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: 23.89). 02/2009; 15(1):35-44. DOI: 10.1016/j.ccr.2008.11.012
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Thomas R Cox, Aug 26, 2015
1 Follower
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 5.94 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastasis is the main cause of prostate cancer-associated deaths. While significant progress has been made in the treatment of primary tumors, efficient therapies that target the metastatic spread of prostate cancer are far from clinical reality. To efficiently treat cancer we need be able to impede its spread. Unfortunately, the majority of current therapeutics approved to treat metastatic cancer were originally selected based on their ability to inhibit primary tumor growth. This inherent flaw precludes these therapies from efficiently targeting the development of secondary metastatic lesions, a process that is distinct from that of primary tumor progression. In this review we will summarize the conceptual, cellular and molecular targets that should be considered to design effective anti-metastatic therapies.
  • Source
    • "Because tumour blood vessels are important for tumour metastasis (Folkman, 1995), inhibiting tumour angiogenesis could be one mechanism for suppressing metastasis by LOX inhibition. Furthermore, LOX is critical for pre-metastatic niche formation and its inhibition prevents metastatic tumour growth through decreased recruitment of bone marrow-derived cells (Erler et al, 2009). However, blood vessels provide an outlet for tumour cells to leave their tumour nests. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Molecules that are highly expressed in tumour endothelial cells (TECs) may be candidates for specifically targeting TECs. Using DNA microarray analysis, we found that the lysyl oxidase (LOX) gene was upregulated in TECs compared with its expression in normal endothelial cells (NECs). LOX is an enzyme that enhances invasion and metastasis of tumour cells. However, there are no reports on the function of LOX in isolated TECs. Methods: TECs and NECs were isolated to investigate LOX function in TECs. LOX inhibition of in vivo tumour growth was also assessed using β-aminopropionitrile (BAPN). Results: LOX expression was higher in TECs than in NECs. LOX knockdown inhibited cell migration and tube formation by TECs, which was associated with decreased phosphorylation of focal adhesion kinase (Tyr 397). Immunostaining showed high LOX expression in human tumour vessels in vivo. Tumour angiogenesis and micrometastasis were inhibited by BAPN in an in vivo tumour model. Conclusion: LOX may be a TEC marker and a possible therapeutic target for novel antiangiogenic therapy.
    British Journal of Cancer 09/2013; 109(8). DOI:10.1038/bjc.2013.535 · 4.82 Impact Factor
Show more