Chemokines: novel targets for breast cancer metastasis

Abstract

Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients.

Figure 1. Schematic representation of the four different classes of chemokines

The position of the two first cysteines in the N-terminal part of the chemokine defines the class to which each chemokine belongs.

Figure 2

Chemokine receptors are seven-transmembrane receptors coupled to G-proteins

Figure 3. Putative model for chemokine action in breast cancer metastasis

The metastatic potential of breast cancer epithelial cells is mediated by two mechanisms. The first one involves the high secretion of chemokines such as CXCL8 by invasive cancer epithelial cells, which in turn can recruit leukocytes to the tumors and at a lesser extent act on endothelial cells and fibroblasts, both types of cells harboring specific receptors (e.g. CXCR1 and CXCR2). In addition, endothelial cells are also producing CXCL8. CXCL8 production on site by the tumor will enhance angiogenesis and basal membrane disruption leading to metastasis. In the breast, Cancer associated fibroblasts (CAFs) secrete CXCL12 which will affect mainly epithelial cancer cells (harboring high levels of CXCR4) and at lower degree, endothelial and leukocytes. These interactions will favor also angiogenesis, degradation of extracellular matrix and invasion of metastatic cancer cells. When reaching the circulation, cancer cells will be attracted by metastatic organs producing high levels of CXCL12, including lymph nodes (LN), bone and lungs. In the bone, cancer cells will then secrete CXCL8 which will in particular enhance osteolysis.

Figure 4. GAG and metastasis spread

Metastatic spread is a multiple step process which involved the interaction of chemokines with glycosaminoglycans (GAG) of endothelial cells. These steps require selectin-mediated rolling, activation by chemokines, integrin-mediated adhesion, extravasation leading to angiogenesis and to metastasis.

Figure 5. Model of regulation of CXC8 gene in breast cancer cells

CXCL8 gene expression is higher in ER-negative breast cancer cells compared to ER-positive breast cancer cells. This difference of expression arises from a higher transcriptional activity of CXCL8 gene in ER-negative breast cancer cells involving the synergistic activation of the gene by NF-κB and AP-1 pathways and at a lower degree by C/EBP factors. NF-κB and AP-1 transcription factors are present at higher levels in ER-negative breast cancer cells.