Breast cancer metastasizes most often to bone (see Erez). By analyzing primary tumor samples from patients who were later diagnosed with metastases, Cox et al. found that hypoxia in the primary tumor correlated with bone metastases in patients whose primary tumor was estrogen receptor–negative (ER–). Mass spectrometry analysis identified lysyl oxidase (LOX) as one of the most abundant proteins secreted by cultured bone-tropic ER– breast cancer cells. The expression of Lox in tumor samples positively correlated with bone metastases in patients with ER–, but not ER+, primary tumors. Compared with tumor-free mice, mice with LOX-expressing ER– mammary tumors had reduced bone mass and an increased number of osteolytic bone lesions. Injecting conditioned medium from hypoxic tumor cells or from LOX-expressing tumor cells also induced bone loss and bone lesions in mice, whereas conditioned medium from LOX-knockdown tumor cells did not. Bone loss and osteolytic lesions were reduced when mice bearing LOX-expressing tumors were injected with an antibody that inhibits LOX or when the mice received tumor cells in which LOX was knocked down. Compared with bone from tumor-free animals, these osteolytic bone lesions had an increased number of bone-resorbing osteoclasts and a decreased number of bone-building osteoblasts, and the number of osteolytic lesions correlated with subsequent formation of bone metastases. RANKL [receptor activator of nuclear factor-κB (RANK) ligand] stimulates the activity of the transcription factor NFATc1 (nuclear factor of activated T cells cytoplasmic 1), which is required for formation of osteoclasts. Adding purified recombinant LOX to cultured osteoclast precursors stimulated formation of osteoclasts in the absence of RANKL, and Lox-induced osteoclasts had more bone-resorbing ability and greater nuclear accumulation of NFATc1 than RANKL-induced osteoclasts. Additionally, exogenously applied Lox reduced proliferation and stimulated terminal differentiation of cultured osteoblasts. Injection of bisphosphonate, a drug that inhibits bone resorption by osteoclasts, reduced the number of bone lesions in tumor-bearing mice. The finding that LOX secreted by primary tumors promotes the formation of a niche permissive to metastatic colonization suggests that treating patients who have LOX-expressing cancers with bisphosphonate may reduce the instance of metastases.
T. R. Cox, R. M. H. Rumney, E. M. Schoof, L. Perryman, A. M. Høye, A. Agrawal, D. Bird, N. A. Latif, H. Forrest, H. R. Evans, I. D. Huggins, G. Lang, R. Linding, A. Gartland, J. T. Erler, The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522, 106–110 (2015). [PubMed]
N. Erez, Opening LOX to metastasis. Nature 522, 41–42 (2015). [PubMed]