title: Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer.
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.
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Kerui
authors.initials: K
authors.lastname: Wu
authors.affiliation: Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, and.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Sambad
authors.initials: S
authors.lastname: Sharma
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Chan
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
authors.forename: Shadi A
authors.initials: SA
authors.lastname: Qasem
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, and.
authors.forename: Radhika
authors.initials: R
authors.lastname: Pochampally
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, and.
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
authors.affiliation: From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, kwatabe@wakehealth.edu.
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D014183:Transplantation, Heterologous
chemical_list: C515370:CCR7 protein, human; D054400:Receptors, CCR7; D051546:Cyclooxygenase 2; D020781:Matrix Metalloproteinase 1
keywords: Astrocyte; Blood-Brain Barrier (BBB); Brain; Breast Cancer; Cancer Initiating Cell; Cyclooxygenase (COX); Matrix Metalloproteinase (MMP); Tumor Metastasis