Recent Advances in Discovering the Role of CCL5 in Metastatic Breast Cancer

Abstract

A variety of therapeutic strategies are currently under investigation to inhibit factors that promote tumor invasion, as metastasis is the most common cause of mortality for cancer patients. Notably, considerable emphasis has been placed on studying metastasis as a dynamic process that is highly dependent on the tumor microenvironment. In regards to breast cancer, chemokine C-C motif ligand 5 (CCL5), which is produced by tumor-associated stromal cells, has been established as an important contributor to metastatic disease. This review summarizes recent discoveries uncovering the role of this chemokine in breast cancer metastasis, including conditions that increase the generation of CCL5 and effects induced by this signaling pathway. In particular, CCL-5-mediated cancer cell migration and invasion are discussed in the context of intertwined feedback loops between breast cancer cells and stromal cells. Moreover, the potential use of CCL5 and its receptor chemokine C-C motif receptor 5 (CCR5) as targets for preventing breast cancer metastasis is also reviewed.

Figure 1

Mesenchymal stem cells (MSCs) secrete chemokine C-C motif ligand 5 (CCL5) in the breast tumor microenvironment. CCL5, combined with hypoxia, stimulates breast cancer cells (BCCs) to secrete colony-stimulating factor 1 (CSF1). CSF1 and MSC-derived CCL5 promote monocyte recruitment. CCL2 (not shown here) also helps recruit monocytes from the blood. Monocytes in the tumor microenvironment differentiate to form tumor-associated macrophages (TAMs). CSF1 from BCCs also stimulates TAMs to release epidermal growth factor (EGF), which enhances BCC invasiveness. TAMs also secrete CCL18, which initiates the epithelial to mesenchymal transition (EMT) in tumor cells. BCCs that have undergone EMT then release lactate and granulocyte macrophage-colony stimulating factor (GM-CSF). These factors promote monocyte differentiation into TAMs, which propel further EMT in BCCS by secreting CCL18.

Figure 2

(a) Under hypoxic conditions, BCCs release placental growth factor (PGF) and chemokine C-XC motif ligand 16 (CXCL16), which recruit MSCs to the site of the primary breast tumor and trigger their secretion of CXCL10 and CCL5. (b) Osteopontin released by BCCs stimulates MSCs to release CCL5. In addition, MSCs also secrete CXCL10 upon stimulation by BCC-derived PGF and CXCL16. CCL5 and CXCL10 enhance the metastatic potential of BCCs. (c) Factors such as CCL2, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) stimulate CCL5 secretion by BCCs. (d) CCL5 stimulates BCCs (not shown) and stromal cells such as fibroblasts to secrete metalloproteinases (MMPs). MMPs break down the proteins of the extracellular matrix (ECM), which enhances metastasis of BCCs.

Figure 3

CCL5, epidermal growth factor (EGF), and CXCL10 improve the invasiveness and motility of cancer cells. MMPs break down the surrounding ECM, thereby facilitating BCC motility. MSCs, monocytes and stromal cells, such as fibroblasts, are recruited to the microenvironment. Monocytes differentiate into TAMs. CCL5 also promotes the later steps of metastasis, by aiding extravasation from blood vessels to the metastatic niche. Breast cancer cells mainly metastasize to the lungs, bones, liver, and brain.