Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche.
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.
Erler
Janine T
JT
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Bennewith
Kevin L
KL
Cox
Thomas R
TR
Lang
Georgina
G
Bird
Demelza
D
Koong
Albert
A
Le
Quynh-Thu
QT
Giaccia
Amato J
AJ
D000818:Animals; D001485:Basement Membrane / Q000166:cytology / Q000201:enzymology; D001854:Bone Marrow Cells / Q000166:cytology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D002469:Cell Separation; D024141:Collagen Type IV / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000166:cytology; D009362:Neoplasm Metastasis / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D024141:Collagen Type IV; D008249:Protein-Lysine 6-Oxidase; D020778:Matrix Metalloproteinase 2