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Cox et al. Lysyl oxidase, induced by hypoxia, initiates pre-metastatic bone lesions


Metastasis of tumour cells is responsible for as much as 90% of cancer-associated mortality, yet the underlying molecular mechanisms responsible for its initiation are poorly understood. Here Cox et al. provide strong evidence that hypoxia is specifically associated with bone relapse in patients with estrogen-receptor negative (ER–) breast cancer and that the hypoxia-inducible factor lysyl oxidase (LOX), enables circulating tumour cells to colonize bone.

LOX, a collagen crosslinking enzyme that enhances extracellular matrix stiffness, promotes adhesion and invasion of circulating tumour cells as they arrive in the targeted tissue microenvironment and is shown to be critical for pre-metastatic niche formation in soft tissues. Additionally, LOX is a mediator of osteoclastogenesis, independent of RANKL, which promotes osteoclast-mediated bone resorption, leading to the formation of osteolytic lesions in animals bearing breast tumours.

This study provides a novel mechanism of regulation of bone homeostasis and metastasis and suggests that LOX could be used as a marker to predict which patients with ER– breast cancer are likely to develop metastases and for whom, therefore, adjuvant therapy with bisphosphonates would be beneficial. It also raises the possibility that LOX inhibitors could be developed as specific therapies to help prevent metastasis.

Editor’s comment: The question arises whether or not the high expression of LOX can be observed only in ER– breast cancer. It will also be important to clarify the mechanism whereby LOX enhances nuclear localization of NFATc1 to stimulate osteoclastic bone resorption.

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