Abstract
Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.
Highlights
Mechanism of brain metastasis of breast cancer is poorly understood
We found that matrix metalloproteinase 1 (MMP1) plays a critical role in blood-brain barrier (BBB) penetration and that COX2-mediated prostaglandin promotes proliferation of tumor initiating cells by activating tumor associated astrocytes followed by secretion of CCL7
We examined the expression of all metalloproteinases in breast cancer cell lines that are known to preferentially metastasize to the brain (MDA-MB231BrM and CN34BrM) as well as in their parental cells using publicly available databases
Summary
Mechanism of brain metastasis of breast cancer is poorly understood. Results: Inflammatory factors secreted from cancer cells degrade tight junction of BBB and stimulate the tumor-microenvironment cross-talk. The tight junction confers low paracellular permeability and high electrical resistance, making the barrier function 50 –100 times tighter than peripheral microvessels [9] This structure is further strengthened by astrocytes that play a decisive role in the maintenance of the barrier properties of the brain microcapillary endothelial cells in controlling the flow of ions, nutrients, and cells into the brain. It is of paramount interest to dissect the role of the activated astrocytes in generating the niche for metastatic breast cancer To address these critical questions, we examined the correlations of the expression of all metalloproteinases with brain metastasis of breast cancer patients and the expression profile of these genes in brain metastatic tumor cell lines followed by in vivo verification. We found that MMP1 plays a critical role in BBB penetration and that COX2-mediated prostaglandin promotes proliferation of tumor initiating cells by activating tumor associated astrocytes followed by secretion of CCL7
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