Emerging role of brain metastases in the prognosis of breast cancer patients

Abstract

Cancer starts with one rogue cell. Through mutations and genomic alterations, the cell acquires specific and stem cell-like characteristics necessary for invasion of a distant organ and ultimately metastasis. Metastatic brain cancer is a particularly formidable disease because of its poor prognosis and the highly resistant nature of the tumor to chemotherapy. Although several types of primary tumors have a tendency to metastasize to the brain, the incidence of brain metastases has increased dramatically in some subsets of breast cancer patients. Several conventional treatments are available, but success is limited and often short-lived. Given that no standard treatment options exist, there is a significant need to investigate the biology of these clinically recalcitrant tumors.

Keywords: blood–brain barrier; breast cancer; epithelial–mesenchymal transition; mesenchymal–epithelial transition; metastasis.

Figure 1

Examples of astroglial-endothelial signaling in infection or inflammation, stroke or trauma, leading to opening of the blood–brain barrier and disturbance of brain function. Bradykinin, produced during inflammation in stroke or brain trauma, acts on endothelial and astroglial bradykinin B₂ receptors, leading to an increase in the concentration of intracellular Ca²⁺. In astrocytes, this can trigger the production of IL-6 through activation of nuclear factor-κB. (1). Bradykinin, substance P, 5-HT (serotonin) and histamine acting on astrocytes can lead to the formation of ATP and PGs, with effects on vascular tone and endothelial permeability (2) by mechanisms that are known to involve endothelium. Lipopolysaccharide (LPS), formed in infections, leads to the release from microglia of TNFα, IL-1β, and reactive oxygen species (including O₂⁻), all of which have the ability to open the blood-brain barrier (3). Astrocytes downregulate tPA production via TGFβ, but there is still sufficient tPA to open the blood–brain barrier, leading to an influx of tPA from the blood (4). Following disruption of the blood–brain barrier involving a decrease in agrin expression, K⁺ and Glu from the blood can reach the brain extracellular space. AQP4 is upregulated on the astroglial endfeet, leading to astroglial swelling (5). Reprinted by permission from Macmillan Publishers Ltd: Nature Publishing Group, copyright 2006. Abbreviations: IL, interleukin; NF-κB, nuclear factor-κB; 5-HT, 5-hydroxytryptamine; PGs, prostaglandins; TNFα, tumor necrosis factor-α; tPA, tissue plasminogen activator; TGFβ, transforming growth factor-β; Glu, glutamate; AQP4, aquaporin 4; ET1, endothelin 1.