Clinical Significance
LOX expression is regulated by hypoxia-inducible factors (HIFs), and, hence, LOX expression is often upregulated in hypoxic breast and head and neck tumors. Patients with high LOX-expressing tumors have poor overall survival. Furthermore, inhibition of LOX has been demonstrated to eliminate metastases in mice. Secreted LOX is responsible for the invasive properties of hypoxic cancer cells through focal adhesion kinase activity and cell-to-matrix adhesion. LOX may be required to create a niche permissive for metastatic growth and, thus, may be required for hypoxia-induced metastasis.
LOX expression was also detected in Megakaryocytes that are bone marrow cells responsible for the production of platelets. Data derived from a mouse model of myelofibrosis implicated LOX in bone marrow fibrosis.
In a rodent model of breast cancer, a small-molecule or antibody inhibitors of LOX abolished metastasis. LOX secreted by hypoxic breast tumor cells crosslinks collagen in the basement membrane and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells in turn adhere to crosslinked collagen and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion of metastasizing tumor cells. In contrast, LOX inhibition prevents CD11b+ cell recruitment and metastatic growth.
Hence, inhibitors of the LOX enzyme may be useful in preventing tumor progression and metastasis as well as treating other fibrotic disease involving remodeling of the extracellular matrix, including neurodegenerative and cardiovascular diseases.
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