Reactive astrocytes promote the metastatic growth of breast cancer stem‐like cells by activating Notch signalling in brain

Abstract

Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

Potential Involvement of Jagged1 in Metastatic Progression of Human Breast Carcinomas

“…It is worth noting that Jagged1 is also assumed to play a role in tumor development when it is present in the normal cells of the tumor microenvironment (18 ). Our present study has shown that Jagged1 expression in tumor stroma cells is correlated with the presence of the proliferation marker Ki-67 in tumor cells.…”

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…Tumorinitiating cells that reach the distant organs need to reprogram stromal cells in the microenvironment to build their niche for proliferation (36). Brain is abundant in astrocytes, and we have previously reported that astrocytes can be activated by metastatic cells to support their growth (33). In this study we have shown that prostaglandin can activate astrocytes to release CCL7, which in turn promotes self-renewal of tumor initiating cells.…”

Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk

“…Activation of the Notch pathway in vascular endothelial cells is triggered by norepinephrine-induced Jagged 1 expression in breast cancer cells Accumulating evidence indicates that tumor cell-stromal cell interaction may be influenced by the Jagged/Notch pathway (Zeng et al 2005, Sethi et al 2011, Lu et al 2013, Xing et al 2013, Zender et al 2013. Results from recent studies have indicated that the Notch signaling pathway is directly involved in physiological and pathological angiogenesis (Dufraine et al 2008, Benedito et al 2009).…”