title: Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer.
abstract: Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remain poorly understood. Here, we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle that generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. Cancer Res; 76(17); 4970-80. ©2016 AACR.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. kwatabe@wakehealth.edu fxing@wakehealth.edu.
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Sambad
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Kerui
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Chan
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Lo
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Carpenter
authors.affiliation: Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Metheny-Barlow
authors.affiliation: Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Shadi A
authors.initials: SA
authors.lastname: Qasem
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. kwatabe@wakehealth.edu fxing@wakehealth.edu.
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; C107773:pterostilbene; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met