Effects of Cancer Stem Cells in Triple-Negative Breast Cancer and Brain Metastasis: Challenges and Solutions

Abstract

A higher propensity of developing brain metastasis exists in triple-negative breast cancer (TNBC). Upon comparing the metastatic patterns of all breast cancer subtypes, patients with TNBC exhibited increased risks of the brain being the initial metastatic site, early brain metastasis development, and shortest brain metastasis-related survival. Notably, the development of brain metastasis differs from that at other sites owing to the brain-unique microvasculature (blood brain barrier (BBB)) and intracerebral microenvironment. Studies of brain metastases from TNBC have revealed the poorest treatment response, mostly because of the relatively backward strategies to target vast disease heterogeneity and poor brain efficacy. Moreover, TNBC is highly associated with the existence of cancer stem cells (CSCs), which contribute to circulating cancer cell survival before BBB extravasation, evasion from immune surveillance, and plasticity in adaptation to the brain-specific microenvironment. We summarized recent literature regarding molecules and pathways and reviewed the effects of CSC biology during the formation of brain metastasis in TNBC. Along with the concept of individualized cancer therapy, certain strategies, namely the patient-derived xenograft model to overcome the lack of treatment-relevant TNBC classification and techniques in BBB disruption to enhance brain efficacy has been proposed in the hope of achieving treatment success.

Keywords: brain metastasis; cancer stem cells; triple-negative breast cancer.

Figure 1

Diagram of molecular pathways involving CSC during the development of BM-TNBC. CSCs in TNBC bulk tumor must invade through the extracellular matrix in primary bulk tumors, intravasate blood vessels, survive the turbid flow of the blood circulation in vasculature, escape from immune surveillance, arrest in the capillary bed, and extravasate blood brain barrier (BBB), with subsequent tumor growth into brain metastasis involving microenvironmental niche–dormant cell interactions, neuroinflammatory cascades, and neovascularization. EMT: epithelial–mesenchymal transition; CAF: cancer-associated fibroblast; IL: interleukin; ATG: autophagy-related protein; VEGF: vascular endothelial growth factor; Exo-miR: microRNA enriched exosome; STAT: signal transducer and activator of transcription; JAK: janus kinase; uPA: urokinase plasminogen activator; MMP: matrix metalloproteinase; PD-L1: programmed death-1ligand 1; CXCL12: stromal cell-derived factor 1; CXCR4: C-X-C chemokine receptor type 4; Ang2: angiopoietin2; ZO: zonula occludens; SOX: SRY-box transcription factor; OCT4: octamer-binding transcription factor 4; PTEN: phosphatase and tensin homolog; TIMP: metallopeptidase inhibitor; MIF: macrophage migration inhibitory factor; SNAIL: zinc finger protein SNAI1; CCL2: monocyte chemoattractant protein-1; iba1+: ionized calcium binding adaptor myeloid cells.