Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche

TY - JOUR

T1 - Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche

AU - Erler, Janine T

AU - Bennewith, Kevin L

AU - Cox, Thomas Robert

AU - Lang, Georgina

AU - Bird, Demelza

AU - Koong, Albert

AU - Le, Quynh-Thu

AU - Giaccia, Amato J

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Animals

KW - Anoxia

KW - Basement Membrane

KW - Bone Marrow Cells

KW - Breast Neoplasms

KW - Cell Differentiation

KW - Cell Line, Tumor

KW - Cell Movement

KW - Cell Separation

KW - Collagen Type IV

KW - Disease Progression

KW - Enzyme Activation

KW - Gene Expression Regulation, Enzymologic

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lung Neoplasms

KW - Matrix Metalloproteinase 2

KW - Mice

KW - Mice, Nude

KW - Myeloid Cells

KW - Neoplasm Metastasis

KW - Protein-Lysine 6-Oxidase

KW - Xenograft Model Antitumor Assays

U2 - 10.1016/j.ccr.2008.11.012

DO - 10.1016/j.ccr.2008.11.012

M3 - Journal article

C2 - 19111879

SN - 1535-6108

VL - 15

SP - 35

EP - 44

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -