Abstract
Tumor-secreted lysyl oxidase (LOX) induces osteolytic lesions that support metastatic colonization.
Major finding: Tumor-secreted lysyl oxidase (LOX) induces osteolytic lesions that support metastatic colonization.
Mechanism: LOX disrupts bone homeostasis by inducing NFATc1-mediated osteoclast differentiation.
Impact: LOX expression may predict metastasis risk in patients with estrogen receptor–negative breast cancer.
The majority of patients with advanced breast cancer develop bone metastases and osteolytic bone lesions, which lead to bone destruction and increased patient mortality. However, little is known about the microenvironmental changes induced by cancer cells and host stromal cells that facilitate osteolytic bone lesion formation. Cox and colleagues found a specific association between hypoxia and bone metastases in patients with estrogen receptor–negative (ER−) breast cancer. Hypoxic tumor–conditioned media was sufficient to induce osteolytic lesion formation and bone loss, indicating that tumor-secreted factors induce early osteolytic lesions. Quantitative analysis of the hypoxic secretome identified upregulation of lysyl oxidase (LOX) as significantly associated with increased osteotropism in ER− breast cancer cell lines and bone relapse in patients with ER− breast cancer. Depletion or inhibition of LOX in tumor cells had no effect on primary tumors but resulted in reduced osteolytic lesions, whereas high LOX expression or injection of recombinant LOX was sufficient to drive the formation of focal osteolytic lesions, which were present prior to the detection of tumor cells in the bone. Mechanistically, LOX disrupted bone homeostasis both in vitro and in vivo by inducing the nuclear translocation of nuclear factor of activated T cells cytoplasmic, calcineurin-dependent 1 (NFATc1), the master transcriptional regulator of osteoclastogenesis, and stimulating osteoclast differentiation in the absence of receptor activator of NFκB ligand. In addition, LOX decreased the proliferation and increased the terminal differentiation of osteoblasts. LOX-mediated osteolytic lesions created a premetastatic niche in the bone marrow that supported tumor cell colonization, whereas treatment with the bisphosphonate zoledronic acid abrogated osteolytic lesion formation and reduced the development of bone metastases. These findings implicate tumor-secreted LOX in the regulation of bone homeostasis and the early steps of bone metastasis and suggest the potential for therapeutic prevention of ER− breast cancer bone metastasis.