the IL8-CXCR1/CXCR2 axis has shown to be of therapeutic potential in a variety of solid tumors [27][28][29][30] ; however, there is little known of its role in hematologic malignancies. Our study reveals that IL8 is significantly overexpressed in AML and MDS LT-HSCs, ST-HSCs, and GMPs compared with healthy controls.…”

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

“…Already known to enhance tumor cell growth and promote angiogenesis (5,6), more recently, IL8 has been proposed to be a potent protumoral factor. In breast cancer and in glioblastoma, it has recently been suggested that IL8 directly favors cancer stem cells (7,8).…”