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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 IL1? 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.

SUBMITTER: Xing F

PROVIDER: S-EPMC5010459 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer.

Xing Fei F Liu Yin Y Sharma Sambad S Wu Kerui K Chan Michael D MD Lo Hui-Wen HW Carpenter Richard L RL Metheny-Barlow Linda J LJ Zhou Xiaobo X Qasem Shadi A SA Pasche Boris B Watabe Kounosuke K

Cancer research 20160630 17

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. Additionall ...[more]

PMID: 27364556

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Project description:Patients with brain-metastatic breast cancer face a bleak prognosis marked by morbidity and premature death. A deeper understanding of molecular interactions in the metastatic brain tumour microenvironment may inform the development of new therapeutic strategies. In this study, triple-negative MDA-MB-231 breast cancer cells or PBS (modelling traumatic brain injury) were stereotactically injected into the cerebral cortex of NOD/SCID mice to model metastatic colonization. Brain cells were isolated from five tumour-associated samples and five controls (pooled uninvolved and injured tissue) by immunoaffinity chromatography, and proteomic profiles were compared using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) discovery platform. Ontology and cell type biomarker enrichment analysis of the 125 differentially abundant proteins (p < 0.05) showed the changes largely represent cellular components involved in metabolic reprogramming and cell migration (min q = 4.59 × 10-5), with high-throughput PubMed text mining indicating they have been most frequently studied in the contexts of mitochondrial dysfunction, oxidative stress and autophagy. Analysis of mouse brain cell type-specific biomarkers suggested the changes were paralleled by increased proportions of microglia, mural cells and interneurons. Finally, we orthogonally validated three of the proteins in an independent xenograft cohort, and investigated their expression in craniotomy specimens from triple-negative metastatic breast cancer patients, using a combination of standard and fluorescent multiplex immunohistochemistry. This included 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), which is integral for gluconeogenic valine catabolism in the brain, and was strongly induced in both graft-associated brain tissue (13.5-fold by SWATH-MS; p = 7.2 × 10-4), and areas of tumour-associated, reactive gliosis in human clinical samples. HIBCH was also induced in the tumour compartment, with expression frequently localized to margins and haemorrhagic areas. These observations raise the possibility that catabolism of valine is an effective adaptation in metastatic cells able to access it, and that intermediates or products could be transferred from tumour-associated glia. Overall, our findings indicate that metabolic reprogramming dominates the proteomic landscape of graft-associated brain tissue in the intracranial MDA-MB-231 xenograft model. Brain-derived metabolic provisions could represent an exploitable dependency in breast cancer brain metastases.

Dataset Information

Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer.

Publications

Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer.

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