Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cancer cell (Impact Factor: 23.52). 02/2009; 15(1):35-44. DOI: 10.1016/j.ccr.2008.11.012
Source: PubMed


Tumor cell metastasis is facilitated by "premetastatic niches" formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.

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    • "Enzyme activity derived from all five lysyl oxidase family genes is required for the biosynthesis of connective tissues, while in cancer these enzymes promote metastatic disease (Barker et al., 2012). Evidence suggests that extracellular matrix modifications by lysyl oxidases promote metastasis by creating a permissive fibrotic extracellular environment (Ahn et al., 2013; Erler et al., 2009; Levental et al., 2009; Moreno-Bueno et al., 2011). The LOX gene, in addition, has tumor suppressor activity (Contente et al., 1990; Kenyon et al., 1991). "
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    ABSTRACT: The lysyl oxidase propeptide (LOX-PP) is derived from pro-lysyl oxidase (Pro-LOX) by extracellular biosynthetic proteolysis. LOX-PP inhibits breast and prostate cancer xenograft tumor growth and has tumor suppressor activity. Although, several intracellular targets and molecular mechanisms of action of LOX-PP have been identified, LOX-PP uptake pathways have not been reported. Here we demonstrate that the major uptake pathway for recombinant LOX-PP (rLOX-PP) is PI3K-dependent macropinocytosis in PWR-1E, PC3, SCC9, MDA-MB-231 cell lines. A secondary pathway appears to be dynamin- and caveola dependent. The ionic properties of highly basic rLOX-PP provide buffering capacity at both high and low pHs. We suggest that the buffering capacity of rLOX-PP, which serves to limit endosomal acidification, sustains PI3K-dependent macropinocytosis in endosomes which in turn is likely to facilitate LOX-PP endosomal escape into the cytoplasm and its observed interactions with cytoplasmic targets and nuclear uptake. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    Molecular Oncology 08/2015; DOI:10.1016/j.molonc.2015.07.005 · 5.33 Impact Factor
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    • "The S1PR1-STAT3 signaling axis was shown to be activated in both tumor cells as well as myeloid cells at a pre-metastatic niche, thus promoting metastatic development11. These studies highlighted the importance of intercellular communication between tumor cells and myeloid cells at a distant site to establish the pre-metastatic niche121314. In this study, we set out to characterize the modulation of macrophage activity by breast cancer cells mediated by cancer-secreted exosomes. "
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    Scientific Reports 07/2014; 4:5750. DOI:10.1038/srep05750 · 5.58 Impact Factor
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    • "Prostate cancer microparticles activate fibroblasts in the metastatic niche through Erk1/2 phosphorylation and MMP-9 upregulation. Fibroblast activation also results in the shedding of fibroblast-derived microparticles, which in turn induce CX3CL1 dependent chemotaxis of prostate cancer cells [77]. "
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