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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